Peritumoral Brain Edema In Patients Research Articles

Effect of osteoporotic conditions on the development of peritumoral brain edema after LINAC-based radiation treatment in patients with intracranial meningioma

PurposeDisruption of the tumor-brain barrier in meningioma is a crucial factor in peritumoral brain edema (PTBE). We previously reported the possible effect of osteoporosis on the integrity of the arachnoid trabeculae because both the bone and the arachnoid trabeculae are composed of type 1 collagen. We hypothesized that osteoporotic conditions may be associated with PTBE occurrence after radiation treatment in patients with meningioma.MethodsA receiver operating characteristic curve analysis was used to identify the optimal cut-off values of mean skull Hounsfield unit for predicting osteopenia and osteoporosis in patients from our registry. Multivariate Cox regression analysis was used to determine whether possible osteoporosis independently predicted PTBE development in patients with meningioma after radiation.ResultsA total of 106 intracranial meningiomas were included for the study. All patients received linear accelerator-based radiation therapy in our hospital over an approximate 6-year period. Multivariate Cox regression analysis identified that hypothetical osteoporosis was an independent predictive factor for the development of PTBE in patients with meningioma after linear accelerator-based radiation treatment (hazard ratio 5.20; 95% confidence interval 1.11–24.46; p = 0.037).ConclusionsOur study suggests that possible osteoporotic conditions may affect PTBE development after linear accelerator-based radiation treatment for intracranial meningioma. However, due to the study’s small number of patients, these findings need to be validated in future studies with larger cohorts, before firm recommendations can be made.Graphic abstract

Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Analysis of Microvascular Permeability in Peritumor Brain Edema of Fibrous Meningiomas

Introduction: This study aims to analyze the permeability of intra- and peri-meningiomas regions and compare the microvascular permeability between peritumoral brain edema (PTBE) and non-PTBE using DCE-MRI. Methods: This was a retrospective of patients with meningioma who underwent surgery. The patients were grouped as PTBE and non-PTBE. The DCE-MRI quantitative parameters, including volume transfer constant (K^trans), rate constant (K_ep), extracellular volume (V_e), and mean plasma volume (V_p), obtained using the extended Tofts-Kety 2-compartment model. Logistic regression analysis was conducted to explore the risk factor of PTBE. Results: Sixty-three patients, diagnosed as fibrous meningioma, were included in this study. They were 17 males and 46 females, aged from 32 to 88 years old. K_ep and V_p were significantly lower in patients with PTBE compared with those without (K_ep: 0.1852 ± 0.0369 vs. 0.5087 ± 0.1590, p = 0.010; V_p: 0.0090 ± 0.0020 vs. 0.0521 ± 0.0262, p = 0.007), while there were no differences regarding K^trans and V_e (both p > 0.05). The multivariable analysis showed that tumor size ≥10 cm³ (OR = 4.457, 95% CI: 1.322–15.031, p = 0.016) and V_p (OR = 0.572, 95%CI: 0.333–0.981, p = 0.044) were independently associated with PTBE in patients with meningiomas. Conclusion: DCE-magnetic resonance imaging·Meningioma·Blood vessel MRI can be used to quantify the microvascular permeability of PTBE in patients with meningioma.

Association between tumor size and peritumoral brain edema in patients with convexity and parasagittal meningiomas.

Peritumoral brain edema (PTBE) is a common complication in meningioma and disruption of the tumor-brain barrier in meningioma is crucial for PTBE formation. To evaluate the association between meningioma size and PTBE, we measured meningioma volumes using the 3D slicer in patients with convexity and parasagittal meningiomas. Receiver operating characteristic curve analysis was used to determine the optimal cut-off meningioma volume values for predicting PTBE occurrence. Logistic regressions were used to estimate the odds ratios for PTBE occurrence in patients with convexity and parasagittal meningiomas according to several predictive factors. A total of 205 convexity or parasagittal meningioma patients with no other brain disease who underwent one or more contrast-enhanced brain MRIs were enrolled in this 10-year analysis in two hospitals. The optimal cut-off meningioma volume value for prediction of PTBE in all study patients was 13.953 cc (sensitivity = 76.1%; specificity = 92.5%). If a meningioma is assumed to be a complete sphere, 13.953 cc is about 2.987 cm in diameter. Our study suggests a cut-off value of 3 cm meningioma diameter for prediction of PTBE in patients with convexity and parasagittal meningiomas. We believe that we have revealed why the meningioma diameter of 3 cm is clinically meaningful.

