Ventriculomegaly or symptomatic hydrocephalus? Beware of atypical neurological syndromes.
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Aged↗
Biomedical subjects
Ian R Whittle
Publications and source records attributed to Ian R Whittle.
Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E(2)-dependent activation of type II protein kinase A.
Dysregulation of enzymes involved in prostaglandin biosynthesis plays a critical role in influencing the biological behavior and clinical outcome of several tumors. In human gliomas, overexpression of cyclooxygenase-2 has been linked to increased aggressiveness and poor prognosis. In contrast, the role of prostaglandin E synthase in influencing the biological behavior of human gliomas has not been established. We report that constitutive expression of the microsomal prostaglandin E synthase-1 (mPGES-1) is associated with increased prostaglandin E(2) (PGE(2)) production and stimulation of growth in the human astroglioma cell line U87-MG compared with human primary astrocytes. Consistently, pharmacologic and genetic inhibition of mPGES-1 activity and expression blocked the release of PGE(2) from U87-MG cells and decreased their proliferation. Conversely, exogenous PGE(2) partially overcame the antiproliferative effects of mPGES-1 inhibition and stimulated U87-MG cell proliferation in the absence of mPGES-1 inhibitors. The EP2/EP4 subtype PGE(2) receptors, which are linked to stimulation of adenylate cyclase, were expressed in U87-MG cells to a greater extent than in human astrocytes. PGE(2) increased cyclic AMP levels and stimulated protein kinase A (PKA) activity in U87-MG cells. Treatment with a selective type II PKA inhibitor decreased PGE(2)-induced U87-MG cell proliferation, whereas a selective type I PKA inhibitor had no effect. Taken together, these results are consistent with the hypothesis that mPGES-1 plays a critical role in promoting astroglioma cell growth via PGE(2)-dependent activation of type II PKA.
Astrocytes↗
Meningiomas.
Meningiomas are by far the most common tumours arising from the meninges. Progressive enlargement of the tumour leads to focal or generalised seizure disorders or neurological deficits caused by compression of adjacent neural tissue. Surgery remains the primary treatment of choice, although the use of fractionated radiotherapy or stereotactic single-dose radiosurgery is increasing for meningiomas that are incompletely excised, surgically inaccessible, or recurrent and either atypical or anaplastic. Although most meningiomas have good long-term prognosis after treatment, there are still controversies over management in a proportion of cases. We review various features of meningioma biology, diagnosis, and treatment and provide an overview of the current rationale and evidence base for the various therapeutic approaches.
Humans↗
Surgical decompression for cerebral edema in acute ischemic stroke.
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Journal Article↗
Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells.
The synthetic glucocorticoid dexamethasone is routinely used to stabilize patients with malignant gliomas. One putative target for glucocorticoid action is inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as well as the host immune cells. In this study, we characterize the stimulatory effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor-alpha (TNFalpha), as well as the inhibitory effect of glucocorticoids, on iNOS gene expression and activity in C6 glioma cells cultured in vitro. LPS significantly increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased with time up to 72 h. Although TNFalpha alone induced neither iNOS mRNA expression nor nitrite formation, it significantly potentiated the effect of LPS on both. iNOS activity induced by LPS with or without TNFalpha was dose-dependently inhibited by dexamethasone, reaching a maximum of approximately 83% inhibition. This was completely reversed by the addition of RU38486, an antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA expression; however, the maximum inhibition obtained was only 10%. These results suggest that as for induction of iNOS activity in C6 cells in vitro, the stimulatory effect of LPS is mainly due to an action at the transcriptional level. TNFalpha does not have intrinsic inducing activity, but has potentiating effects at the transcriptional and possibly at the posttranscriptional levels in the presence of LPS. The inhibitory effect of dexamethasone is GR-mediated and is mainly due to action at the posttranscriptional level.
Animals↗
Morphological changes and stress responses in neurons in cerebral cortex infiltrated by diffuse astrocytoma.
Local dysfunction in cerebral cortex infiltrated by astrocytoma can cause epilepsy and focal neurological deficits, but the cellular pathology of peritumoral cortex remains poorly defined. The aims of the present study were to define the morphological changes which occur in neurons in tumor-infiltrated cerebral cortex, and to determine whether peritumoral neurons show expression of cell stress-related proteins. Archival specimens of diffuse astrocytoma (n = 28) were identified with areas of both tumor-infiltrated cortex and apparently non-infiltrated cortex. Immunohistochemistry was performed to structural neuronal proteins (MAP-2, neurofilament proteins), beta-amyloid precursor protein, growth associated protein-43 and to injury response proteins (poly(ADP-ribose) polymerase, poly(ADP-ribose), c-fos, and c-jun). Tumor-infiltrated cortex revealed neuronal loss and architectural disarray compared to non-infiltrated cortex. Pyramidal neurons showed thinning of the cytoplasmic rim and their neuritic processes showed increasing tortuosity, varicosity, fragmentation and loss, with axonal spheroid formation and dendritic beading. Poly(ADP-ribose) polymerase, poly(ADP-ribose) and c-fos were up-regulated in both infiltrated and non-infiltrated cortex, but c-jun expression was greater in areas of tumor-infiltrated cortex. Surviving neurons in cortex infiltrated by astrocytoma demonstrate, therefore, a sequence of morphological alterations in their dendritic, somatic and axonal compartments, and demonstrate a cell stress response. The patterns of cellular pathology identified suggest possible mechanisms, by which neurons are damaged and eventually lost in peritumoral brain.
