Meningioma Proliferation Research Articles

Grading meningiomas with diffusion metrics: a comparison between diffusion kurtosis, mean apparent propagator, neurite orientation dispersion and density, and diffusion tensor imaging.

To compare the histogram features of multiple diffusion metrics in predicting the grade and cellular proliferation of meningiomas. Diffusion spectrum imaging was performed in 122 meningiomas (30 males, 13-84years), which were divided into 31 high-grade meningiomas (HGMs, grades 2 and 3) and 91 low-grade meningiomas (LGMs, grade 1). The histogram features of multiple diffusion metrics obtained from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator (MAP), and neurite orientation dispersion and density imaging (NODDI) in the solid tumours were analysed. All values between the two groups were compared with the Man-Whitney U test. Logistic regression analysis was applied to predict meningioma grade. The correlation between diffusion metrics and Ki-67 index was analysed. The DKI_AK (axial kurtosis) maximum, DKI_AK range, MAP_RTPP (return-to-plane probability) maximum, MAP_RTPP range, NODDI_ICVF (intracellular volume fraction) range, and NODDI_ICVF maximum values were lower (p < 0.0001), whilst the DTI_MD (mean diffusivity) minimum values were higher in LGMs than those in HGMs (p < 0.001). Amongst the DTI, DKI, MAP, NODDI, and combined diffusion models, no significant differences were found in areas under the receiver operating characteristic curves (AUCs) for grading meningiomas (AUCs, 0.75, 0.75, 0.80, 0.79, and 0.86, respectively; all corrected p > 0.05, Bonferroni correction). Significant but weak positive correlations were found between the Ki-67 index and DKI, MAP, and NODDI metrics (r = 0.26-0.34, all p < 0.05). Whole tumour histogram analyses of the multiple diffusion metrics from four diffusion models are promising methods in grading meningiomas. The DTI model has similar diagnostic performance compared with advanced diffusion models. • Whole tumour histogram analyses of multiple diffusion models are feasible for grading meningiomas. • The DKI, MAP, and NODDI metrics are weakly associated with the Ki-67 proliferation status. • DTI has similar diagnostic performance compared with DKI, MAP, and NODDI in grading meningiomas.

Association between preoperative hematologic markers and aggressive behavior in meningiomas

IntroductionMeningiomas have varying degrees of aggressive behavior. Some systemic hematologic makers are associated with malignancy, but their value in predicting aggressive meningioma behavior is not fully understood. ObjectiveTo evaluate the association between preoperative markers such as neutrophil-lymphocyte ratio (NLR), neutrophil-monocyte ratio (NMR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), and diagnostic and prognostic factors including WHO grade, proliferation index, presence of edema on preoperative MRI, and tumor recurrence. MethodsA retrospective review of patients treated between 2000 and 2019 with a preoperative complete blood count (CBC) differential lab draw before intracranial meningioma resection was conducted. All preoperative steroid dosages were converted to dexamethasone equivalents. Primary outcomes included presence/absence of perilesional edema, WHO grade, Ki-67/MIB-index, and recurrence. Univariate and multivariable regression analyses were conducted. ResultsA total of 209 meningioma patients were included. Of these, 143 (68 %) were WHO grade I, 61 (29 %) grade II and 5 (2 %) were grade III. Recurrence was reported in 19 (9.1 %) tumors. No hematologic markers were associated with recurrence. In separate multivariable logistic analyses, no biomarkers were associated with perilesional edema or WHO grade. MLR was associated with higher MIB-index (p = 0.018, OR 6.57, 95 % CI 1.37–30.91). ConclusionMost hematologic markers were not associated with meningioma invasiveness, grade, proliferative index, or aggressiveness. Preoperative MLR was associated with high proliferation index in patients undergoing surgery for intracranial meningioma. Higher MLR could be a surrogate for meningioma proliferation and has potential to be used as an adjunct for risk-stratifying meningiomas.

