Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model.

Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.

Prediction of blood supply in vestibular schwannomas using radiomics machine learning classifiers.

This study attempts to explore the radiomics-based features of multi-parametric magnetic resonance imaging (MRI) and construct a machine-learning model to predict the blood supply in vestibular schwannoma preoperatively. By retrospectively collecting the preoperative MRI data of patients with vestibular schwannoma, patients were divided into poor and rich blood supply groups according to the intraoperative recording. Patients were divided into training and test cohorts (2:1), randomly. Stable features were retained by intra-group correlation coefficients (ICCs). Four feature selection methods and four classification methods were evaluated to construct favorable radiomics classifiers. The mean area under the curve (AUC) obtained in the test set for different combinations of feature selecting methods and classifiers was calculated separately to compare the performance of the models. Obtain and compare the best combination results with the performance of differentiation through visual observation in clinical diagnosis. 191 patients were included in this study. 3918 stable features were extracted from each patient. Least absolute shrinkage and selection operator (LASSO) and logistic regression model was selected as the optimal combinations after comparing the AUC calculated by models, which predicted the blood supply of vestibular schwannoma by K-Fold cross-validation method with a mean AUC = 0.88 and F1-score = 0.83. Radiomics machine-learning classifiers can accurately predict the blood supply of vestibular schwannoma by preoperative MRI data.

Imaging-documented repeated intratumoral hemorrhage in vestibular schwannoma: a case report.

Intratumoral hemorrhage in vestibular schwannomas is rare. Symptoms often have an acute onset and include headache, nausea, vomiting, vertigo, and depressed consciousness. Intratumoral hemorrhage is probably caused by vascular fragility associated with tumor characteristics and growth. With hemorrhage in VS being rare, repeated hemorrhage has only been reported twice, and on clinical grounds only. The present report details the case of acute neurological deterioration in a patient with repeated intratumoral hemorrhage inside a vestibular schwannoma with computed tomography and magnetic resonance imaging confirmation. To our knowledge, repeated hemorrhage in vestibular schwannoma with radiological confirmation has not been reported before.

Characterization of Skull Base Lesions Using Pseudo-Continuous Arterial Spin Labeling.

PURPOSE: Pseudo-continuous arterial spin labeling (pCASL) is a non-invasive magnetic resonance (MR) perfusion technique. Our study aimed at estimating the diagnostic performance of the pCASL sequence in assessing the perfusion of skull base lesions both qualitatively and quantitatively and at providing cut-off values for differentiation of specific skull base lesions. METHODS: In this study 99 patients with histopathologically confirmed skull base lesions were retrospectively enrolled. Based on a pathological analysis, the lesions were classified as hypervascular and non-hypervascular. Patients were divided into two subgroups according to the anatomical origin of each lesion. The MRI study included pCASL and 3D T1-weighted fat-saturated post-contrast sequences. Of the patients seven were excluded due to technical difficulties or patient movement. The lesions were classified by two raters, blinded to the diagnosis as either hyperperfused or non-hyperperfused, based on the pCASL sequence. The normalized tumor blood flow (nTBF) of each lesion was determined. Qualitative and quantitative characteristics of hypervascular and non-hypervascular lesions were compared. RESULTS: Visual assessment enabled correct classification of 98% of the lesions to be performed. Quantitatively, we found significant differences between the nTBF values for hypervascular and non-hypervascular lesions (p < 0.001) and provided cut-off values, allowing meningioma and schwannoma to be distinguished from meningioma and adenoma. Significant differences were also found within the hypervascular group, namely, paraganglioma was more hyperperfused than meningioma (p = 0.003) or metastases (p = 0.009). CONCLUSION: The present study demonstrates the high diagnostic performance of pCASL in characterizing skull base lesions by either visual assessment or nTBF quantification. Adding the pCASL sequence to the conventional protocol of skull base assessment can be recommended.

Anti-VEGF treatment improves neurological function in tumors of the nervous system.

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas.

Expression of vascular endothelial growth factor and basic fibroblast growth factor in sporadic vestibular schwannomas correlates to growth characteristics.

