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Randy L Jensen

Publications and source records attributed to Randy L Jensen.

At least 19 recordsLinked to original sources
PubMed2007

Celecoxib inhibits meningioma tumor growth in a mouse xenograft model.

BACKGROUND: Treatments for recurrent meningiomas are limited. We previously demonstrated universal expression of COX-2 in meningiomas and dose-dependent growth inhibition in vitro with celecoxib, a COX-2 inhibitor. We therefore tested the effects of celecoxib on meningioma growth in a mouse xenograft model. METHODS: Meningioma cell lines (IOMM-Lee, CH157-MN, WHO grade I primary cultured tumor) were transplanted into flanks of nude mice fed mouse chow with celecoxib at varying concentrations (0, 500, 1000, 1500 ppm) ad libitum. Tumors were measured biweekly and processed for MIB-1, Factor VIII, COX-2, and VEGF, and assayed with transferase-mediated dUTP-biotin nick-end labeling (TUNEL). RESULTS: Celecoxib reduced growth of mean tumor volume by 66% (P < .05), 25% (P > .05), and 65% (P < .05) compared with untreated controls in IOMM-Lee, CH157-MN, and benign tumors, respectively. IOMM-Lee tumors removed from celecoxib treatment regained a growth rate similar to the control. Blood vessel density decreased and apoptotic cells increased in treated flank tumors. Diminished COX-2 expression and VEGF were observed in treated IOMM-Lee tumors. Mean plasma celecoxib levels were 845, 1540, and 2869 ng/mL, for low-, medium-, and high-dose celecoxib, respectively. CONCLUSIONS: Celecoxib inhibits meningioma growth in vivo at plasma levels achievable in humans. Celecoxib-treated tumors were less vascular with increased apoptosis. IOMM-Lee tumors treated with celecoxib showed decreased COX-2 and VEGF expression. COX-2 inhibitors may have a role in the treatment of recurrent meningiomas.

Animals↗
PubMed2006

Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms.

Hypoxia strongly up-regulates tissue factor and promotes plasma clotting by glioblastoma multiforme, but transcriptional mechanisms remain undefined. Here, we investigated the potential roles of early growth response gene-1 (Egr-1), Sp1, nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and hypoxia-inducible factor-1 (HIF-1) in the hypoxic regulation of tissue factor by glioblastoma multiforme cells in vitro. Hypoxia (1% O2) strongly induced Egr-1 mRNA within 1 hour and led to nuclear localization of Egr-1 protein. Using luciferase reporter plasmids in glioma cells, we found that hypoxia dramatically increased luciferase activity in cells with constructs containing Egr-1-binding sites but not in cells with constructs containing AP-1- or NF-kappaB-binding sites. Electrophoretic mobility shift assays revealed hypoxia-induced Egr-1, but not Sp1, binding to oligonucleotides containing the Egr-1/Sp1 motif of tissue factor gene promoter. Using an expression vector containing the minimal tissue factor promoter (-111 to +14 bp) and small interfering RNA (siRNA) directed at Egr-1 and Sp1 mRNAs, we found that Egr-1 was required for maximal hypoxic induction of promoter activity. Forced overexpression of Egr-1 but not Sp1 by cDNA transfection caused up-regulation of tissue factor in glioma cells under normoxia (21% O2), whereas siRNA directed at Egr-1 strongly attenuated hypoxia-induced tissue factor expression. To examine the effects of HIF-1alpha on tissue factor expression, we used glioma cells stably transfected with a HIF-1alpha siRNA expression vector and found that HIF-1alpha mRNA silencing did not affect tissue factor expression under hypoxia. We conclude that hypoxic up-regulation of tissue factor in glioblastoma multiforme cells depends largely on Egr-1 and is independent of HIF-1.

Cell Hypoxia↗
PubMed2006

Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures.