The expression of platelet-derived growth factor and its receptor in canine and feline meningiomas.

Feline meningiomas usually have benign biological behavior, while canine and human meningiomas are often classified as grade 2 or 3. Activation of the platelet-derived growth factor (PDGF) and its receptor signal pathway through PDGFβ/Rβ autocrine and paracrine is considered to play an important role in the tumor proliferation and malignant transformation of human meningiomas. However, there have been few studies about the expression of these molecules in canine meningiomas and no studies about their expression in feline meningiomas. We analyzed the PDGFα/Rα and PDGFβ/Rβ expression in canine and feline meningiomas by immunohistochemistry and western blotting. Immunohistochemically, most canine meningiomas showed the expression of PDGFα (42/44; 95.5%), PDGFRα (44/44; 100%) and PDGFRβ (35/44; 79.5%), and a few showed the expression of PDGFβ (8/44; 18.2%). In contrast, feline meningiomas were immunopositive for PDGFRα and PDGFRβ in all cases (14/14; 100%), while no or a few cases expressed PDGFα (0/14; 0%) and PDGFβ (2/14; 14.3%). Western blotting revealed specific bands for PDGFα, PDGFRα and PDGFRβ, but not for PDGFβ in a canine meningioma. In a feline meningioma, specific bands for PDGFRα and PDGFRβ were detected, but not for PDGFα and PDGFβ. These results suggested that canine meningiomas commonly express PDGFα/Rα, and thus autocrine or paracrine PDGFα/Rα signaling may be involved in their initiation and progression. Moreover, PDGF negativity may be related to benign biological behavior and a low histopathological grade in feline meningioma.

Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma.

Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. SIGNIFICANCE: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.

NF2 Gene Participates in Regulation of the Cell Cycle of Meningiomas by Restoring Spindle Assembly Checkpoint Function and Inhibiting the Binding of Cdc20 Protein to Anaphase Promoting Complex/Cyclosome

The neurofibromatosis type 2 (NF2) gene mutation is the leading genetic event in meningiomas, usually accompanied by malignant features. Dysfunction of the spindle assembly checkpoint (SAC) induces tumorigenesis. However, the crosstalk between NF2 and SAC in meningiomas remains unclear. Cell proliferation, invasion, apoptosis, and cell cycle of meningiomas were determined by cell counting kit-8 assay, transwell assay, and flow cytometry, respectively. The expression of SAC in meningioma cells was detected by quantitative real-time polymerase chain reaction and Western blot. The interaction between anaphase promoting complex/cyclosome (APC/C) and cell division cycle 20 (Cdc20) protein in meningioma cells was further explored by co-immunoprecipitation. We found that the expression of NF2/merlin was low or absent in malignant meningiomas. Overexpression of NF2 suppressed the proliferation and invasion of meningioma cells, prolonged the G2/M phase, and elevated the expression of SAC proteins at posttranscription. Furthermore, the interaction between APC/C and Cdc20 was inhibited by NF2. Our findings suggested that NF2 might restore SAC function by impairing the binding of APC/C and Cdc20, thereby limiting the mitotic rate and inhibiting proliferation of meningiomas.

