Transient Obstructive Hydrocephalus due to Intraventricular Hemorrhage: A Case Report and Review of Literature.

BACKGROUND: Acute transient obstructive hydrocephalus is rare in adults. We describe a patient with intraventricular hemorrhage (IVH) who experienced the delayed development of acute transient hydrocephalus. CASE REPORT: A 33-year-old man with a previously diagnosed Spetzler-Martin Grade 5 arteriovenous malformation presented with severe headache, which was found to be due to IVH. Forty hours after presentation he developed significant obstructive hydrocephalus due to the thrombus migrating to the cerebral aqueduct, and a ventriculostomy placement was planned. However, shortly thereafter his headache began to improve spontaneously. Within 4 hours after onset the headache had completely resolved, and an interval head CT scan revealed resolution of hydrocephalus. CONCLUSIONS: In patients with IVH, acute obstructive hydrocephalus can develop at any time after the ictus. Though a delayed presentation of acute but transient obstructive hydrocephalus is unusual, it is important to be aware of this scenario and ensure that deterioration secondary to thrombus migration and subsequent obstructive hydrocephalus do not occur.

Meningiomas in pregnancy: a clinicopathologic study of 17 cases.

BACKGROUND: Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause. OBJECTIVE: We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy. METHODS: Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed. RESULTS: Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra- and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis. CONCLUSION: Our series suggests that pregnancy-associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation.

Impact of lateral mass anatomic variation on ideal polyaxial screw head mobility: technical considerations.

OBJECTIVE: To assess optimal angulation characteristics of lateral mass screws for subaxial (C3 to C6) fixation of the cervical spine in the neutral position. BACKGROUND: In the typical Magerl or Anderson placement technique, the screw trajectory is ideally parallel to the facet joint. For the rod and screw to align properly, the screw head must rotate enough to become perpendicular to the rod. If the optimal angle for the screw head is limited by the screw design, abnormal torsional forces will be generated at the rod/screw interface inducing kyphosis. In this paper, we examined the spinal anatomy in patients with normal CTs to determine the necessary range of motion between tulip head and screw to prevent forced persuasion and abnormal cervical spine alignment. METHODS: We examined subaxial radiographs of 292 vertebrae from C3 to C6 in 73 normal subjects. Computed tomography (CT) scans of the cervical spine with multiplanar reconstructions were evaluated in the axial and sagittal planes. A planned screw entry angle of 30° based upon the midpoint of the lateral mass was used in the axial plane, and parallel to the facet joint in the sagittal plane. The screw head angle (SHA) was then calculated from this 3D measured angle. RESULTS: The measured SHA ranged from 27 to 60°. The average SHA was 43.8°. The average SHA was not significantly different between the levels measured with consistent range and standard deviation. Seventy-six percent (223/292) of levels measured required a SHA >40°, and 12% (36/292) required a SHA >50°. CONCLUSION: The authors recommend using cervical instrumentation systems that allow for at least 55° of freedom of the polyaxial head to prevent abnormal segmental forces. In systems with lesser angulation, technique modifications must be applied to prevent translational forces.

Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays.

Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validation step, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-α protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multi-cohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.

Glioblastomas with giant cell and sarcomatous features in patients with Turcot syndrome type 1: a clinicopathological study of 3 cases.

BACKGROUND: Turcot syndrome (TS) is a rare genetic disorder of DNA mismatch repair predisposing to glioblastoma (GBM) in the type 1 variant. OBJECTIVE: We report the clinicopathological and genetic features of 3 gliomas in TS type 1 patients. METHODS: Three cases were reviewed from our clinical and pathology files at Washington University with the diagnosis of TS 1 and GBM over the past 14 years. All 3 had classic features of GBM, but also demonstrated bizarre multinucleated giant cells and remarkably high mitotic indices. Sarcomatous regions were found in 2. Despite these features, the patients had prolonged survival times of 44, 55, and >29 months (ie, currently alive). Demographic and clinical courses were abstracted from retrospective chart review. Histopathology was reviewed from all cases and reticulin histochemistry was added to identify possible foci of sarcomatous differentiation. RESULTS: All 3 had classic features of GBM, and Ki-67 labeling indices ranged from 18 to 45%. All 3 also showed strong nuclear p53 positivity. Two cases were negative for the isocitrate dehydrogenase 1 (IDH1) mutation, and O-Methylguanine methyltransferase promoter methylation was seen in one. Fluorescence in situ hybridization was done using 1p/1q, 19p/19q, centromere 7/epithelial growth factor receptor (EGFR), and PTEN/DMBT1 probes. Focal EGFR amplification was seen in one case, although other common alterations of either primary GBMs or gliomas with prolonged survival (1p/19q codeletion) were lacking. CONCLUSION: We conclude that 1) the giant cell variant of GBM is overrepresented in TS; 2) gliosarcomas may also be encountered; and 3) survival is often favorable, despite histological anaplasia and exuberant proliferation.

Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases.

BACKGROUND: Patients with limited intracranial metastatic disease traditionally have been treated with surgery followed by WBRT. However, there is growing concern for the debilitating cognitive effects after WBRT in long-term survivors. We present a series of patients treated with surgery followed by SRS, while reserving WBRT as a salvage therapy for disease progression. METHODS: Medical records from 15 patients with 1 to 2 cerebral metastases who underwent both resection and SRS were reviewed. Outcome measures included overall survival, survival by RPA class, EOR, local tumor control, progression of intracranial disease, need for WBRT salvage therapy, and COD. RESULTS: Fifteen patients with cerebral metastases were treated with the combined surgery-SRS paradigm. Eight of the 15 patients (53.3%) were designated RPA class 1, with 6 of 15 (40.0%) in class 2 and 1 of 15 (6.7%) in class 3. Gross total resection was achieved in 12 cases (80.0%). Overall median survival was 20.0 months, with values of 22.0 and 13.0 months for RPA classes 1 and 2, respectively. Local recurrence occurred in 16.7% of those patients with GTR. Six patients (40.0%) went on to receive WBRT at a median of 8.0 months from initial presentation. Twelve patients (80.0%) had died at the completion of the study, and the COD was CNS progression in 33.3%. CONCLUSIONS: Surgical resection combined with SRS is an effective treatment for selected patients with limited cerebral metastatic disease. Survival using this combined treatment was equivalent to or greater than that reported by other studies using surgery + WBRT or SRS + WBRT.

Intramedullary capillary hemangioma of the thoracic spine: case report and review of the literature.

Capillary hemangiomas are benign vascular neoplasms. When associated with the spine, these growths frequently involve the vertebral body, but rarely have they been reported to occur as intradural lesions, while even more rarely occurring in a true intramedullary location. We report a rare case of an intramedullary capillary hemangioma of the thoracic spinal cord and a review of the literature.

Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma.

Although meningiomas are common central nervous system tumors, little is known about the genetic events responsible for malignant progression. In this study, we employed gene expression profiling to identify transcripts whose expression was lost in anaplastic (WHO grade III) versus benign (WHO grade I) meningioma. Approximately 40% of genes down-regulated in anaplastic meningioma were localized to chromosomes 1p and 14q. One specific gene located at 14q11.2, NDRG2, was consistently down-regulated in grade III meningioma, a finding which we validated at both the transcript and protein levels in independent sets of clinically and pathologically diverse meningiomas. Loss of NDRG2 expression was also seen in a subset of lower-grade meningiomas, including atypical meningiomas (WHO grade II) with clinically aggressive behavior. Furthermore, we found that the loss of NDRG2 expression was significantly associated with hypermethylation of the NDRG2 promoter. Collectively, these data identify NDRG2 as the first specific candidate tumor suppressor gene on chromosome 14q that is inactivated during meningioma progression. In addition, these findings highlight the utility of combining genomic, epigenetic, and expression data to identify clinically significant tumor biomarkers, and suggest that NDRG2 expression will be a useful and functionally relevant biomarker to predict aggressive behavior in patients with meningioma.

High throughput screening of meningioma biomarkers using a tissue microarray.

