Molecular stratification of diagnostically challenging high-grade gliomas composed of small cells: the utility of fluorescence in situ hybridization.

PURPOSE: There is considerable morphologic overlap between various entities of high-grade gliomas, and, therefore, a further planning of their optimal treatment is a controversial issue. The aim of this study was molecular stratification of morphologically ambiguous high-grade gliomas composed from small cells. Fluorescence in situ hybridization (FISH) with commercially available probes was used for this purpose. EXPERIMENTAL DESIGN: We analyzed a set of 114 high-grade small-cell gliomas that were difficult to interpret diagnostically because of their distinct cytological origin. FISH assay with locus probes for EGFR, p16, PTEN, and 1p and 19q was done. RESULTS: Morphologically uniform high-grade gliomas composed of small cells varied greatly in terms of molecular features and clinical outcome. Four clinically relevant subsets of patients whose tumors showed distinctly different molecular profiles were identified as follows: (a) 13 patients whose tumors exhibited no discernable molecular alterations (5-year survival rate, 83%); (b) 20 patients whose tumors harbored either 1p/19q codeletion or isolated deletion of 19q unaccompanied by other molecular abnormalities (5-year survival rate, 59%); (c) 35 patients whose tumors showed p16 and/or PTEN deletions unaccompanied by EGFR amplification (5-year survival rate, 8%); and (d) 46 patients whose tumors harbored EGFR amplification (5-year survival rate, 0). CONCLUSIONS: The FISH method provides clinically useful information in the molecular analysis of morphologically ambiguous malignant small-cell gliomas that could potentially enhance the quality of patient care.     

Postoperative assessment of the efficiency of the radical removal of glioblastomas in the cerebral hemispheres

The paper analyzes the capacities of computed tomography (CT) and magnetic resonance imaging (MRI) in the postoperative period to evaluate the efficiency of surgical removal of the most malignant type of gliomas of the cerebral hemispheres. A total of 45 patients with different histological forms of cerebral hemispheral gliomas were examined, 37 of them with glioblastomas. Comparison of the results obtained by CT and MRI within the first 24 hours indicated that the latter was of greater informative value in all cases. At the same time only the use of a strict methodological approach to postoperatively estimating the remaining portions of glioblastomas makes it possible to apply these two methods as objective criteria for evaluating the efficiency of removal of a glioblastoma and hence the efficiency of subsequent therapeutic protocols. Contrast-enhanced MRI may be regarded as the method of choice in the primary assessment of patients with suspected recurrent glioblastoma.     

Immunohistochemical Markers for Prognosis of Ependymal Neoplasms

Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. One-hundred and twelve patients with intracranial ependymomas were examined retrospectively for immuno-expression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR) and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and apoptotic index (AI), and lower LI for cyclin-dependent kinase inhibitors p27/Kip1 and p14ARF. For low-grade ependymomas the progression-free survival time (PFS) was found to be significantly shorter for Ki-S1 LI>5%, and for tenascin, VEGF and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for p27 LI<20%, p14ARF LI<10%, for p53 positivity, and for AI<1%. The CART modeling process exhibited five final groups of ependymoma patients (1) low-grade and tenascin-negative; (2) low-grade and tenascin-positive; (3) high-grade and p53-negative with p14 LI>0%; (4) high-grade with combination of either p53 positivity and p14 LI>10% or p53 negativity and p14 LI<10%; (5) high-grade and p53-positive with p14 LI<10%. In summary, some immunohistochemical variables were found to be the strong predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimens together with tumor grade. For histologically benign ependymomas immunohistochemical study should be focused on Ki-S1, tenascin, EGFR and VEGF evaluation, whereas p53 expression and number of p27, p14 and ISEL-positive nuclei will be of value in determining PFS from high-grade ependymomas.     

Inhibition of nitric oxide synthesis increases focal ischemic infarction in rat.

We investigated whether inhibition of nitric oxide (NO) biosynthesis with N-omega-nitro-L-arginine (NNA), a competitive inhibitor of NO synthase (NOS), would modify the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery (MCA) in spontaneously hypertensive rats. NNA was infused for 1 h (2.4 mg/kg/h) immediately following occlusion of the MCA. NNA increased lesion volume 24 h later by 32% over controls (150.8 +/- 16.6 to 199.2 +/- 17.4 mm3; p less than 0.001, n = 6). This effect was antagonized by co-infusion of L- but not D-arginine. The antihypertensive rilmenidine (0.75 mg/kg) reduced the lesion by 27% (p less than 0.05, n = 4). Changes in lesion size were confined to the penumbra. NNA increased arterial pressure (AP) (118 +/- 8.9 to 149 +/- 16.0 mm Hg; p less than 0.01, n = 3) but did not change regional CBF. However, elevation of AP did not change the lesion volume or distribution. We conclude that inhibition of the constitutive form of NOS in vivo increases the volume of focal ischemic infarction as a consequence of reduced NO biosynthesis. The absence of NO availability may extend lesion formation by inhibition of reactive hyperemia, platelet disaggregation, and/or release of neuroprotective neuromodulators in the penumbra, which may counteract and override any of its neurotoxic actions.     