EXTH-64. SMALL GTPASES IN MENINGIOMAS: PROLIFERATION, MIGRATION, SURVIVAL, POTENTIAL TREATMENT AND INTERACTIONS

Abstract PURPOSE To evaluate the role of the small GTPases RhoA, Rac1 and Cdc42 in meningiomas as therapeutic targets and their interactions in meningiomas. EXPERIMENTAL DESIGN We analyzed expression of GTPases in human meningioma samples and meningioma cell lines of various WHO grades. Malignant IOMM-Lee meningioma cells were used to generate shRNA mediated knockdowns of GTPases RhoA, Rac1 or Cdc42 and to study knockdown effects on proliferation and migration, as well as analysis of cell morphology by confocal microscopy. The same tests were used to investigate effects of the two inhibitors Fasudil and EHT-1864 of malignant IOMM-Lee, KT21 and benign Ben-Men cells and the effects of these drugs on IOMM-Lee knockdown cells. The effects of GTPase knockdowns and Fasudil treatment were studied in terms of overall survival by intracranial xenografts of mice. Potential interactions of GTPases regarding NF2, mTOR and FAK-Paxillin were examined. RESULTS Small GTPases were upregulated in meningiomas of higher tumor grades. Reduced proliferation and migration could be achieved by GTPase knockdown in IOMM-Lee cells. Additionally, the ROCK-inhibitor Fasudil and Rac1-inhibitor EHT-1864 reduced proliferation in different meningioma cell lines and reduced proliferation and migration independent of GTPase knockdowns/status. Moreover, overall survival in vivo could also be increased by knockdowns of RhoA and Rac1 as well as Fasudil treatment. GTPase expression was affected dependent on the NF2 status but effects were not very distinct, indicating that NF2 is not strongly involved in GTPase regulation in meningiomas. In terms of mTOR and FAK-Paxillin signaling, each GTPase changes those pathways in a different manner. CONCLUSION Small GTPases are important effectors in meningioma proliferation and migration in vitro as well as survival in vivo and their inhibition should be considered as potential treatment option.

The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations.

BackgroundMeningiomas with Neurofibromin 2 gene mutations (NF2-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease.MethodsExpression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (NF2 wildtype) and CH157-MN (NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2-mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models.ResultsLow Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling.ConclusionsThis study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in NF2-mutant meningioma.

Comprehensive Molecular Profiling Identifies FOXM1 as a Key Transcription Factor for Meningioma Proliferation

SUMMARYMeningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma.

Alteration of the Ki-67 Proliferative Index following Surgical Resection with or without Radiation Therapy of Intracranial Meningiomas.

The Ki-67 proliferative index is a widely accepted assay for cycling cells within tumor specimens of multiple histological subtypes. While it is not a substitute for the World Health Organization (WHO) grading, the Ki-67 proliferative index is thought to correlate with the biological activity of selected tumors. In the case of intracranial meningiomas, many lesions may be resected multiple times, with radiation therapy juxtaposed between surgical procedures. A retrospective review of 3,900 consecutive patients undergoing intracranial surgical resection at the University of Pittsburgh Medical Center over a five year period was undertaken. Of these patients, 604 had multiple resections. Multiple Ki-67 index scores were available for 42 patients with WHO grade I and II meningiomas, who suffered a recurrence or progression after their initial resection. Evidence of radiation therapy in the interval between pathology reports was also recorded. Data was evaluated for significant differences (p<0.05). WHO grade II meningiomas were more likely to have a higher Ki-67 index score on second resection than WHO grade I tumors (p=0.051). Furthermore, radiation-treated meningiomas demonstrated similar first Ki-67 index scores and higher second Ki-67 index scores (p=0.057 and p=0.022). Male patients tended to have less change in proliferation rates than female patients between the first and second resections (p=0.083), with a greater proportion of female patient tumors demonstrating accelerating proliferation rates. Treatment with radiation was associated with diminishing changes in meningioma proliferation rates compared to non-treated patients for tumors showing both accelerating rates (p=0.067) and decelerating rates (p=0.081). Ki-67 proliferation indices of recurrent or progressive meningiomas indicate that there are potentially distinct types of growth patterns of meningiomas, consisting of accelerating and decelerating proliferation rates. Meningioma growth is related to WHO grade, patient gender, and treatment with radiation. Radiation treatment appears to stabilize or “inactivate” tumor proliferation and thus normalize changes in meningioma growth rates.

Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling

BackgroundMeningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas.MethodsOGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed.ResultsOGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT.ConclusionWe identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression.