In this article, the author provides a brief description of the role of hypoxia in the tumorigenesis of gliomas and suggests potential ways of exploiting this role to design treatment modalities. Tumor hypoxia predicts the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiation therapy, invasive potential, and decreased patient survival for many human malignancies. Various methods of measurement of tumor hypoxia are discussed, including direct measurement and imaging methods. The role of hypoxia-responsive molecules, especially hypoxia-inducible factor-1 (HIF-1), in glioma tumorigenesis is explored. Treatment modalities regulated by hypoxia are proposed and some potential strategies reviewed. The progression of a low-grade astrocytoma to a glioblastoma multiforme may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of cells that overexpress hypoxia-responsive molecules, such as HIF-1. In this model, intratumoral hypoxia causes genetic changes that produce a microenvironment that selects for cells of a more aggressive phenotype.

Animals↗
PubMed2006

Inhibition of hypoxia inducible factor-1alpha (HIF-1alpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas.

INTRODUCTION: Hypoxia inducible factor-1alpha (HIF-1alpha) regulates vascular endothelial growth factor (VEGF), the presumed principal mediator of angiogenesis in malignant gliomas, under normal physiologic conditions. We examined the effect of HIF-1alpha on VEGF secretion, tumor growth, and angiogenesis in malignant gliomas. METHODS: We examined 175 human gliomas for expression of HIF-1alpha and its downstream-regulated proteins. HIF-1alpha expression and VEGF secretion in glioma cell lines under normoxia and hypoxia were examined using ELISA and Western blot. Malignant glioma cell lines were transfected with dominant-negative HIF-1alpha (DN-HIF-1alpha) expression vector or siRNA constructs against the HIF-1alpha gene. Growth studies were conducted on cells with the highest VEGF/HIF-1alpha inhibition isolated from stable transfected cell lines. MIB-1-labeling index and microvascular density (MVD) measurements were performed on the in vivo tumors. RESULTS: HIF-1 expression correlates with malignant glioma phenotype and was not confined to perinecrotic, pseudopalisading cells. VEGF and HIF-1 expression was high in glioma cell lines even under normoxia, and increased after exposure to hypoxia or growth factor stimulation. Cells transfected with DN-HIF-1alpha or HIF-1alpha siRNA demonstrated decreased HIF-1alpha and VEGF secretion. In vivo but not in vitro growth decreased in response to VEGF and HIF-1 inhibition. HIF-1 siRNA studies showed decreased VEGF secretion and in vitro and in vivo growth of glioma cell lines. MVD was unchanged but MIB-1 proliferation index decreased for both types of HIF-1 inhibition. CONCLUSIONS: VEGF and HIF-1alpha are elevated in malignant gliomas. HIF-1alpha inhibition results in VEGF secretion inhibition. HIF-1alpha expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment.

Adult↗
PubMed2006

Primary spinal yolk sac tumor with brain metastasis: case report and review of the literature.

OBJECT: Central nervous system primary germ cell tumors are typically pineal or suprasellar. Primary germ cell tumors of the spinal axis are very rare, with only a few case reports of germinomas and teratomas described in the literature. METHODS: We present the unique case of a 25-year-old woman with an intradural, extramedullary primary yolk sac tumor (YST) at and below the level of the conus medullaris. The patient was treated with a subtotal resection and within a month had rapid regrowth of her YST. She was subsequently treated with four cycles of chemotherapy (intravenous cisplatin and etoposide), 40-Gy fractionated focal external beam radiation to the spine, and consolidation with four additional cycles of chemotherapy (intravenous carboplatin, vinblastine, etoposide, and bleomycin). Despite an initial reduction in tumor size and clinical improvement in her neurologic exam, she re-presented a year after surgery with gross enlargement of her spinal tumor and CSF dissemination with metastasis to her brain. Despite further chemotherapy and radiotherapy, the patient died from her disseminated YST. CONCLUSIONS: This case demonstrates that primary YSTs may occur in the spine, and like their intracranial counterparts, are associated with poor prognosis and dissemination through the neuroaxis. When feasible (no evidence of CSF dissemination, metastasis, or multifocal disease), optimal treatment includes as extensive resection of tumor as possible followed by adjuvant chemotherapy and radiation. The authors review the available literature on the treatment of intracranial malignant germ cell tumors, extrapolated to apply to the much rarer spinal lesions.

Adult↗
PubMed2006

Development of contrast enhancement after long-term observation of a dysembryoplastic neuroepithelial tumor.

