Factors In Meningiomas Research Articles

The immunohistochemical expression of SSTR2A and 5 are independent prognostic factors in meningiomas

The immunohistochemical expression of SSTR2A and 5 are independent prognostic factors in meningiomas

H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort.

BackgroundA loss of the trimethylation of lysine 27 of histone H3 (H3K27me3) in meningioma has been recently suggested as an adjunct to identify subsets of higher risk of recurrence. The aim of the present study was to assess the prognostic value of H3K27 histone trimethylation and its potential clinical utility in the “Tübingen meningioma cohort.”MethodsPatients who underwent meningioma resection between October 2003 and December 2015 at the University Hospital Tübingen were included. Immunohistochemical stainings for H3K27me3 and the proliferation marker MIB1 were assessed and correlated with clinical parameters using univariate and multivariate Cox regressions as well as Pearson's chi-squared and log-rank test.ResultsOverall, 1268 meningiomas were analyzed with a female to male ratio of 2.6 and a mean age of 58.7 years (range 8.3–91.0). With 163 cases lost to follow up, 1103 cases were available for further analysis with a mean follow-up of 40.3 months (range 1.1–186.3). Male gender, younger age, intracranial tumor localization, progressive tumor, subtotal resection, higher WHO grade, increased MIB1 rate, and loss of H3K27me3 were significant negative prognostic factors in the univariate analysis. H3K27me3 status and all other prognostic factors, except age and tumor location, remained significant in the multivariate model. Furthermore, adjuvant radiotherapy was an independent positive prognostic factor.ConclusionsLoss of H3K27me3 combined with MIB1 labeling index are independent prognostic factors in meningioma. These data from the Tübingen meningioma cohort support the clinical utility of H3K27me3 immunohistochemical staining in meningioma and its integration into the routine histopathological workup.

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management.

Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications. The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Overweight, obesity and height as risk factors for meningioma, glioma, pituitary adenoma and nerve sheath tumor: a large population-based prospective cohort study

Background: In 2016, the International Agency for Research on Cancer (IARC) has announced that avoiding body fatness (i.e. overweight and obesity) contributes to prevent meningioma occurrence, but considered the available evidence for glioma inadequate. The association of body fatness with other CNS tumor subgroups is largely unknown.Objectives: To assess whether body fatness or body height are associated with risk for meningioma, glioma, pituitary adenoma (PA) or nerve sheath tumor (NST) in a large population-based Norwegian cohort.Methods: In this prospective cohort study of 1.8 million Norwegian residents, weight and height were measured at baseline and incident intracranial tumors were subsequently identified by linkage to the Cancer Registry of Norway. Cox regression analyses were performed to estimate risk for each tumor subgroup in relation to anthropometric measures, stratified by sex and in different age groups.Results: During 54 million person-years of follow-up 3335 meningiomas, 4382 gliomas, 1071 PAs and 759 NSTs were diagnosed. Obesity (BMI ≥30 kg/m2) was not associated with risk for meningioma or glioma, but was significantly associated with risk for PA (HR 1.43; 95% CI 1.09–1.88) compared with the reference group (BMI 20–24.9 kg/m2). For intracranial NSTs, obesity was associated with reduced tumor risk (HR 0.68; 95% CI 0.46–0.99). Body height was associated with increased risk for all four tumor subgroups.Conclusions: This study does not confirm overweight or obesity as risk factors for meningioma. Additionally, overweight and obesity can be quite confidently excluded as risk factors for glioma. However, this study indicates that body fatness increases the risk for PA, while it reduces the risk for NST.

Epidemiologic study of risk factors for meningioma in the Mayo Clinic Study of Aging.