P38MAPK activation and DUSP10 expression in meningiomas

The mitogen activated protein kinase (MAPK) p38MAPK has been implicated in regulation of cell proliferation and apoptosis. However, expression, activation and regulation has not been studied in meningiomas, to our knowledge. p38MAPK is regulated, in part, by dual specificity phosphatases (DUSP) that inactivate signaling by dephosphorylation. DUSP10 is also a likely participant in regulating meningioma proliferation. Five fetal and an adult human leptomeninges and 37 meningioma cultures (MC) were evaluated for DUSP10 as well as phosphorylation of its substrates p38MAPK and p44/42MAPK by western blot and DUSP10 expression by polymerase chain reaction. Platelet derived growth factor-BB (PDGF-BB), transforming growth factor B1 (TGFB1) and cerebrospinal fluid effects on DUSP10 and signaling were also studied in vitro. DUSP10 and phospho-p38MAPK and phospho-p44/42MAPK were detected in all six leptomeninges. DUSP10 was detected in 13 of 17 World Health Organization grade I, 11 of 14 grade II and four of six grade III meningiomas. Phospho-p38MAPK was detected in nine of 17 grade I, two of six grade II, and four of six grade III meningiomas. In the majority of meningiomas DUSP10 expression correlated inversely with phosphorylation of p38MAPK. PDGF-BB increased DUSP10 in MC2 and MC4 and weakly in MC3. TGFB1 increased phosphorylation of p38MAPK and caspase 3 activation. Thus p38MAPK and DUSP10 likely participate in the pathogenesis of meningiomas.

MNGO-02GANODERIC ACID (A AND DM) INDUCED NDRG2 OVEREXPRESSION INHIBITS TUMORGENIC POTENTIAL OF MALIGNANT MENINGIOMA CELLS

Meningiomas are the second most common brain tumor, with a small proportion of these tumors being atypical or malignant. The aggressive subtypes are characterized by a capacity for invasion of normal brain with frequent recurrence patterns. Effective local therapies include surgery and radiation, but novel target specific drugs are needed to improve survival and reduce morbidity patients with for malignant anaplastic meningiomas (WHO Grade III) patients. Recently, an identified N-myc downstream-regulated gene 2 (NDRG2) protein was shown to be consistently down-regulated in grade III meningioma, demonstrating its role in tumorigenesis. In order to overexpress the tumor suppressor gene NDRG2 that inhibits tumorgenic pathways and proliferation of meningiomas, we used two bioactive triterpene compounds derived from Ganoderma lucidum (ganoderic acid A and ganoderic acid DM) in a preclinical meningioma model. Our in vitro and in vivo experiments demonstrated that overexpression of NDRG2 by the novel agents ganoderic acid (A/DM) inhibits proliferation, invasion and suppressed metastatic potential of high grade meningioma tumor growth via NDRG2 modulation of intracellular signals pathways while preserving normal brain tissue. Our results strongly demonstrate the effect of the novel agent ganoderic acid (A/ DM) on NDRG2 tumorigenesis establishing their translational potential for the treatment of patients with aggressive malignant meningiomas.

Molecular Targets and Treatment of Meningioma

Meningiomas are by far the most common tumors arising from the meninges. A myriad of aberrant signaling pathways involved with meningioma tumorigenesis, have been discovered. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. An understanding of the genetic and molecular profile of meningioma would provide a valuable first step towards developing more effective treatments for this intracranial tumor. Chromosomes 1, 10, 14, 22, their associated genes, and other potential targets have been linked to meningioma proliferation and progression. It is presumed that through an understanding of these genetic factors, more educated meningioma treatment techniques can be implemented. Future therapies will include combinations of targeted molecular agents including gene therapy, si-RNA mediation, proton therapy, and other approaches as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas. This review provides an overview of the current knowledge of the genetic, signaling and molecular profile of meningioma and possible treatments strategies associated with such profiles.