Dysembryoplastic neuroepithelial tumors (DNET) are usually benign lesions that arise in cortical regions and are discovered after new onset of seizure. These lesions have many different imaging characteristics. We report a patient with a presumed low-grade medial temporal lobe lesion that was followed for many years without any change in size or imaging characteristics. This previously non-enhancing tumor evolved to become contrast enhanced on routine imaging without apparent tumor growth. The patient underwent surgery, and the pathology was confirmed as a DNET with no atypical changes. This case demonstrates the potential that DNETs may exhibit a changing MRI pattern over time. Natural history, imaging characteristics, and management are reviewed.

Adult↗
PubMed2006

Variations of disseminated choroid plexus papilloma: 2 case reports and a review of the literature.

BACKGROUND: Choroid plexus papillomas are typically considered benign lesions, but histology is not always predictive of their behavior. These tumors can metastasize anywhere along the neuraxis and may be intraventricular, subarachnoid, or intraparenchymal. We present 2 cases that illustrate the wide diversity with which choroid plexus papillomas can disseminate. CASE DESCRIPTIONS: The patient described in case 1 had a primary fourth ventricular choroid plexus papilloma that produced diffuse cystic subarachnoid and leptomeningeal lesions. Patient 2 also had a primary fourth ventricular tumor but with subsequent suprasellar and spinal drop metastases. Patient 1 was treated with temozolomide, resulting in regression of symptoms including headache and dizziness. Patient 2 has been treated with several modalities, including radiation therapy and chemotherapy, with slowing of symptom progression. CONCLUSIONS: Variations of choroid plexus papilloma dissemination include intraventricular, subarachnoid, and leptomeningeal nodules or cystic lesions, and intraparenchymal locations. There is no consensus on the most effective treatment for choroid plexus papilloma metastases; surgical resection, chemotherapy, and radiation therapy may all yield benefits. The prognosis for patients with disseminated choroid plexus papilloma can range from prolonged stable disease and symptoms to death within months.

Adult↗
PubMed2006

Epidermal growth factor receptor gene amplification and protein expression in glioblastoma multiforme: prognostic significance and relationship to other prognostic factors.

Epidermal growth factor receptor (EGFR) overexpression occurs in a significant percentage of cases of glioblastoma multiforme (GBM), and amplification has been found in approximately 40% of these neoplasms. Controversy exists as to the prognostic significance of EGFR gene amplification: some reports have indicated that amplification is associated with a poor prognosis, while other authors have reported no relationship between gene amplification and prognosis. Some reports have found a poor prognosis to be associated with amplification of the EGFR gene in patients of all ages with GBM, while other authors have found EGFR amplification to be an independent predictor of prolonged survival in patients with GBM who are older than 60 years of age. The authors studied a series of 34 specimens (32 patients) with histologically proven GBM by immunohistochemistry for the presence of EGFR overexpression and by fluorescence in situ hybridization (FISH) for gene amplification of the EGFR gene. Results of these studies and data on patient age, sex, functional status, therapy, and survival were correlated to determine which variables were predictive of survival. p53 expression was also determined by immunohistochemistry and correlated with the other variables and survival.

Adult↗
PubMed2006

Surgical strategies for recurrent craniofacial meningiomas.

OBJECTIVE: Recurrent cranial base meningiomas are among the most difficult tumors to treat surgically. Although they are histologically benign, these tumors often invade through the cranial base into the infratemporal and pterygopalatine fossae. We reviewed our experience with these tumors to describe the natural history of these lesions as well as provide a possible treatment paradigm. METHODS: Between 2000 and 2004, seven patients with meningiomas recurring through the cranial base into facial structures were treated at the University of Utah. Five patients were treated with transcranial approaches only, and two were treated with a combination of transcranial and transfacial approaches. RESULTS: The average age of our patients (6 women, 1 man) was 55 years. The original site of tumor was the sphenoid wing in four patients, the middle fossa in two patients, and the left frontal region in one patient. The average interval between the most recent tumor resection and recurrence into the face was 9.9 years. The mean number of resections a patient underwent before invasion into the face was two. All but one patient had adjunctive therapy (including either radiation or chemotherapy) before recurrence into the face. CONCLUSION: Meningiomas that recur into facial structures present a unique treatment challenge. These lesions have a high rate of recurrence once they have invaded through the cranial base. Although combined approaches may be necessary to achieve a gross total resection, these lesions can often be reached using standard transcranial techniques.