Astrocytoma↗
A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.
A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P </= 0.05). Adverse events were comparable for the 2 groups, except for CSF leak (5% in the BCNU wafer-treated group vs. 0.8% in the placebo-treated group) and intracranial hypertension (9.1% in the BCNU wafer-treated group vs. 1.7% in the placebo group). This study confirms that local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma.
Adult↗
Measurements of water diffusion and T1 values in peritumoural oedematous brain.
Using quantitative MR imaging, values for the mean water diffusivity ( ), the diffusion anisotropy and the longitudinal relaxation time (T1) were measured for tumour, oedematous and normal brain in a group of treatment-naive patients with high-grade glioma and low-grade meningioma. The mean values of and T1 for enhancing tumour and oedematous brain were significantly higher in high-grade glioma than meningioma, while the diffusion anisotropy was reduced. Values of and T1 were also positively correlated in oedematous brain in both pathologies. There was, however, no clear evidence of similar correlations in apparently normal contralateral white matter. Such results illustrate the potential of MR imaging to improve not only the characterization of brain oedema, but also the monitoring of treatment response.
Aged↗
Anaplastic progression in low grade glioneural neoplasms.
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Brain Neoplasms↗
Surgery for gliomas.
PURPOSE OF REVIEW: To assess selected papers on surgery for glioma for their impact on clinical practice. RECENT FINDINGS: Recent developments in surgical neuro-oncology for gliomas have centred around technological advances that enable the fusion of preoperative structural and functional imaging datasets, the use of intraoperative magnetic resonance imaging scanning, and awake craniotomy and cortical stimulation as means to maximize glioma resection, minimize postoperative morbidity, and improve survival times. Correlations of preoperative functional imaging information with operative awake neurophysiological findings are good, but the problem of brain shift during resective surgery remains problematical and is a cogent reason for using intraoperative magnetic resonance imaging. Two reviews showed little evidence to support the concept that 'aggressive' resection of both high and low-grade gliomas significantly prolongs the life of patients. Attempting radical excision of these tumours can have unfortunate consequences in eloquent brain regions, particularly as functional studies confirm brain activity within the limits of many gliomas. SUMMARY: Despite amazing technical advances in the investigation, assessment and surgical management of patients with glioma, the lack of an evidence basis for 'aggressive' resective management continues to pose dilemmas for surgeons.
Brain Neoplasms↗
Diffusion tensor MR imaging of high-grade cerebral gliomas.
BACKGROUND AND PURPOSE: Optimizing high-grade glioma treatment requires the delineation of edematous and normal brain from tumor, perhaps by using potential differences in the absolute diffusion parameters of water. Our purpose was to determine whether mean diffusivity and diffusion anisotropic MR imaging data help in this differentiation. METHODS: Nine patients with high-grade cerebral glioblastoma underwent contrast-enhanced structural and diffusion tensor MR imaging before therapy. Tumor, edematous brain, and apparently normal white matter regions were determined on T2-weighted and contrast-enhanced T1-weighted structural images. Fractional anisotropy (FA) and were measured in each tissue type. Differences in these values among the tissue types were assessed with a standard analysis of variance. RESULTS: was highest in the necrotic tumor core (1825.38 +/-404.06) x 10(-6) mm(2)/s, followed by edematous brain (1411.23 +/- 322.31) x 10(-6) mm(2)/s, enhancing tumor core (1308.67 +/- 292.50) x 10(-6) mm(2)/s, enhancing tumor margin (1229.80 +/- 206.80) x 10(-6) mm(2)/s, and normal brain (731.53 +/- 35.21) x 10(-6) mm(2)/s. FA was highest in normal brain (0.47 +/- 0.08) and lowest in the necrotic core (0.09 +/- 0.03). was significantly different in enhancing tumor margins and edematous brain in all patients; FA was significantly different in only seven. These values were significantly different from those of normal brain in all cases in which they were measurable. CONCLUSION: values can be used to differentiate normal white matter, edematous brain, and enhancing tumor margins. Diffusion anisotropic data added no benefit to tissue differentiation. Further studies are required to determine if a value that corresponds to the limit of tumor invasion can be identified.
Adult↗