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.

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.

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.

Usefulness of PRESTO magnetic resonance imaging for the differentiation of schwannoma and meningioma in the cerebellopontine angle.

The principles of echo-shifting with a train of observations (PRESTO) magnetic resonance (MR) imaging technique employs an MR sequence that sensitively detects susceptibility changes in the brain. The effectiveness of PRESTO MR imaging was examined for distinguishing between cerebellopontine angle (CPA) schwannomas and meningiomas in 24 patients with CPA tumors, 12 with vestibular schwannomas, and 12 with meningiomas. Histopathological study of surgical specimens showed that 11 of the 12 schwannomas contained hemosiderin deposits and all had microhemorrhages. One meningioma contained hemosiderin deposits and two involved microhemorrhages. Abnormal vessel proliferation, and dilated and thrombosed vessels were observed in all schwannomas and in 4 meningiomas. In addition to MR imaging with all basic sequences, PRESTO MR imaging and computed tomography were performed. PRESTO imaging showed significantly more schwannomas (n = 12) than meningiomas (n = 2) exhibited intratumoral spotty signal voids which were isointense to air in the mastoid air cells (p < 0.001). These spotty signal voids were significantly associated with histopathologically demonstrated hemosiderin deposits (p < 0.001), microhemorrhages (p < 0.01), and abnormal vessels (p < 0.04). The visualization of spotty signal voids on PRESTO images is useful to distinguish schwannomas from meningiomas.

Tumor-associated macrophages are related to volumetric growth of vestibular schwannomas.

HYPOTHESIS: Tumor-associated macrophages contribute to vestibular schwannoma development. OBJECTIVE: An important clinical problem regarding vestibular schwannoma treatment is their variable growth rate. Tumor biological research can help to clarify this growth rate and may offer targets for therapy. Inflammation is an important biological process involved in the development of many solid tumors. Macrophages are major determinants of intratumoral inflammation. Macrophages can be divided into two groups; the M1- and M2-type macrophages. M2-type macrophages are associated with tumor-promoting processes like angiogenesis, tumor cell growth, and downregulation of the antitumor immune response. Both macrophages and angiogenesis can serve as targets for therapy. CD163 is a specific marker for M2-type macrophages. The goal of this study was to investigate if the expression of CD163 positive macrophages in sporadic vestibular schwannomas is associated with angiogenesis and tumor growth. METHODS: CD163 expression in 10 fast-growing vestibular schwannomas was compared with CD163 expression in 10 slow-growing vestibular schwannomas. Tumor growth was determined by comparing preoperative tumor volume measurements on MRI. The relation between macrophage expression and angiogenesis was evaluated by assessing microvessel density (CD31). RESULTS: CD163 expression and microvessel density were significantly higher in fast-growing vestibular schwannomas (p < 0.001 and p = 0.019, respectively). Tumors with higher CD163 expression contained significantly more microvessels (p = 0.014). CONCLUSION: This study demonstrates that M2-type macrophages in vestibular schwannomas relate to angiogenesis and volumetric tumor growth. These results imply that the M2-type macrophage infiltrate contributes to progressive tumor growth, making it a potential target for pharmacologic therapy.

Assessment of antiangiogenic effect of imatinib mesylate on vestibular schwannoma tumors using in vivo corneal angiogenesis assay.

OBJECT: Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a corneal angiogenesis assay. METHODS: From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue). RESULTS: The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p <0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p <0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-α as well as PDGF-B and PDGFR-ß expression in sporadic VS and NF2-associated VS also differed significantly (p <0.05) from the levels in controls. Additionally the level of PDGFR-ß was significantly higher in sporadic VS than in NF2-associated VS (p <0.05). CONCLUSIONS: The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery.

Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas.

Vestibular schwannomas show a large variation in growth rate, making prediction and anticipation of tumor growth difficult. More accurate prediction of clinical behavior requires better understanding of tumor biological factors influencing tumor progression. Biological processes like intratumoral hemorrhage, cell proliferation, microvessel density, and inflammation were analyzed in order to determine their role in vestibular schwannoma development. Tumor specimens of 67 patients surgically treated for a histologically proven unilateral vestibular schwannoma were studied. Preoperative magnetic resonance imaging (MRI) scans were used to determine tumor size and to classify tumors as homogeneous, inhomogeneous, and cystic. Immunohistochemical studies evaluated cell proliferation (histone H3 and Ki-67), microvessel density (CD31), and inflammation (CD45 and CD68). Intratumoral hemorrhage was assessed by hemosiderin deposition. The expression patterns of these markers were compared with tumor size, tumor growth index, MRI appearance, patients' age, and duration of symptoms. No relation between cell proliferation and clinical signs of tumor volume increase or MRI appearance was found. Intratumoral hemosiderin, microvessel density, and inflammation were significantly positively correlated with tumor size and the tumor growth index. Cystic and inhomogeneous tumors showed significantly more hemosiderin deposition than homogeneous tumors. The microvessel density was significantly higher in tumors with a high number of CD68-positive cells. The volume increase of vestibular schwannomas is not based on cell proliferation alone. Factors like intratumoral bleeding, (neo)vascularization, and intensity of the inflammatory reaction also influence tumor volume.