Adult↗
PubMed2006

Subependymomas: an analysis of clinical and imaging features.

OBJECTIVE: Subependymomas are slow-growing, benign tumors usually found incidentally in the fourth ventricle at autopsy. They are typically associated with the ventricular system and become apparent clinically only when symptoms of hydrocephalus or mass effect develop. We review clinical, histological, and contemporary radiographic presentations of 16 subependymomas, including 2 intraparenchymal tumors. METHODS: We retrospectively evaluated eight patients with pathologically proven subependymomas. Initial magnetic resonance imaging and magnetic resonance spectroscopy were reviewed when available. Imaging was also available on eight outside subependymoma cases reviewed by our radiology department. RESULTS: Twelve of these subependymomas were intraventricular, one was in the posterior fossa, two were intraparenchymal, and one was an intramedullary spinal cord tumor. These lesions were hypo- to hyperintense on T1- and T2-weighted magnetic resonance imaging, with minimal to moderate enhancement. Initial complaints included headache, seizures, tingling sensations, and weakness. Among our eight patients who underwent gross total resection with no adjuvant therapy, no recurrences have been noted on follow-up magnetic resonance imaging. CONCLUSION: Subependymomas are rare, representing only 0.51% of all central nervous system tumors operated on during an 8-year period at the University of Utah. Clinical symptoms were associated with tumor location: intracranial masses caused headaches, seizures, and neurological complaints, and spinal cord locations resulted in neurological deficit. The authors review the clinical presentation, management, and contemporary radiographic appearance of this rare tumor.

Adult↗
PubMed2006

Calcium channel antagonists augment hydroxyurea- and ru486-induced inhibition of meningioma growth in vivo and in vitro.

OBJECTIVE: Although the chemotherapy drug hydroxyurea (HU) and the antiprogesterone mifepristone (RU486) have been used to treat meningiomas for which surgical and radiation therapies have failed, results have been disappointing. The addition of calcium channel antagonists (CCAs) to chemotherapeutic drugs enhances tumor growth inhibition in other tumor types, and the authors demonstrated that CCAs can block meningioma growth in vitro and in vivo. The purpose of this study was to test the effects of the addition of a CCA to HU or RU486 on meningioma growth. METHODS: Primary and malignant (IOMM-Lee) meningioma cell lines were treated with HU, RU486, or either of these plus diltiazem or verapamil. Assays for cell growth, apoptosis, and fluorescent-activated cell sorting were performed on in vitro cultures. Similar cell lines were implanted into nude mice and were treated with HU or RU486, in combination with a CCA. Tumors were analyzed by light microscopy, MIB-1, and factor VIII immunohistochemical staining studies. RESULTS: The addition of diltiazem or verapamil to HU or RU486 augmented meningioma growth inhibition by 20 to 60% in vitro. In vivo, tumors treated with combination drugs were smaller; and immunohistochemical analysis of the IOMM-Lee tumors showed a 10% decrease in the MIB-1 ratio (from 0.41 to 0.30) and an approximate 75% decrease in microvascular density. CONCLUSION: The addition of diltiazem or verapamil to HU or RU486 augments meningioma growth inhibition in vitro by inducing apoptosis and G1 cell-cycle arrest. The combination of HU and diltiazem inhibited the growth of meningiomas in vivo by decreasing proliferation and microvascular density. These results suggest a possible role for these drugs as an additional adjuvant therapy for recurrent or unresectable meningiomas.

Aged↗
PubMed2005

Molecular genetics of meningiomas.

In this article the authors provide a brief description of the current understanding of meningioma genetics. Chromosome 22 abnormalities, especially in the Neurofibromatosis Type 2 (NF2) gene, have been associated with meningioma development. Loss of heterozygosity of chromosome 22 occurs in approximately 60% of meningiomas; however, loss of NF2 gene function occurs in only one third of these lesions. This discrepancy supports the theory that a second tumor suppressor gene exists on chromosome 22, and the authors introduce several possible gene candidates, including BAM22, LARGE, INI1, and MN1 genes. Deletions of 1p have also been shown to correlate with meningioma progression. The genetic similarities and differences among sporadic, NF2-associated, pediatric, and radiation-induced meningiomas are discussed, with the observation that the nonsporadic meningiomas have a higher incidence of multiple chromosomal abnormalities at presentation. Ultimately, a better understanding of the molecular pathways of meningioma tumorigenesis will lead to new, successful treatments.