Meningiomas are histologically and clinically diverse CNS neoplasms with few available immunohistochemical markers of differentiation and progression. Therefore, we investigated a panel of potentially useful meningioma-associated biomarkers using high throughput tissue microarray immunohistochemistry (TMA-IHC) with a TMA that includes 9 hemangiopericytomas (HPCs) and 41 meningiomas spanning all grades, as well as two subsets of atypical meningiomas, stratified according to clinical behavior. Antibodies utilized were progesterone receptor (PR), epithelial membrane antigen (EMA), cathepsin D, E-cadherin, platelet derived growth factor (PDGF) receptor beta, PDGF BB ligand, survivin, epithelial growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). In most cases, frequencies of tumor positivity were similar to those previously reported using whole section IHC. EMA, E-cadherin, and PDGFR-beta staining patterns distinguished the anaplastic meningiomas from the HPCs (P < 0.001, P = 0.02, P = 0.015, respectively). As in prior studies, PR and cathepsin D expression were inversely proportional to tumor grade. However, PR and EGFR were also differentially expressed between symptomatic, surgically resected benign meningiomas and incidental meningiomas found at autopsy. We conclude that (1) TMA-IHC is an accurate and efficient way to rapidly assess biomarkers in meningeal tumors, (2) EMA, E-cadherin, and PDGFR-beta are useful in distinguishing anaplastic meningiomas from HPCs, and (3) the expression patterns for incidental meningiomas differ slightly from their surgically resected symptomatic counterparts.

Meningothelial hyperplasia: a detailed clinicopathologic, immunohistochemical and genetic study of 11 cases.

Meningothelial hyperplasia is a poorly characterized entity, often associated with advanced age, chronic renal failure, trauma, hemorrhage, and neoplasia. In order to elucidate the nature of this lesion, 11 cases defined by the presence of nests of 10 or more cell layers thick, were compared with normal arachnoidal cap cells and meningiomas. Immunohistochemistry and FISH were performed to determine NF2 (merlin), protein 4.1B, EMA, progesterone receptor (PR), EGFR, survivin, VEGF, PDGF-BB, PDGFR-beta, E-cadherin, and cathepsin D status. All cases had at least one putative predisposing factor, including hemorrhage (7), chronic renal disease (5), old age (5), trauma (1), and an adjacent optic nerve pilocytic astrocytoma (1). There was typically a discontinuous growth pattern, with no invasion of surrounding normal tissue. No gene deletions were found, though scattered polyploid cells were seen in 2 cases. The immunoprofile was similar to normal cap cells with one exception; whereas normal cells were uniformly negative for PR, nuclear positivity was seen in 64% of hyperplasias, a frequency similar to that of benign meningiomas. Our data suggest that meningothelial hyperplasia is a reactive process that is usually distinguishable from meningioma based on clinicopathologic and genetic features. It may be preneoplastic in some, though further studies are needed to test this hypothesis.

Effects of cilostazol on human venous smooth muscle.

In this study, we evaluated the effect of therapeutic doses of cilostazol on human venous smooth muscle. Saphenous vein rings (two to four per patient sample) were suspended in tissue baths for isometric tension recordings. At the beginning of the experiment, optimal tension for isometric contraction was achieved for each ring in a stepwise fashion in the presence of norepinephrine (10(-2) M). Norepinepherine was then added cumulatively in half-molar increments and isometric tension developed by the rings was measured, thereby obtaining a dose-response curve. Following washout and reequilibration, the rings were precontracted with a 30-50% submaximal dose of norepinepherine determined from the dose-response curve and allowed to contract until a stable plateau was reached. Cilostazol was then added in a cumulative manner (680-2,720 microg/L), and the tension generated was recorded. A total of 76 venous rings were tested, and all relaxed in the presence of cilostazol. The amount of relaxation increased as the concentration of cilostazol increased. Relaxation of 15 +/- 1.9% (mean +/- SEM) at low cilostazol doses (680 microg/L) to 37+/-3% at high cilostazol doses (2,720 microg/L) was demonstrated. A second finding of this study was demonstrated when the patient samples were divided according to the presence or absence of risk factors for arteriosclerosis. The specific risk factors examined included diabetes mellitus, smoking, hypercholesterolemia, and hypertension. The presence or absence of hypertension (n = 52) or hypercholesterolemia (n = 18) did not affect the amount of relaxation of the venous rings. Smokers (n = 46) had less relaxation 16 +/- 2.4% (680 microg/L) to 41 +/- 3.6% (2,720 microg/L) compared to nonsmokers (n = 53) who relaxed 22 +/- 3.5% (680 microg/L) to 48 +/- 5.7% (2720 microg/L). This did not reach statistical significance at any concentration cilostazol (p = 0.11-0.18). Diabetics (n = 53) did have statistically significantly less relaxation at every concentration of cilostazol compared to nondiabetics (n = 11, p < 0.05). All venous rings relaxed in the presence of cilostazol. Veins of nondiabetics relaxed statistically significantly more than those of diabetics. Smokers had less relaxation than non-smokers, but this was not statistically significant. We are the first to demonstrate that human venous smooth muscle cells undergo relaxation when exposed to therapeutic concentrations of cilostazol.