2067 Background: An estimated 2% of the general population has a meningioma (Vernooij et al. 2007), which accounts for about 36% of all primary intracranial tumors (Ostrom et al. 2015). The most established risk factors are older age and female gender. One small study identified gender but no other risk factors with meningioma (Krampla et al 2004). A larger study using the Iowa Women’s Health study data found lower levels of physical activity, greater body mass index (BMI), greater height and uterine fibroids were associated with meningioma (Johnson et al. 2011). We sought to replicate these findings and to identify additional risk factors related to meningioma in a large population-based sample. Methods: Study participants were enrolled in the Mayo Clinic Study of Aging (MCSA), a population-based sample of Olmsted County, Minnesota residents used to study prevalence, incidence, and risk-factors for Mild Cognitive Impairment and dementia and includes a variety of medical factors. Using a text search of radiologists’ notes of 2,402 MCSA individuals, mean age 77±8 years and scanned between 2004-2014.We identified 52 subjects who had at least one meningioma. We estimated the association of selected potential risk factors with presence of meningioma using odds ratios and 95% confidence intervals from logistic regression models adjusted for age and gender, which informed the multivariable models. Results: In the initial models, significant risk factors identified included BMI (as a continuous variable) (OR = 1.06 95%CI 1.01 to 1.12), taking NSAIDS (OR = 2.11, 95%CI 1.13 to 3.95), aspirin (OR = 1.90, 95%CI 1.04 to 3.46), and blood pressure lowering medication (OR = 2.06, 95%CI 1.07 to 3.99). Protective factors included male gender (OR = 0.51, 95%CI 0.29 to 0.90), coronary artery disease (CAD; OR = 0.46, 95%CI 0.22 to 0.97) and higher Beck Anxiety Inventory (BAI) total score (OR = 0.88, 95%CI 0.78 to 0.98). Simultaneous adjustment for these factors in a multivariable model did not attenuate these associations. Conclusions: Findings reveal gender and BMI as risk factors for meningioma. Additionally, certain medications such as NSAIDS and BP lowering medications warrant follow up as potential factors related to development of meningioma.

Hormonal Contraceptive Exposure and Risk Factors for Meningioma in Soetomo Hospital 2012–2016

Hormonal Contraceptive Exposure and Risk Factors for Meningioma in Soetomo Hospital 2012–2016

Meningioma

Meningiomas represent the most common primary brain tumor and comprise 3 World Health Organization (WHO) grades, the most frequent being WHO grade I (90%). Surgery is mandatory to establish the diagnosis and to remove the tumor; however, complete resection can be achieved in only <50% of patients. Depending on the extent of resection, tumor location and the WHO grade radiation therapy can be applied. The issue of systemic treatment such as chemotherapy or targeted therapy (eg, somatostatin receptors, antiangiogenic agents) is yet not solved, particularly as current data are derived from small uncontrolled series in patients with long-standing disease and after several pretreatments. A more thorough understanding of molecular genetics, signaling pathways and prognostic factors in meningiomas should lead to the design of studies which stratify according to these factors. These studies have to be conducted in newly diagnosed patients after incomplete resection and in tumors of WHO grade II and III.

Angiogenesis in meningiomas

Neoangiogenesis has been correlated to biological aggressiveness and an adverse clinical course of several neoplasias. Its prognostic role in meningiomas appears to be controversial. Nonetheless, if adequately quantified with specific markers and appropriate scoring methods, angiogenesis seems to be significantly associated with a high growth fraction, development of recurrences and shorter overall survival of meningiomas. As a consequence, neoangiogenesis may represent a target for therapies aimed at reducing the growth of inoperable meningiomas or recurrence risk of totally resected tumors. Even more significantly, the identification of the factors that mediate angiogenesis in meningiomas could help us to determine appropriate novel anti-angiogenic therapies for these tumors. Herein the methods for quantification of angiogenesis as well as its regulating factors in meningiomas are reviewed.

Semaphorin3A immunohistochemical expression in human meningiomas: correlation with the microvessel density

The immunoexpression of the antiangiogenic factor semaphorin3A (SEMA3A) was evaluated in a series of meningiomas. Then, its correlations with the microvessel density (MVD) of the tumors and with the clinicopathological parameters as well with the survival time or recurrence-free interval were investigated. A positive SEMA3A immunostaining was found in most of meningiomas and a significant association was found between a high expression of this protein and a low MVD of the tumors. Moreover, a low SEMA3A immunoexpression was significantly correlated with a higher recurrence rate of meningiomas. In conclusion, our findings suggest a role for SEMA3A as an antiangiogenic factor in meningiomas with its decrease being associated with the development of recurrences. The supplementation of SEMA3A might be used in novel therapeutic antiangiogenic strategies to prevent the recurrence of highly vascularized meningiomas.