Animals↗
PubMed2005

Role of stereotactic radiosurgery in the treatment of brain metastases.

Stereotactic radiosurgery (SRS) is a highly conformal form of radiation therapy designed to deliver a high dose in a single treatment to the target volume while sparing adjacent normal tissues. Its role in the treatment of brain metastases continues to be defined, but the recently reported RTOG 95-08 trial demonstrated a survival benefit with the addition of SRS to whole-brain radiation therapy in select patients with a single brain metastasis, as well as a local control and palliative benefit in select patients with 1 to 3 brain metastases. The authors review the role of SRS in the treatment of brain metastases and discuss the use of SRS with or without whole-brain radiation therapy, optimal dose of SRS, SRS delivery methods, and selection of appropriate patients for SRS.

Brain Neoplasms↗
PubMed2005

Safety and feasibility of convection-enhanced delivery of Cotara for the treatment of malignant glioma: initial experience in 51 patients.

OBJECTIVE: We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (Peregrine Pharmaceuticals, Inc., Tustin, CA), a novel radioimmunotherapeutic agent, to patients with malignant glioma. METHODS: Between April 1998 and November 2002, 51 patients with histologically confirmed malignant glioma received Cotara by convection-enhanced delivery. Most patients (88%) were treated with Cotara targeting tumor volume-dependent, single or multiple administrations of activity ranging from 0.5 to 3.0 mCi/cm3 of baseline clinical target volume. Two weeks after infusion, single-photon emission computed tomographic imaging determined the spatial distribution of Cotara. Patients were followed for as long as 41 months (average follow-up, 5 mo). Safety was evaluated on the basis of incidence of procedure-related, neurological, and systemic adverse events. Feasibility was evaluated in a subset of patients on the basis of the correlation between the prescribed activity and the actual activity administered to the targeted region. RESULTS: Fifty-one patients, 37 with recurrent glioblastoma multiforme, 8 with newly diagnosed glioblastoma multiforme, and 6 with recurrent anaplastic astrocytomas, were treated. Average tumor volume was 36 +/- 27.6 cm3 (range, 5-168 cm3). Of the 67 infusions, 13 (19%), 52 (78%), and 2 (3%) delivered less than 90%, 100 +/- 10%, and more than 110%, respectively, of the prescribed administered activity to the targeted region. Treatment-emergent, drug-related central nervous system adverse events included brain edema (16%), hemiparesis (14%), and headache (14%). Systemic adverse events were mild. Several patients had objective responses to Cotara. CONCLUSION: The majority of Cotara infusions delivered between 90 and 110% of the prescribed administered activity to the targeted region. This method of administration has an acceptable safety profile compared with literature reports of other therapeutics delivered by convection-enhanced delivery.

Adolescent↗
PubMed2005

Ubiquitous expression of cyclooxygenase-2 in meningiomas and decrease in cell growth following in vitro treatment with the inhibitor celecoxib: potential therapeutic application.