Angiogenesis in vestibular schwannomas: expression of extracellular matrix factors MMP-2, MMP-9, and TIMP-1.

OBJECTIVES/HYPOTHESIS: Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are potent mediators of tumor angiogenesis. It has been demonstrated that vestibular schwannoma VEGF expression correlates with tumor growth pattern, whereas knowledge on the expression of MMPs is lacking. This study targets the angiogenic process by investigation of tumor expression of MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored. STUDY DESIGN: Prospective vestibular schwannoma tissue sampling for ELISA and immunohistochemical determination of MMP-2, MMP-9 and TIMP-1. METHODS: Thirty-four patients with a sporadic, noncystic, vestibular schwannoma were selected prospectively. Repeated, preoperative magnetic resonance imaging determined the tumor growth pattern. Following translabyrinthine resection, an enzyme-linked immunosorbent assay was used for determination of the MMP-2, MMP-9, and TIMP-1 concentration in tumor sample homogenates. Immunohistochemical labeling was performed in 12 randomly selected tumors. RESULTS: : All tumor homogenates expressed measurable MMP-9, MMP-2, and TIMP-1. Immunolabeling localized MMP-9 expression to the tumor cells, whereas MMP-2 and TIMP-1 was found interstitially. A significant correlation existed between the concentration MMP-9 and absolute tumor growth rate, whereas a weak correlation occurred for the relative growth rate. CONCLUSIONS: Vestibular schwannomas express MMP-2, MMP-9, and TIMP-1 and the tumor concentration of MMP-9 correlates with absolute tumor growth rate, but not with age, gender, symptom duration, or preoperative tumor size. No correlations existed between any clinical parameter and MMP-2 or TIMP-1 expression. We conclude that MMP-9 appears to be involved in the growth of vestibular schwannomas.

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.

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.

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.

Hypervascular intracisternal acoustic neuroma.

The diagnosis of acoustic neuroma is usually evoked in a patient presenting with a long history of hearing disturbance in whom an enhancing lesion within the internal auditory canal and/or the cerebellopontine angle is found on MRI. Hypervascularity with arteriovenous shunting and early filling of enlarged veins is a common feature of malignancy and has been reported very rarely in benign acoustic neuroma. We present the case of a patient without hearing disturbance, who showed a highly vascular lesion with no component in the internal auditory canal, making the preoperative diagnosis of acoustic neuroma very challenging. We discuss here the intracisternal site of origin and hypervascularity of acoustic neuroma, and also the differential diagnoses and management of such tumors.

Hypervascular vestibular schwannomas.

BACKGROUND: Vestibular schwannoma (VS) is usually hypovascular and can be resected totally without major morbidity. Resection of the more uncommon hypervascular VS is complicated by excessive tumor bleeding. We have attempted to clarify the clinical characteristics and management of hypervascular VS. METHODS: Surgical reports and videos of 78 patients with unilateral VS (5 hypervascular, 73 nonhypervascular) were retrospectively reviewed and clinical characteristics, radiological findings, and case management were compared. RESULTS: Hypervascular VS presented at a younger age than nonhypervascular VS (29 +/- 12 vs. 52 +/- 16 years old) (p < 0.01). Magnetic resonance imaging (MRI) showed that hypervascular VS was solid, without tumor cyst, and significantly larger than nonhypervascular VS (p < 0.05). The surface of hypervascular VS consistently showed multiple flow voids representing large draining veins. The characteristic angiographical findings of hypervascular VS were extensive tumor vessels, tumor stains, and early filling of draining veins; vertebrobasilar arteries supplied hypervascular VS. A multi-stage surgical approach was used since torrential tumor bleeding in the first surgery interfered with resection, resulting in partial tumor removal. Angiography before the second surgery showed much reduced tumor vascularity, bleeding was much reduced, and tumor was resected with less difficulty. In this approach, all 5 hypervascular VS were resected totally (1 case) or near-totally (4 cases) without major morbidity. CONCLUSIONS: Hypervascular VS, a solid and large tumor, presents at an earlier age. Although angiography provides characteristic findings, MRI can confirm the diagnosis of a hypervascular VS by showing multiple flow-voids on the tumor surface. Since partial tumor removal (first surgery) extensively reduces tumor vascularity and intraoperative tumor bleeding considerably, hypervascular VS should be managed by a multi-staged surgical approach.