HYPOTHESIS: Expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) may have an impact on the growth characteristics of sporadic vestibular schwannomas (VSs). BACKGROUND: Vestibular schwannoma is a benign, slow-growing neoplasm that accounts for 6% of all intracranial tumors. The biological backgrounds for neoplastic growth and especially for the various growth patterns of VS remain largely unknown. Because several angiogenic and cytotrophic factors have been described to be involved in the growth of malignant tumors, we initiated this study to examine 2 major representatives of such growth factors in VS and their possible correlation to the growth characteristics of sporadic VSs. METHODS: Surgical specimens from 17 patients with sporadic VS were examined, and the expression of 2 major angiogenic and neurotrophic factors, bFGF and VEGF, was quantitatively analyzed at the mRNA and protein levels. The microvessel density (MVD) was defined by CD31 staining. RESULTS: All tumors showed expression of bFGF and VEGF at both the mRNA and protein levels. The mRNA expression and the protein expression of both growth factors correlated positive to tumor volume, to tumor growth index, and to MVD. CONCLUSION: The bFGF and VEGF mRNA expression and the bFGF and VEGF protein expression in sporadic VS correlates to the tumour volume, to the tumor growth index, and to the MVD. This might indicate an angiogenic and neurotrophic influence of these factors and a possible involvement in the growth of sporadic VS.

Microhemorrhage, a possible mechanism for cyst formation in vestibular schwannomas.

OBJECT: Cystic vestibular schwannoma (VS) is a unique subgroup of VSs characterized by unpredictable expansion of the cyst component. Little is known, however, about the mechanism of cyst formation. In this study the authors compared neuroimaging and histological characteristics of cystic with solid VS to determine the pathogenesis of the cystic subgroup. METHODS: Two cohorts, one comprising 10 patients with cystic VS and the other comprising 10 patients with solid VS, were studied. Surgery was chosen as the primary treatment in all patients, with no other modality applied. Preoperative magnetic resonance images and histological characteristics of the tumor in patients with cystic VSs were evaluated and compared with those in the group with solid VSs. Differences between the two groups were assessed using the chi-square test. Neuroimaging findings revealed that either fluid-fluid level or hemosiderin deposit was present in all cystic VSs. Histological evidence of microhemorrhage, such as hemosiderin-laden macrophages (p = 0.069), hemosiderin deposits (p = 0.019), thrombotic vessels (p = 0.008), and abnormal vessel proliferation (p = 0.006) were more prominent in cystic VSs compared with solid ones. There was no difference in Antoni type dominance and Ki-67 proliferative index between the two groups. CONCLUSIONS: Intratumoral microhemorrhage is a possible mechanism of pathogenesis in cystic VS.

alpha(v)beta(3) Integrin in central nervous system tumors.

alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is one of the most potent mediators of angiogenesis, which is a mandatory process during tumor growth. Immunohistochemical studies have demonstrated VEGF expression in vestibular schwannomas (VS), and a semi-quantitation of staining intensity indicated a correlation between tumor growth rate and VEGF expression. The present objectives were to determine the concentration of VEGF and the high-affinity receptor VEGFR-1 in VS homogenates and to examine a possible correlation with symptom duration, tumor size, or growth rate. STUDY DESIGN, PATIENTS, AND METHODS: Prospective selection of 27 patients with VS growth determined by repeated magnetic resonance imaging. Patient files were reviewed for symptom duration and all magnetic resonance images reviewed for determination of tumor size and growth rate. ELISA was used for determination of the VEGF and VEGFR-1 concentration in tumor homogenates. SETTING: Tertiary University Hospital Clinic. RESULTS: All tumor homogenates contained VEGF and VEGFR-1. A significant correlation existed between the concentration of both VEGF and VEGFR-1 and tumor growth rate but not symptom duration or tumor size. CONCLUSION: The concentration of VEGF and VEGFR-1 in VS homogenates correlates with tumor growth rate but not with tumor size or symptom duration. We conclude that VEGF and VEGFR-1 appear to be directly involved in the growth pattern of VS.

The immunohistochemical localisation of somatostatin receptors 1, 2, 3, and 5 in acoustic neuromas.

AIMS: Acoustic neuroma is a benign tumour, which develops through an overproliferation of Schwann cells along the vestibular nerve. Somatostatin is a naturally occurring peptide, which exerts antiproliferative and antiangiogenic effects via five membrane bound receptor subtypes. The aim of this study was to determine whether somatostatin receptor subtypes (SSTRs) 1, 2, 3, and 5 are present in acoustic neuromas. METHODS: The expression of SSTRs 1, 2, 3, and 5 was studied in both the Schwann cells and blood vessels of eight acoustic neuroma specimens, by means of immunohistochemistry using novel rabbit polyclonal antibodies raised against human SSTR 1, 2, and 5 subtype specific peptides, and a commercial anti-SSTR3 antibody. RESULTS: SSTR2 was the most prevalent subtype in Schwann cells (seven of eight), with intermediate expression of SSTR3 (six of eight), and lower expression of SSTRs 1 and 5 (four of eight and five of eight, respectively). There was ubiquitous vascular expression of SSTR2, with no evidence of SSTR 1, 3, or 5 expression in blood vessels. CONCLUSION: SSTRs 1, 2, 3, and 5 are differentially expressed in acoustic neuromas. Somatostatin analogues may have a therapeutic role in the management of this rare and challenging condition.