Prognostic Significance of the Mitotic Index Using the Mitosis Marker Anti–Phosphohistone H3 in Meningiomas

Mitotic activity is one of the most reliable prognostic factors in meningiomas. The identification of mitotic figures (MFs) and the areas of highest mitotic activity in H&E-stained slides is a tedious and subjective task. Therefore, we compared the results from immunostaining for the mitosis-specific antibody anti-phosphohistone H3 (PHH3 mitotic index [MI]) with standard MF counts (H&E MI) and the Ki-67 labeling index (LI). The relationship between these proliferation indices and prognosis was investigated in a retrospective series of 265 meningiomas. The PHH3 staining method yielded greater sensitivity in the detection of MFs and facilitated MF counting. Mitotic thresholds of H&E MI of 4 or more per 10 high-power fields (HPF) and PHH3 MI of 6 or more per 10 HPF were found as the most appropriate prognostic cutoff values for the prediction of recurrence-free survival. All 3 proliferation indices were univariately associated with recurrences and deaths. In contrast with the Ki-67 LI, H&E MI and PHH3 MI also remained as independent predictors in the multivariate Cox hazards modeling (P = .0007 and P = .0004, respectively).

Prognostic value of HER2 expression in meningiomas: an immunohistochemical and fluorescence in situ hybridization study

The aggressiveness of meningiomas is unpredictable. HER2 represents a well-known prognostic factor in various tumors such as breast carcinomas. This work was designed to study HER2 protein expression and HER2 gene amplification in meningiomas and to evaluate their prognostic value. Frozen sections of 35 meningiomas were immunostained for HER2, estrogen receptor, progesterone receptor, E-cadherin, and MIB-1. Meningiomas immunostained for HER2 were further examined for the HER2 gene amplification by dual-color fluorescence in situ hybridization using probes for centromere 17 and 17q11.2-q12. Complete clinical information was obtained in all cases. The study included 15 atypical meningiomas, 3 anaplastic meningiomas, and 17 classic meningiomas. Five atypical/anaplastic meningiomas and 5 classic meningiomas of the whole 35 (28.5%) meningiomas expressed HER2 protein. This was considered as an overexpression in comparison with negative normal meninges. Fluorescence in situ hybridization demonstrated more HER2 gene copy in 4 of these 10 HER2-positive meningiomas. At equivalent histologic grading, meningiomas with HER2 overexpression exhibited similar immunohistochemical parameters of prognostic value than their HER2-negative counterparts; however, the rate of tumor recurrence was significantly higher in meningiomas with HER2 overexpression than in HER2-negative meningiomas. Conversely, HER2 amplification was not associated with recurrence. Some meningiomas exhibit HER2 protein overexpression in part induced by gene amplification. However, only HER2 overexpression could represent an independent prognostic factor in meningiomas.

Role of HER-2/neu Overexpression and Clinical Features at Presentation as Predictive Factors in Meningiomas

Prediction of outcome in patients with meningiomas remains a significant problem to date. We have evaluated the role of symptoms at presentation and overexpression of her-2/neu overexpression as independent prognostic factors in meningiomas. In a retrospective study on patients with biopsy-proven diagnosis of meningioma, her-2/neu overexpression was evaluated using immunohistochemistry (IHC) performed on paraffin-embedded specimens. An IHC score of > or =2+ was considered positive for overexpression. Two hundred thirty-seven patients thus identified between January 1986 and December 1999 included 149 females and 88 males, with a mean age of 63.44 years. Survival was estimated using the Kaplan-Meier method. Incidence of meningiomas in females (62.8%) was significantly greater than in males. Focal neurodeficits, headache, and seizures (39.66%) were the most common presenting complaints and were not related to tumor behavior/outcome. Syncope at presentation was associated with a decreased survival, but this symptom constituted only 2.53% of the total, so reliable conclusions could not be drawn. Only 6 (2.53%) specimens revealed HER-2/neu overexpression by IHC. HER-2/neu overexpression is not a predictor of tumor behavior and has no role as a prognostic factor in meningiomas. Syncope as the clinical presentation at diagnosis may predict a poor outcome, but needs further investigation.

Predictive value of progression-associated chromosomal aberrations for the prognosis of meningiomas: a retrospective study of 198 cases.