Preoperative Serum Level of Vitamin D is a Possible Protective Factor for Peritumoral Brain Edema of Meningioma: A Cross Sectional Study

Meningioma is associated with the development of vasogenic edema defined as disrupted blood brain barrier. Vitamin D3 through its own nuclear receptor can regulate the expression of many effective agents on the integrity of the blood brain barrier. This study aimed to investigate the association between preoperative serum levels of 25(OH)D and peritumoral brain edema in patients with meningioma. One hundred and twelve patients with meningioma completed the study. Serum 25(OH)D levels assessment and magnetic resonance imaging (MRI) were done for all patients at the beginning of the study. The percentage of edema index (EI) was used to estimate the extent of peritumoral brain edema through preoperative MRI. The median serum level of 25(OH)D in the patients with the percentage of EI < 100% was significantly higher than those with > 100% (65.58 vs. 37.33, P < 0.001). The median percentage of EI was 24.9. Preoperative serum levels of 25(OH)D had an inverse and significant correlation with the percentage of EI as by increasing each 1 ng/mL of serum 25(OH)D, EI was decreased approximately 4% (95% CI; −5.984 to −1.952, P < 0.001). Vitamin D may be a protective factor for peritumoral brain edema of meningioma.

Peritumoral Brain Edema in Meningiomas Depends on Aquaporin-4 Expression and Not on Tumor Grade, Tumor Volume, Cell Count, or Ki-67 Labeling Index.

The aim of this study was to investigate to which degree the peritumoral brain edema in patients with meningiomas depends on aquaporin-4 (AQP4) expression, tumor grade, tumor volume, Ki-67 expression, and cell count. Thirty-three patients (25 women, 8 men; mean age 56.6±16.0years) with an intracranial meningioma underwent a standardized magnetic resonance (MR) examination prior to surgical resection. Edema indices (EIs) and tumor volumes were measured on the MR images. Tumor grade was classified according to the World Health Organization, and the proliferation index was estimated on Ki-67 antigen-stained specimens. Tumor cell count was evaluated. Eighteen specimens were stained for AQP4 expressioon. Significant intergroup differences between AQP4 expression grades and EIs were observed (P=0.03), and a positive correlation was detected between EIs and AQP4 expression grades (r=0.54; P<0.05). A ROC analysis with EI as a test variable revealed an AUC of 0.77 (95% CI 0.55-0.99) for the prediction of a moderate-to-strong AQP4 expression. An EI ≥1.5 predicted a moderate-to-high AQP4 expression with a sensitivity of 77% and a specificity of 60%. EI values of 2.2 and 3.5 reached sensitivity/specificity values of 69/80% and 54/100%, respectively. The AQP4 expression did not show any significant correlations with tumor grading, tumor volume, Ki-67 expression, or cell count. Moreover, we observed no significant positive or negative correlations between the EI and tumor grading (P=0.7), tumor volume (P=0.19), Ki-67 index (P=0.9), and cell count (P=0.34). Peritumoral brain edema in patients with meningiomas may depend on AQP4 expression grades and not on tumor grade, tumor volume, Ki-67 expression, and cell count. The amount of edema predicted AQP4 expressions with moderate-to-good sensitivity and specificity.

Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases

To analyze the prognostic value of the extent of peritumoral brain edema in patients operated for single brain metastases (BM), we retrospectively evaluated pre-operative magnetic resonance images in a discovery cohort of 129 patients and a validation cohort of 118 patients, who underwent neurosurgical resection of a single BM in two different hospitals. We recorded clinical parameters and immunohistochemically assessed the Ki67 index, the microvascularization patterns and the expression of hypoxia-induced factor 1 alpha (HIF1a) in the BM tissue specimens retrieved at neurosurgery. Statistical analysis including uni- and multivariate survival analyses were performed. Baseline characteristics were well balanced between the discovery and validation cohorts. In univariate analysis, we found a significant association of favorable overall survival time with young patient age, high Karnofsky performance score, low graded prognostic assessment (GPA) class, absence of extracranial metastases, adjuvant treatment with whole brain radiotherapy and, surprisingly, large brain edema. In multivariate analysis, only GPA and extent of brain edema remained independent prognostic parameters. The prognostic impact of the extent of brain edema was consistent in the two patient cohorts. Furthermore, we found a significant correlation of small brain edema with brain-invasive tumor growth pattern as assessed intraoperatively by the neurosurgeon, low neo-angiogenic activity and low expression of HIF1a. Extent of brain edema independently correlates with prognosis in patients operated for single BM. In conclusion, patients with small peritumoral edema have shorter survival times and their tumors are characterized by a more brain-invasive growth, lower HIF1a expression and less angiogenic activity.

Vascular endothelial growth factor A protein level and gene expression in intracranial meningiomas with brain edema

Meningiomas are the second most common primary intracranial tumors in adults. Although meningiomas are mostly benign, more than 50% of patients with meningioma develop peritumoral brain edema (PTBE), which may be fatal because of increased intracranial pressure. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and angiogen. VEGF-A protein, which is identical to vascular permeability factor, is a regulator of angiogenesis. In this study, 101 patients with meningiomas, and possible co-factors to PTBE, such as meningioma subtypes and tumor location, were examined. Forty-three patients had primary, solitary, supratentorial meningiomas with PTBE. In these, correlations in PTBE, edema index, VEGF-A protein, VEGF gene expression, capillary length, and tumor water content were investigated. DNA-branched hybridization was used for measuring VEGF gene expression in tissue homogenates prepared from frozen tissue samples. The method for VEGF-A analysis resembled an ELISA assay, but was based on chemiluminescence. The edema index was positively correlated to VEGF-A protein (p = 0.014) and VEGF gene expression (p < 0.05). The capillary length in the meningiomas was positively correlated to the PTBE (p = 0.038). If VEGF is responsible for the formation of PTBE, the edema may be treated with the anti-VEGF drug Bevacizumab (Avastin), which has been shown to reduce PTBE in patients with glioblastoma multiforme.

The effect of corticorelin acetate on peritumoral brain edema: An interim report of an open-label study as part of a phase III program

9095 Background: Steroid treatment of peritumoral brain edema (PBE) in patients with malignant brain tumors (BTs) is frequently associated with debilitating steroid side effects. The investigational agent corticorelin acetate injection, a synthetic peptide identical to h-corticotropin-releasing factor (hCRF), compared favorably to dexamethasone in reducing PBE in animal models of primary or metastatic BT. Toxicology and clinical studies including a pilot study in patients with malignant BTs published in ASCO's Annual Meeting Proceedings, showed hCRF to be safe and virtually devoid of steroid side effects. Methods: Following completion of follow-up periods for one of 2 randomized, double-blind phase III trials comparing corticorelin acetate to placebo or dexamethasone, patients with primary or metastatic BTs, PBE on pre-randomized study MRIs, and Karnofsky Performance Scores =50 were enrolled in an open-label extension study in which they took 1.0 mg corticorelin acetate by subcutaneous injection bid. We tapered dexamethasone maximally as tolerated. Patients were assessed every 4 weeks. Results: Of 47 patients who received open-label corticorelin acetate for up to one year, 28 patients continue to take it. Corticorelin acetate was safe and well tolerated, with no related deaths or SAEs. Patients typically refractory to reducing steroids - including at least 5 patients &gt;55 years of age, 7 patients with recurrent brain tumor, and 11 patients in whom prior attempt(s) to reduce dexamethasone had been unsuccessful – reduced dexamethasone with improvement or resolution of steroid side effects. We will present data in the first 30 patients to take corticorelin acetate for at least 12 weeks [the largest and longest-treated group reported to date] including changes in steroid side effects correlated with net cumulative changes in dexamethasone, and treatment-emergent AEs. Conclusions: This interim analysis supports corticorelin acetate's long-term safety, tolerability, and steroid-sparing potential. The outcome of the ongoing randomized trials may determine whether this innovative agent leads to fundamental changes in the management of PBE in patients with primary or metastatic BTs. [Table: see text]