Microsurgical relationships of the anterior inferior cerebellar artery and the facial-vestibulocochlear nerve complex.

The relationship of the anterior inferior cerebellar artery (AICA) to the facial (7th) and vestibulocochlear (8th) nerves was studied using 3x to 20x magnification in 50 cerebellopontine angles (CPAs) from 25 adult cadavers. The AICA originated from the basilar artery as a single (72% of the CPAs), duplicate (26%), or triplicate (2%) artery. Each of the 50 CPAs had one or more arterial trunks that coursed in close proximity to the 7th and 8th cranial nerves and thus were said to be nerve-related. The nerve-related arterial trunks were divided into three segments based on their relationship to the nerves and meatus: the premeatal, meatal, and postmeatal segments. The meatal segment projected to the meatus or into the canal in 64% of the CPAs. In relation to the nerves, the premeatal segment was most commonly anteroinferior, the meatal segment was inferior, and the postmeatal segment was posteroinferior. The nerve-related branches of the AICA gave rise to internal auditory arteries in 100% of the 50 CPAs, recurrent perforating arteries in 82%, and the subarcuate artery in 72%. The internal auditory and recurrent perforating arteries arose most commonly from the premeatal segment, and the subarcuate artery arose most commonly from the postmeatal segment. There were one to four internal auditory arteries per CPA, zero to three recurrent perforating arteries, and zero or one subarcuate artery. The effects of occlusion of the nerve-related arteries and their involvement in conditions treated by neurosurgeons are reviewed.

Growth of human schwannomas in the subrenal capsule of the nude mouse.

To develop a reproducible in vivo model for the growth of human schwannomas we implanted tumor specimens from 14 different patients (13 acoustic neurinomas; 1 trigeminal schwannoma) into the subrenal capsule of 108 nude mice. In 11 experiments, the animals were implanted with only solid tumor from the surgical specimens. In two experiments, the tumor implants were made from solid tumors and cell clusters. In one experiment, the tumor implants were made from cell clusters alone. The size and neovascularization of these tumors were serially determined during a 1.5- to 3-month period. The percentages of tumors that survived or grew were 77.3% from solid tumors and 70% from cell clusters. Maximum tumor volume varied as did the time span to reach that volume. Tumor enlargement and stability correlated well with neovascularity; regressing tumor showed minimal or no neovascularity. Histological analysis of the implanted tumors showed spindle cells that are similar to the original tumor. Immunohistochemical staining for S100 demonstrated the Schwann cell nature of the implants. Analysis of genomic DNA from an acoustic neurinoma that had been implanted for 3 weeks was consistent with its human origin. There were no significant microscopic differences among groups receiving solid tumor implants or cell clusters. These studies suggest that implantation of human schwannomas into the subrenal capsule of the nude mouse is a reproducible method to study tumor growth that may be useful in testing potential therapeutic regimens or genetic modulation of schwannomas.

Acoustic neurinoma presenting as intratumoral bleeding.

The authors report a case of acoustic neurinoma presenting as intratumoral bleeding. This is the tenth reported occurrence. The literature is reviewed. All cases that have been reported have appeared with sudden onset of headache, vomiting, and decreased levels of consciousness. Aneurysm rupture, an arteriovenous malformation, or other vascular anomalies are suspected first. Preexisting unilateral hearing impairment is a valuable clue to differential diagnosis. Contrast-enhanced computed tomographic scans and cerebral angiograms are important tools for correct diagnosis. The tumor size (greater than 2 cm) and the thin, dilated vessels within the tumor are considered as pathogenetic factors for bleeding. When neurological status is not stable, placement of a ventriculoperitoneal shunt followed by urgent extirpation of the tumor is indicated.

Acoustic schwannomas in children.

The clinical presentation and treatment of three cases of acoustic schwannoma occurring in children are described. All the tumors were detected late, when they had attained a large size and were extremely vascular. The use of preoperative tumor embolization as an adjunct to surgical excision is discussed.

Hypervascular acoustic neuroma.

The authors present a patient with a large acoustic neuroma that exhibited an unusual vascular architecture. Magnetic resonance imaging demonstrated multiple flow voids in and around the mass. At surgery, intra- and extratumoral vascularity was arterialized due to luxurious shunting. Two attempts at removal produced severe engorgement and pulsatility of the surrounding brain, dramatically narrowing the operative exposure. Piecemeal resection of the tumor seemed to redistribute blood flow resulting in engorgement of the surrounding brain, analogous to perfusion breakthrough following AVM resection. Treatment strategies similar to those used for AVM resection may be indicated when encountering a hypervascular tumor.