Loss of tumor suppressor in lung cancer-1 (TSLC1) expression in meningioma correlates with increased malignancy grade and reduced patient survival.

Meningiomas represent the second most common central nervous system tumor affecting adults. Two of the most frequent early events in meningioma tumorigenesis involve loss of expression of the neurofibromatosis 2 (NF2) and 4.1B genes. Recently, 4.1B was shown to interact with the tumor suppressor in lung cancer-1 (TSLC1) protein, prompting us to examine the expression of TSLC1 in meningiomas. We developed specific anti-TSLC1 antibodies to examine TSLC1 expression in normal human leptomeninges, human meningioma cell lines, and human meningiomas of different pathological grades by Western blot (n = 10) and immunohistochemistry (n = 123). Whereas TSLC1 was expressed in normal human leptomeninges by immunohistochemistry, TSLC1 expression was absent in 3 human malignant meningioma cell lines and markedly reduced or absent in 30% of benign meningiomas by Western blot. Restoration of TSLC1 expression in a TSLC1-deficient human meningioma cell line resulted in reduced cell proliferation. In a series of 123 meningiomas (98 adult and 25 pediatric), TSLC1 expression was absent in 48% of benign (WHO grade I), 69% of atypical (grade II), and 85% of anaplastic (grade III) meningiomas. Moreover, TSLC1 loss was associated with decreased patient survival, within the overall group, and in the atypical meningiomas. Collectively, these results suggest that TSLC1 plays an important role in meningioma pathogenesis.

Meningioma: an update.

PURPOSE OF REVIEW: Recent clinical and molecular research has shed new light on the biology of meningiomas--a common but understudied CNS neoplasm. This review will focus on recent advances and their significance for future research and treatment. RECENT FINDINGS: Meningiomas represent the second most common brain tumor in adults, and while improved diagnostic modalities are available, these tumors remain underreported. Radiosurgery is an effective adjuvant therapy against meningioma; however, no effective chemotherapy exists. In addition to histologic grading and estimates of the extent of resection, biomarkers, such as progesterone receptor, cyclooxygenase 2, S100A5 and ornithine decarboxylase may be useful in predicting tumor recurrence and/or progression potential in patients with meningioma. On the genetic level, cytogenetic losses on chromosomes 1, 7, 10 and 14 and telomerase activation are observed in clinically aggressive meningioma, whereas monosomy 22 is a common early molecular event in tumor formation. Several candidate growth regulatory genes have been identified, including the Neurofibromatosis 2 (NF2), Tumor Suppressor in Lung Cancer-1 (TSLC1), Protein 4.1B, p53/MDM2 and S6-Kinase genes. The roles of these genes in meningioma formation and progression, as well as the clinical implications of these genetic changes, are discussed. SUMMARY: The recent insights into the molecular biology and genetics of meningioma provide new avenues for basic science research aimed at understanding the mechanisms underlying meningioma formation and malignant progression. These advances may be useful in improving our ability to predict clinical outcome and developing targeted therapies to improve outcomes in patients with clinically aggressive meningiomas.

Functional significance of S6K overexpression in meningioma progression.

One common genetic change in anaplastic meningiomas is amplification of chromosome 17q23 containing the S6 kinase (S6K) gene. We show, for the first time to our knowledge, increased S6K mRNA expression in anaplastic meningiomas compared with benign tumors. To evaluate S6K as a candidate meningioma progression gene, we generated IOMM-Lee human meningioma cell lines overexpressing S6K. Whereas no effect of S6K overexpression on meningioma cell growth, motility, or adhesion was observed in vitro, S6K overexpression resulted in increased tumor size in vivo. Collectively, these results suggest that S6K is functionally important for meningioma progression and may represent a target for future meningioma therapy.