The goal of this study was to determine whether in meningiomas cytogenetic findings are suitable as a predictive parameter relevant to prognosis. Between 1992 and 1998 at the Department of Neurosurgery, Saarland University, 198 patients underwent surgery to resect meningiomas. The meningiomas were investigated cytogenetically and the patients were followed up for a mean period of 33 months. On the basis of the cytogenetic findings, the meningiomas were subdivided into four groups: Group 0 meningiomas displayed a normal diploid chromosome set; Group 1 tumors were found to have monosomy 22 as the sole cytogenetic aberration; Group 2 tumors were markedly hypodiploid meningiomas with loss of additional autosomes in addition to monosomy 22; and Group 3 meningiomas had deletions of the short arm of a chromosome 1, as well as additional chromosomal aberrations including loss of one chromosome 22. One hundred ninety-eight patients in whom tumor resections were determined to be Simpson Grade I or II could be followed up after complete tumor extirpation. In 20 patients, one or several recurrences were documented during the period of observation. The tumors were classified according to their different, but mostly uniform chromosomal aberrations. Recurrences were found in six (4.3%) of 139 tumors in Groups 0 and 1 and in two (10.5%) of 19 tumors in Group 2; the highest rate of recurrence was found in 12 (30%) of 40 tumors in Group 3. This supports the notion that the deletion of the short arm of one chromosome 1 is an important prognostic factor in meningiomas. The results of this study document a significant correlation between histological grade (p < 0.0001), location (p < 0.0001), and recurrences of meningiomas (p < 0.0001) (significance determined using chi-square tests). The cytogenetic classification of meningiomas provides a significant contribution to the predictability of tumor recurrence and is, therefore, a valuable criterion for the neurosurgeon's postoperative management protocol.

Intrinsic expression of drug resistance-associated factors in meningiomas.

Meningiomas, commonly benign tumors, rarely display aggressive behavior by recurrences and invasion. In addition to surgery, irradiation is beneficial for recurrent, atypical, and malignant meningiomas. The role of chemotherapy, however, remains controversial, although there is evidence that meningiomas respond well to adjuvant chemotherapy. A major obstacle in chemotherapy remains drug resistance with reduced cellular drug accumulation through membrane efflux pumps, drug detoxification, and alterations in drug target specificity. In 84 classic, atypical, and malignant meningiomas, the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase IIalpha were studied. All types of meningiomas showed constant expression of P-gp, LRP, MRP, and topoisomerase IIalpha; metallothionein was found in 67% of the tumors, especially in atypical and malignant meningiomas. Furthermore, metallothionein. P-gp, LRP, and topoisomerase IIalpha were strongly expressed by normal and neoplastic vessels, which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. Neither recurrent nor previously irradiated meningiomas revealed any significant difference to primary tumors. These intrinsic drug resistances indicate that successful chemotherapy may require additional inhibition of these factors to be a promising approach in the management of meningiomas.

Vascular endothelial growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placenta growth factor in human meningiomas and their relation to angiogenesis and malignancy.

Angiogenesis is mediated by a number of different growth factors and appears vital for tumor growth. The understanding of angiogenic mechanisms could offer new therapeutic perspectives; in this context, the role of four potentially angiogenic growth factors was analyzed in a large series of meningiomas of different grades. Vascular endothelial growth factor (VEGF), placenta growth factor, hepatocyte growth factor/scatter factor, and basic fibroblast growth factor were quantified in 69 tumors by enzyme-linked immunosorbent assay. Microvessel density and proliferative activity were determined on paraffin sections, and clinical tumor invasiveness was rated. Induction of endothelial chemotaxis and capillary-like tube formation were studied in vitro using modified Boyden chamber assays and three-dimensional collagen gel assays, respectively. Tumors included 40 benign (World Health Organization [WHO] Grade I), 21 atypical (WHO Grade II), and 8 anaplastic/malignant (WHO Grade III) meningiomas. We found a correlation between meningioma grade and VEGF content (r = 0.37, P = 0.002), which was 2-fold higher in atypical than in benign meningiomas (P = 0.022) and 10-fold higher in malignant than in benign meningiomas (P = 0.025). Among different subtypes of Grade I meningiomas, VEGF levels were 10-fold higher in meningothelial than in fibrous meningiomas (P = 0.015). None of the other three factors investigated showed any association with tumor grade, microvessel density, or invasiveness, and VEGF also did not correlate with vascularity or invasiveness. Moreover, vascularity did not increase with malignancy grade. Endothelial chemotaxis and capillary-like tube formation in vitro were induced by meningioma extracts and were most effectively blocked by co-addition of antibodies against basic fibroblast growth factor, followed by anti-VEGF, whereas anti-hepatocyte growth factor/scatter factor was not effective. The chemotactic activity of meningioma extracts on endothelial cells correlated with their VEGF content (r = 0.6, P = 0.003). Meningiomas do not show an angiogenic switch involving VEGF and/or hepatocyte growth factor/scatter factor, as has previously been found in gliomas. Nevertheless, the biological activity of VEGF and basic fibroblast growth factor in meningiomas suggests that both are potential targets for antiangiogenic therapy in meningiomas of all WHO grades.