The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients

BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and occur most often in children and young adults. These neoplasms continue to generate considerable controversy with regard to their rational clinical management. It has been shown that the histologic classification of ependymoma is a significant predictor of clinical outcome in patients with ependymoma. METHODS: Ependymomas from 258 patients who underwent microsurgery at a single institution were evaluated histologically to elucidate the prognostic utility of a recently proposed grading scheme. Pathologic and clinical data then were compared using univariate and multivariate analyses. RESULTS: Increasing grade of ependymoma malignancy was found to be associated strongly and independently with worse clinical outcomes in terms of both event-free survival and overall survival. The effect of radiotherapy also was found to be related to histologic grade and was more beneficial for patients who had anaplastic ependymomas and had undergone complete tumor removal. CONCLUSIONS: The application of a uniform diagnostic criteria for grading ependymomas highlighted the key role of tumor histology in clinical outcome in a cohort of patients who were treated in the microsurgical era. The recently proposed grading scheme is likely to be practically useful, reproducible, and clinically applicable.     

Proliferative markers of meningiomas: immunohistochemical analysis and prognostic value

Routine pathological examination cannot precisely predict the clinical course of meningiomas because even histologically benign tumors may recur after total removal. And so, numerous efforts have been made for evaluation of meningioma growth fraction and its prognostic value. In this study the prognostic significance of DNA toposiomerase II alpha (topoII) and cyclin A immunohistochemistry was examined in a series of 263 meningiomas. The topoII and cyclin A scores exhibited a close correlation with Ki-67 immunostaining. Significant differences between the indices for all the three markers were noted among the three grades of meningiomas. The scores for all the three markers were significantly different between recurrent and non-recurrent meningiomas including removed benign tumors. The most important information for an individual clinical outcome of histologically benign meningiomas should be elicited from simultaneous evaluation of all the three proliferative markers.     

Pleomorphic Xanthoastrocytomas: Immunohistochemistry,Grading and Clinico-pathologic Correlations. An Analysis of 34 Cases From a Single Institute

Pleomorphic xanthoastrocytomas (PXAs) are characterized as a well-delineated tumor entity with clear peculiarities in clinico-radiological picture, pathological appearance and biological behavior. Usually the PXAs are associated with relatively good prognosis. Nevertheless, up to 35% of patients die following one and more recurrence with or without tumor malignant transformation. Till now, there is no agreement on what histopathological features constitute to objective and reliable signs of PXAs malignancy and clinical outcome. Thirty-four PXAs were subdivided on three subsets: typical (Grade I) – tumors without mitoses per 20 high power fields, proliferating (Grade II) – tumors with mitoses but without necroses, and malignant (Grade III) – tumors with elevated mitotic index and necrotic foci. Also, immunohistochemical investigation with various tumor-associated antigens was performed. All PXAs subtypes showed differences in clinical outcomes. There were no recurrences and death among the tumors Grade I. Five out of 14 (36%) Grade II PXAs have recurred and one of them died. All 5 patients with PXAs Grade III have rapidly recurred and four of them died. Immunohistochemical variables, such as Ki-S1, p27/Kip1, vascular endothelial growth factor expression, p53 immunoreactivity and apoptotic index also exhibited significant differences among the three PXAs grades. The progression-free survival was significantly reduced for PXAs grade and presence of mitoses, whereas overall survival was reduced for mitotic index 3 and presence of necroses. No one from immunohistochemical variables reached significant value. In summary, the three-tiered PXAs subdivision proposed by us is carrying some element of rationality but, undoubtedly, requires further prospective studies.     

Development of Noninvasive Technology of Stereotaxic Radioablation Using Linear Accelerators for the Treatment of Life-Threatening Ventricular Tachycardias in Experiment

Bulletin of Experimental Biology and Medicine - We developed a new technique of noninvasive stereotactic radioablation for the treatment of life-threatening tachyrhythmias. The study is performed...     

CENTRAL NEUROGENIC NEUROPROTECTION: PROTECTION OF BRAIN FROM FOCAL ISCHEMIA BY CEREBELLAR STIMULATION

Electrical stimulation of the cerebellar fastigial nucleus (FN) elevates regional cerebral blood flow (rCBF) independently of cerebral metabolism (rCGU) throughout brain. One hour of FN stimulation also reduces, by up to 50%, the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery in rat. Protected areas correspond to the ischemic penumbra. Neuroprotection, while reversible, persists for weeks after 1h of stimulation. It cannot be attributed to increasing rCBF and/or reducing rCGU to improve matching of flow and metabolism. Conditional stimulation of FN initiates long-lived inhibition of expression of peri-infarction depolarizing waves, possibly by altering potassium-channel function and suppresses induction of inducible nitric oxide synthase (iNOS) and ICAM in cerebral microvessels. The brain contains intrinsic networks which may protect the brain from ischemic injury, possibly by producing widespread and longterm suppression of electrical excitability and/or and expression of proinflammatory molecules.     

Gains at the 1p36 chromosomal region are associated with symptomatic leptomeningeal dissemination of supratentorial glioblastomas

Symptomatic craniospinal dissemination of glioblastomas is considered rare, and unambiguous pathologic or molecular predictors of tumor leptomeningeal spread remain to be defined. We performed molecular analysis of 8 glioblastomas with symptomatic leptomeningeal dissemination by using fluorescence in situ hybridization and array-based comparative genomic hybridization (array-CGH). The most frequently encountered alteration was gain of the 1p36 locus, which was found in all 8 samples examined. Array-CGH analysis of 3 available samples also disclosed numerous gains at the 1pter-p36.1 locus involving at least 3 DNA clones from this chromosomal region. Consequently, an analysis of 1p copy number status might be kept in mind as an additional tool for further predicting the clinical course of glioblastoma.