The relationship between peritumoral brain edema and the expression of vascular endothelial growth factor and its receptors in intracranial meningiomas

We examined the radiological and histological features of, and the influences of the expression of VEGF and its two major receptors, Flt-1 and Flk-1, on the development of peritumoral brain edema (PTBE) in patients with intracranial meningiomas. The expressions of VEGF and VEGF receptors in the immunohistochemical study were analyzed in relation to several factors, including tumor size, location, vascularity, and blood supply, as seen on digital subtraction angiographic studies. The edema volume (P = 0.0003) and edema index (P < 0.0001) had a significantly positive relation to VEGF expression. The positivity of Flt-1 and Flk-1 was mainly observed in tumor vessels; 44 cases (37.2%) were positive for the Flt-1 antibody and 37 cases (31.4%) for the Flk-1 antibody. The mean value of the edema index of the positive-Flt-1 group (5.220 +/- 11.586) was significantly higher than that of the negative-Flt-1 group (1.782 +/- 2.559) (P < 0.0001). The mean value of the edema index of the positive-Flk-1 group (3.925 +/- 5.870) was slightly higher than that of the negative-Flk-1 group (2.671 +/- 8.136) (P < 0.0001). Our data suggest that the expressions of VEGF and VEGF receptors positively relate to each other and to the formation of PTBE in patients with meningiomas.

Alterations in diffusion and perfusion in the pathogenesis of peritumoral brain edema in meningiomas.

Magnetic resonance perfusion and diffusion studies were undertaken to clarify the significance of ischemia in the pathogenesis of peritumoral brain edema in patients with meningiomas. Included in this study were 26 patients with 27 meningiomas and 5 gliomas. Perfusion-weighted imaging (PWI) was performed using a gradient-echo, echo-planar-imaging (EPI) sequence for calculation of the relative regional cerebral blood volume (rrCBV) and the relative regional cerebral blood flow index (rrCBFi). Furthermore, multi-slice spin-echo EPI sequences were applied in order to obtain anisotropic and isotropic diffusion-weighted imaging (DWI). Apparent diffusion coefficient (ADC) values were then calculated for peritumoral brain parenchyma from tumors, with and without edema, using various diffusion sensitivities. Meningiomas without edema demonstrated a minimal increase of perfusion parameters in the peritumoral brain tissue. In contrast, cases with brain edema had highly significant ( p<0.0005) lower rrCBV and rrCBFi. The edema index (EI) correlated strongly with the rrCBV. A fitting procedure resulted into the following mathematical relation: EI=0.1/rrCBV(2). The DWI showed a significantly larger ADC value within areas of brain edema, compared with the normal white matter (0.74 x 10(-3) vs 1.55 x 10(-3) mm(2)/s; p<0.0001). Increases in EI correlated with increases in ADC values. In 31% of the meningiomas associated with edema, areas with increased signal, probable ischemia, demonstrated significantly lower ADC values, in comparison with the rest of the edematous areas. These areas were confined to tissue immediately adjacent to the tumor. In general, the decrease in rrCBV in brain edema represents a consequence from, rather than a cause of, vasogenic edema. Ischemic alterations can be regarded as secondary, facultative phenomena in the pathogenesis of meningioma-related brain edema.