99mTc-Tetrofosmin SPECT for the detection of glioma recurrence

Dear Sir, We read with great interest the article by Gomez-Rio et al. concerning the distinction between tumor recurrence and radiation necrosis using thallium-201 (Tl) singlephoton emission computed tomography (SPECT) and 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) [1]. The authors studied 76 brain tumor patients suspicious of glioma recurrence after surgical excision and radiotherapy. The results showed that although FDG-PET yielded a slight higher specificity, the sensitivity was considerably lower. Thus, Tl-SPECT was superior in detecting radiation necrosis, especially in low-grade tumors. Radiation necrosis is one of the most serious complications of radiation therapy for the brain and is usually indistinguishable from true tumor recurrence by means of computed tomography and magnetic resonance imaging (MRI) alone. Furthermore, an accurate diagnosis is crucial for the patient’s management because therapy and prognosis are so distinctly different for these lesions. Several advanced MRI techniques, that provide significantly more information about tissue characterization, have been evaluated toward distinguishing radiation necrosis from tumor recurrence, such as diffusionand perfusion-weighted imaging and magnetic resonance spectroscopic evaluation. Functional metabolic imaging by PET and SPECT has also been evaluated; nonetheless, PET is often cost-prohibitive and not widely available. Brain SPECT has been proposed as an alternative imaging technique. Tl was among the first tracers evaluated, while technetium-99m (Tc)-labeled compounds have also been studied and proved advantageous over Tl due to the 140-keV γ-ray energy and higher photon flux, resulting in improved spatial resolution with significantly lower radiation burden to the patient [2]. Among Tc-labeled compounds, Tc-Sestamibi has been proven a suitable radiotracer [2, 3]. Over the last few years, we have investigated the imaging properties of Tc-Tetrofosmin (Tc-TF), a tumor-seeking lipophilic diphosphine routinely used for myocardial perfusion imaging [3]. Tc-TF does not cross the intact blood–brain barrier and its uptake depends on regional blood flow and cell membrane integrity, thus reflecting on cellular metabolic status and viability. We fount that Tc-TF could reliably distinguish between tumor recurrence and radiation injury [4]. We also evaluated the relationship between glioma and meningioma proliferation (as expressed by the Ki-67 index and flow cytometry) and the uptake of Tc-TF. In both tumor types, we verified a strong positive linear correlation between tracer uptake and tumor aggressiveness [5–7]. Soricelli et al. have also reported, in a study of 26 brain tumor patients, that Tc-TF was superior to Tl in depicting tumor margins, exhibiting higher lesion-to-background ratio [8]. Eur J Nucl Med Mol Imaging (2008) 35:1571–1572 DOI 10.1007/s00259-008-0824-z

Immunohistochemical expression of apoptosis regulating proteins and sex hormone receptors in meningiomas

Meningiomas are well known to be responsive to estrogen/progesterone stimulation, and their expression of estrogen/progesterone receptor (ER/PR) has been documented. On the other hand, there are several reports studying expression of apoptosis-regulating proteins (ARPs) and its significance in meningiomas. However, very limited published information exists on the exact relation among sex hormone receptor status, apoptosis, proliferation index (PI), and histological grade in meningiomas. A total of 57 cases of non-malignant meningiomas were selected, and histologically reviewed and graded (WHO grades 1, 2). All these cases were immunostained for ER, PR, Ki-67, and ARPs including bax, bcl-2, and bcl-xL. Sections were graded semiquantitatively for intensity and extent of immunostaining. PI was expressed as a percentage of Ki-67 positive tumor cells. Expression of bax, bcl-2, bcl-xL, ER, and PR was seen in 100, 35.1, 24.6, 10.4, and 87.2% of cases, respectively. Bax was expressed diffusely and strongly, while Bcl-2 tended to be expressed weakly and focally. Bcl-xL appeared to be expressed relatively strongly and diffusely in a small subset. There was significantly higher PI as well as expression of PR in grade 1 group than in grade 2 group. A weak negative correlation was observed between Bcl-2 and PR (r =-0.472, P < 0.0014). Given high-level expression of pro-apoptotic bax, which seems to be constitutionally expressed, in contrast to low-level expression of antiapoptotic bcl-2 and bcl-xL, other antiapoptotic proteins may involve the proliferation of meningiomas. A significant negative relation exists between PR and Bcl-2 in meningiomas, which might have some biological and clinical significance.