OBJECT: Meningiomas are the second most common symptomatic primary central nervous system tumor in adults. Findings of epidemiological studies link meningiomas with a history of head trauma, indicating a causal relationship between the inflammatory response and meningioma tumorigenesis. Cyclooxygenase-2 (COX-2), an inducible inflammatory enzyme, converts arachidonic acid to prostaglandins, which have angiogenic, cell-proliferative, and antiapoptotic effects. The authors investigated COX-2 expression in meningiomas and the effects of celecoxib, a COX-2 inhibitor, on meningioma cell growth in vitro. METHODS: Four meningioma surgical specimens were immunohistochemically stained and graded (0 to 4) for COX-2. In addition, a Western blot analysis was performed to detect the presence of COX-2. Human meningioma cells grown in cell culture were treated with vehicle or celecoxib (0.25-1 mM). An immunohistochemical analysis of COX-2, a methylthiotetrazole cell proliferation assay, a TUNEL apoptosis assay, and a Western blot analysis for the proapoptotic protein BAX were performed in vitro. One hundred eleven (87%) of 128 benign meningiomas and six (86%) of seven atypical meningiomas displayed a high COX-2 immunoreactivity (Grade 4 staining). In the Western blot analysis all four surgical specimens (100%) stained positive for a 70-kD band consistent with COX-2. Celecoxib inhibited cell growth in a dose-dependent fashion and induced apoptosis by Day 2, with no change noted in the expression of the BAX protein. CONCLUSIONS: The COX-2 enzyme is universally expressed in meningiomas. Celecoxib inhibits meningioma growth in vitro in a dose-dependent fashion, with evidence of apoptosis. Inhibitors of COX-2 may have a role in the treatment of recurrent meningiomas.

Adult↗
PubMed2004

Cauda equina syndrome as a postoperative complication of lumbar spine surgery.

OBJECT: The term "cauda equina syndrome" (CES) has been used to describe the signs and symptoms in patients with compressive neuropathy of multiple lumbar and sacral roots. This syndrome is well known as an indication for surgical intervention in treating lumbar spine disease, but relatively unknown as a postoperative complication following surgery for disease. In this study the author describes two cases of CES that occurred following uneventful lumbar spine procedures--one microdiscectomy and one decompressive laminectomy. METHODS: Preoperative, operative, and postoperative management is discussed and the relevant literature reviewed. One patient suffered perineal numbness and bowel and bladder difficulty following a decompressive laminectomy. Postoperative imaging studies were negative for residual lesion and the treatment goal pursued was partial long-term resolution of symptoms. The second patient had progressive numbness and weakness in the lower extremities. Results of urgent postoperative magnetic resonance imaging studies were inconclusive and repeated exploration was performed within hours of the initial procedure. The patient made a full recovery, although the intraoperative findings did not reveal a clear cause of the patient's symptoms. CONCLUSIONS: Postoperative symptoms of partial or complete CES represent a medical emergency, especially if they are progressive. It is necessary to perform urgent postoperative imaging in patients, but the results are not always helpful. Surgical exploration is warranted if a mass lesion is demonstrated on imaging studies or if symptoms progress and the disease origin is not clear based on available information.

Adult↗
PubMed2004

Meningioma of the jugular foramen: glomus jugulare mimic and surgical challenge.

OBJECTIVES: Meningiomas involving the jugular foramen are rare lesions, with approximately 34 cases reported in the English literature. Clinically, these tumors mimic the more common glomus jugulare tumor. After surgical resection, meningiomas have worse cranial nerve outcomes and higher recurrence rates than glomus tumors. There is controversy regarding the selection of surgical approach, particularly with regard to management of the facial nerve. A reliable means of accurate preoperative diagnosis would help surgical planning and patient counseling. STUDY DESIGN: We present a series of six consecutive large jugular foramen meningiomas resected by a single surgeon from 1996 to 2002. METHODS: Retrospective case series (chart review). RESULTS: The preoperative diagnosis was correct in nearly all (6/7) cases on the basis of the characteristic imaging findings seen with a combination of temporal bone dedicated computed tomography and high-resolution enhanced magnetic resonance imaging. Five of six patients had lateral facial nerve rerouting (infratemporal fossa Fisch type A), and three patients also had posterior rerouting (transcochlear approach with division of greater superficial petrosal nerve). Total tumor removal was accomplished in 83%. One patient suffered recurrence over a mean follow-up period of 2.5 years. New postoperative vocal cord palsies occurred in 50% of patients, and all required vocal cord medialization. At 1 year, 50% of patients had normal or near normal (House-Brackmann I or II) facial function. Postoperative cerebrospinal fluid leaks occurred in two patients, and both eventually required ventriculoperitoneal shunts. CONCLUSIONS: Meningiomas involving the jugular foramen are surgically challenging tumors that pose unique diagnostic issues. The majority of these lesions can be completely resected. A relatively high postoperative complication rate, which can be controlled with appropriate intervention, is seen with these surgeries.

Cranial Nerve Diseases↗