Three-dimensional phase contrast MR cerebral venography with zero filling interpolation in the slice encoding direction.

The purpose of this study was to evaluate the magnetic resonance (MR) cerebral venography findings of a three-dimensional phase contrast MR sequence with zero filling interpolation of the data in the slice encoding direction. Fifty volunteers were enrolled in the study. Images were obtained on a 1.5 MR imaging system with acquisition time of 12 min. MIP images were reconstructed throughout the entire imaging volume. A grading scale system was used to assess dural venous sinuses, major deep veins, cortical, and cortical eponymic veins. Inferior group of dural venous sinuses, inferior sagittal sinus, and cortical eponymic veins were poorly demonstrated. Score of the superior sagittal sinus, the straight sinus, the confluence of the superior sinus group, the right transverse and sigmoid sinuses, the internal veins, and the vein of Galen was excellent. The score of the left transverse and sigmoid sinuses was good. In conclusion, when using zero filling interpolation of the data in a three-dimensional phase contrast MR cerebral venography sequence, the superior group of dural venous sinuses and main major deep veins are demonstrated with good conspicuity.

Distal mycotic aneurysm of the AICA mimicking intracanalicular acoustic neuroma.

BACKGROUND: Among cases of cerebellopontine angle lesions, vascular lesions involving the internal auditory canal are extremely rare. We report a distal fusiform mycotic pseudoaneurysm of the anterior inferior cerebellar artery (AICA) that simulated an acoustic neuroma on presentation. METHODS: A 60-year-old woman was investigated for recent onset of acute dizziness. Laboratory and radiographic investigations are presented, as well as the surgical management of the patient and pathological examination of the aneurysm. CONCLUSIONS: An exceptionally rare case of distal mycotic intracanalicular pseudoaneurysm of the AICA with intraluminal thrombus and fusiform anatomy is described. In our review of the literature (1966-present), only five other intracanalicular AICA-aneurysms were encountered, none of which were infectious in etiology. The possible pathophysiologic mechanisms of distal AICA-aneurysms are discussed along with the currently available literature.

Acoustic neurinoma with intratumoral bleeding.

The Authors present a case of acoustic neurinoma which has caused intratumoral bleeding. Although acoustic neurinomas are about 8-10% of all intracranial tumors there are only few cases about acoustic neurinomas causing hemorrhage. Pathologic changes of intratumoral vessels in tumors larger than 2 cm were considered to be a cause of the hemorrhage. This rare pathology must be remembered as one of the causes of the intracranial bleeding.

Light and electron microscopic observations of blood vessels in neurilemoma.

A study of 105 cases of neurilemoma disclosed frequent alterations of blood vessels, including hyalinized walls. Many vascular walls were formed by tumor cells. Two cases were analyzed by electron microscopy, and showed fenestrae, patent interendothelial gap junctions, and leakage of RBCs. The presence of erythrocytes in the gap junction and outside vessels is a factor acounting for xanthochromia of the CSF, and serum leakage for the frequent increase in CSF protein in cases of neurilemoma. Attenuation of endothelial cells increases the liability of vessels to bleed within the tumor. Massive bleeding may cause subarachnoid hemorrhage on rare occasions. Hyalinized vessels and dense collagen are features contributing to the relative infrequence of major hemorrhage. Evidence is presented that Schwann and perineural cells are similar.

Ultrastructure of capillaries in acoustic neurilemmoma.

The microvasculature of normal acoustic nerve tissue and small intracanalicular and large extracanalicular neurilemmomas was analyzed by electron microscopy. The capillaries of normal acoustic nerve were nonfenestrated, but the microvasculature in nerve-sheath neoplasms was fenestrated. Hypertrophy and hyperplasia of endothelial cells were observed only in the small lesions. The proliferated and enlarge endothelial cells often partially occluded the vascular lumen and formed multichannel vascular lumina. Many fenestrae of capillaries were found in small neoplasms, but these were rarely identified in the large extracanalicular lesions. The gap junctions of endothelium in small nerve-sheath neoplasms were long, wavy, and convoluted, had no openings, and differed from those of large lesions in which the tight junctions were short, straight, and occasionally patent. Additionally, heavy vascularization and erythrocytes within basement membranes were observed only in large neurilemmomas. These ultrastructural features may constitute a basis for differences between large and small acoustic neurilemmomas noted in cerebrospinal fluid findings.