Adjuvant therapy for unresectable meningiomas: benign and malignant

traaxial primary brain tumor and are discovered not infrequently in otherwise asymptomatic patients. The authors of natural history observational studies have suggested that the majority of asymptomatic meningiomas grow at a slow incremental rate and therefore may be reasonably followed without intervention. Nonetheless, a substantial number of them become symptomatic and are treated surgically. Not all meningiomas, however, can be safely or completely resected, and adjuvant therapeutic intervention is often warranted. This issue of Neurosurgical Focus is directed at aggressive or malignant meningiomas, as well as ones that cannot be completely excised. Our goal is to present current knowledge of meningiomas and highlight potential new therapies. The symposium opens with a general overview of intracranial meningiomas by Chamberlain and is followed by a discussion of epidemiology and etiopathogenesis of meningiomas by Barnholtz-Sloan. Commins reviews the pathological nature and classification of meningiomas. Rogers next discusses the use of conventional externalbeam radiotherapy in the management of these lesions. Loeffler and colleagues summarize their extensive experience with stereotactic radiotherapy for benign meningiomas. Davidson then presents a single-institution perspective on the utility of Gamma Knife surgery for meningiomas of the cranial base. In the next section of the meningioma symposium, the authors discuss medical management of meningiomas beginning with Couldwell’s paper regarding the use of cyclooxygenase inhibition with COX-2 agents. Roser discusses the eicosanoid cascade as a target for meningioma chemotherapy, and this is followed by Jensen’s discussion of calcium channel antagonists as inhibitors of meningioma proliferation. Chen presents laboratory data demonstrating that the protease inhibitor, nelfinavir, has at least additive cytotoxicity when combined with imatinib. Newton next summarizes the literature regarding hydroxyurea as a chemotherapeutic agent for meningiomas, and this is followed by Wen’s eloquent review of targeted therapy and potential strategies for the treatment of meningioma. The symposium concludes with two special reviews: intraosseous meningiomas reviewed by Elder and intraspinal meningiomas summarized by Vrionis. As editors of this issue of Neurosurgical Focus highlighting the treatment of meningiomas, we would like to thank the contributors for their timely and thoughtful reviews, and hope that this symposium will contribute to an improved understanding and appreciation of new and evolving therapies for meningiomas.

Correlation of peritumor brain edema with proliferation of meningiomas

目的 探讨脑膜瘤周围水肿与肿瘤增殖能力之间的相关性.方法46例脑膜瘤患者,按术前CT所反映的瘤周脑水肿程度分为无、轻、中、重度水肿组,术后取病理标本测定各组肿瘤的增殖细胞核抗原表达水平,并对瘤周水肿程度与增殖细胞核抗原(PCNA)标记指数进行相关性分析.结果46例轻度水肿18例,中度水肿10例,重度水肿5例,三组的PCNA LI分别为(2.83±1.57)、(3.14±2.04)、(4.13±2.43),相关分析表明水肿程度与PCNA LI之间有显著的相关性.结论脑膜瘤周围水肿程度与肿瘤的增殖活性密切相关。

Holistic and network analysis of meningioma pathogenesis and malignancy

Meningiomas, which originate from arachnoid cells and constitute the largest subgroup of all intracranial tumors, are generally benign, yet have the capacity to progress into a higher histological grade of malignancy associated with an increase in biological aggressivity and/or capacity to recur. To elucidate meningioma pathogenesis and malignancy, we applied a holistic and network approach analyzing cDNA and tissue microarray results. A potential pathway leading to meningioma angiogenesis, apoptosis and proliferation was evidenced as well as a regulatory network of the biomarkers including Ki-67, AR, CD34, P53, c-MYC, etc. which might support clinical research. In this potential pathway, ITGB1 could be the most important "superoncogene" playing a vital role in apoptosis and proliferation, while FOXO3A, MDM4 and MT3 are important to the malignancy process. Some genes are first reported that could explain why radiation induces meningioma and why more female than male patients are affected. Further, we present the hypothesis that HIV-Tat protein might have a close relationship with meningioma pathogenesis and malignancy.