Platelet-derived growth factor expression and stimulation in human meningiomas

The platelet-derived growth factor (PDGF) family consists of subunits A and B and receptors alpha and beta. This paper evaluates the potential role of the homodimer PDGF-BB as a growth factor in meningiomas. It analyzes the expression of messenger RNA in members of the PDGF family in these tumors, measures the growth response of meningiomas to exogenous PDGF-BB in culture, and examines the induction of the c-fos proto-oncogene by PDGF-BB. Northern blot analysis was carried out on tissue from 20 meningiomas to measure the expression of PDGF-A, PDGF-B, PDGF-alpha receptor (PDGF-alpha-R) and PDGF-beta receptor (PDGF-beta-R). All tumors expressed PDGF-A and PDGF-B subunits. Nineteen of the 20 tumors expressed PDGF-beta-R and none expressed PDGF-alpha-R as measured by this technique. Because the beta receptor is selectively sensitive to stimulation by the PDGF-B subunit, these data suggest that meningiomas might be susceptible to stimulation by PDGF-BB. To test this hypothesis, the effect of exogenous PDGF-BB on meningioma growth was evaluated by incubating cells from 10 human meningiomas. Tritiated thymidine incorporation was used to evaluate stimulation of growth over a 48-hour period using PDGF-BB concentrations of 1, 3, or 6 ng/ml. Linear regression analysis and multiple-factor analysis of variance were used to measure PDGF-BB effects. Three of the 10 tumor specimens responded significantly to PDGF-BB, with a three- to sixfold increase in thymidine incorporation over 72 hours of exposure, and there was a significant overall growth-stimulating effect of PDGF-BB in the 10 tumor specimens tested. In the last set of experiments, the functionality of the PDGF-beta-R was determined by examining the induction of the proto-oncogene c-fos by PDGF-BB in meningioma cell cultures. A significant increase in c-fos protein was observed 3 hours after PDGF-BB addition. These findings demonstrate that PDGF-A, PDGF-B, and PDGF-beta-R are expressed in meningiomas and suggest that the beta receptor is functional: when it is activated, c-fos levels are increased, and an increase in meningioma cell division is observed after the addition of PDGF-BB. These studies support the hypothesis that PDGF acts as a growth factor in meningiomas.

Correlation between Cytogenetic and Histopathological Findings in 75 Human Meningiomas

The correlations between cytogenetic and histopathological findings were analyzed in 75 human meningiomas. The tumors were classified according to increasing degrees of anaplasia into three grades: Grade I, benign; Grade II, atypical; Grade III, anaplastic. In 45 tumors of Grade I (benign), we more often observed a normal karyotype or monosomy 22. In 23 tumors of Grade II (atypical), we observed karyotypes with structural and/or numerical abnormalities with the presence of telomeric associations in 8 of them. These last tumors were fibroblastic. In seven Grade III tumors (anaplastic), we also observed complex abnormalities, and in one case, we observed telomeric associations. Our observations show that complex chromosome abnormalities and telomeric associations are observed in tumors that histologically display a certain degree of anaplasia. It is possible that the result of histopathological and cytogenetic correlations might represent a prognostic factor in meningiomas.

Transforming growth factor (TGF)-β like activity of intracranial meningioma and its effect on cell growth

Polypeptides, characterized by their ability to confer a transformed phenotype on an untransformed indicator cell have been isolated directly from surgical specimens of intracranial meningioma by using an acid/ethanol extraction procedure. Transforming activity in meningeal cells was based on the ability to induce NRK 49F rat kidney fibroblasts to form colonies in soft agar. This polypeptide was separated by gel filtration into two fragments of 15 and 40 kilodalton (kDa) molecular weight. Among other cases of brain neoplasms, one case of glioblastoma multiforme had moderate TGF-β activity, but medulloblastoma and neurinoma had no activity. Purified TGF-β also stimulated DNA synthesis in primary cultured meningioma cells, but no effect was seen in U 251MG human glioma cells. While the physiological function of TGF-β is still ill-defined and the molecular character of its receptor has not been analyzed, intracranial meningiomas are noted to have TGF-β-like activity. TGF-β also induces the DNA synthesis of cultured meningioma cells. From these results, TGF-β would be considered one of the growth promoting factors in meningioma.