Positron emission tomography elucidates transport system and tumor proliferation in meningiomas

To test the in vivo transport system and tumor proliferation of meningiomas, in comparison with gliomas, 25 patients with meningiomas and 8 gliomas underwent quantitative kinetic analysis of ([18F])fluoro-2-deoxy-D-glucose (FDG) - positron emission tomography (PET) imaging and immunohistochemical study. Kinetic analysis was obtained by calculation of the rate constants: K1 (ml/g/min), which represents the transport of FDG from plasma to tissue; k2 (min(-1)), which demonstrates the transport back from tissue to plasma; and k3 (min(-1)), an indicator of glucose metabolism, using Gjedde's plot methods in a three-compartment model. Surgical specimens were evaluated by means of three different methods: i) immunoreactivity to vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1), representing the permeability of tumor vessels; ii) immunostaining for von Willebrand Factor (vWF), reflecting vascular surface areas of arterioles; and iii) the MIB-1 labeling index (MIB-1 LI), representing the proliferative potential. K1 was higher in meningiomas than in gliomas and was higher in atypical than in benign meningiomas. k3 was correlated with MIB-1 LI in meningiomas, but not in gliomas. Immunohistochemically, meningiomas were less reactive to VEGF or Glut-1 than gliomas but atypical meningiomas stained more intensely than benign meningiomas. The vascular surface area was significantly larger in meningiomas than in gliomas and atypical meningiomas had high values for both permeability and surface area than benign meningiomas. High values for K1 and k3 indicate the aggressive proliferation of meningiomas and, in atypical meningiomas, the synergistic interaction of the high permeability and the large surface area yielded conditions conducive to glucose metabolism and tumor proliferation. Evaluation of K1 and k3 facilitates to predict the tumor aggressiveness and to optimize the surgical management.

Different Activation of Mitogen-Activated Protein Kinase and Akt Signaling Is Associated with Aggressive Phenotype of Human Meningiomas

Activation of intracellular signaling cascades has been implicated in the growth control of benign meningiomas, but their role for meningioma progression and outcome is unknown. Here we determined the expression and function of proteins involved in mitogen-activated protein kinase (MAPK) and phosphinositol-3 kinase (PI3K)/Akt signaling in benign, atypical, and malignant meningiomas and studied their association with clinicopathologic data including meningioma recurrence. Expression of various MAPK and PI3K signaling proteins was determined in 70 primary meningiomas and, if present, in recurrent tumors by immunohistochemistry and Western blotting. The expression patterns in primary and recurrent tumors were related to clinical data. The effect of MAPK and PI3K pathway inhibition on cell proliferation and apoptosis was determined using a primary malignant meningioma cell culture. Atypical and malignant meningiomas showed higher levels of phospho-Akt compared with benign tumors, and their proliferation could be inhibited by PI3K blocking using wortmannin. PI3K inhibition did not induce apoptosis in malignant meningioma cells. In contrast, expression of phospho-Raf and phospho-MAPK was decreased in aggressive meningiomas compared with benign tumors, but MAPK inhibition by PD98059 resulted in tumor cell apoptosis and decreased proliferation. Reduced MAPK activation was associated with meningioma recurrence, and PI3K activation was associated with poor preclinical condition and brain invasion of malignant meningiomas. Both MAPK and PI3K/Akt pathways are activated at different levels in benign and malignant meningiomas. Activation of PI3K/Akt signaling contributes to the aggressive behavior of malignant meningiomas, whereas MAPK activation is involved in both proliferation and apoptosis of malignant meningiomas.