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Brian T Ragel

Publications and source records attributed to Brian T Ragel.

16 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

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

Failure of cerebrospinal fluid shunts: part I: Obstruction and mechanical failure.

Ventricular shunts are commonly employed to treat children with hydrocephalus. Complications from shunts are common and can present with a variety of signs and symptoms. This pair of reviews discusses the common findings in patients with shunt malfunction, including physical examination and imaging findings. Part I of the series discusses obstruction and mechanical failure of shunts; Part II discusses overdrainage, loculation, and abdominal complications of shunts. An understanding of the presentation and etiology of shunt dysfunction is critical for neurologists and pediatricians who often are the first to evaluate and triage these children.

Cerebrospinal Fluid Shunts↗
PubMed2006

Failure of cerebrospinal fluid shunts: part II: overdrainage, loculation, and abdominal complications.

Complications from cerebrospinal fluid shunts are common and can present with a variety of signs and symptoms. In this second part of a two-part review, shunt overdrainage, loculation of the ventricular system in patients with shunts, and abdominal complications related to ventriculoperitoneal shunts are discussed. Familiarity with these types of shunt failure is essential for neurologists and pediatricians because they are often the first to evaluate and triage these children.

Abdomen↗
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

Self-assessment in neurological surgery: the SANS wired white paper.

OBJECTIVE: Periodic self-assessment is an important component of postgraduate medical education and certification. The Self-assessment in Neurological Surgery (SANS) examination has a history of usefulness for neurosurgical written and oral board examination preparation. The SANS Wired test represents a recreation of the original SANS test using an Internet-based platform. Advanced functionality and contemporary content have been added to meet the increasing requirements for demonstration of lifelong learning and self-assessment as part of the Maintenance of Certification (MOC) process. METHODS: A needs assessment was performed before the development of SANS Wired. Postexamination surveys for users obtaining continuing medical education credit were analyzed for user satisfaction with the platform and content. Test-item performance metrics were analyzed based on first-attempt responses. The economic value of SANS Wired as a component of the mandatory MOC process was evaluated. RESULTS: The needs assessment identified a deficiency of available content and mechanisms for neurosurgery-specific self-assessment. As of October 15, 2005, a total of 588 individuals had subscribed to SANS Wired (28 institutional licenses accounted for 229 users). Eighty-eight post-test surveys were analyzed for user satisfaction. Ninety-four percent of responses indicated that learning objectives had been met. Initial performance metrics show an average point-biserial discrimination index of +0.18 for all test items. CONCLUSION: The SANS Wired system seems to be an effective platform for neurosurgical self-assessment and is acceptable to users. The system satisfies, in part, two of the four required components of MOC, namely, periodic self-assessment and demonstration of cognitive expertise. It is endorsed by the American Board of Neurological Surgeons for MOC.

Certification↗
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↗
PubMed2006

Surgical shunt infection: significant reduction when using intraventricular and systemic antibiotic agents.

OBJECT: Infection represents the most common serious complication of shunt surgery, and typically its incidence ranges between 5 and 15%, despite the use of systemic antibiotic agents. Because systemic antibiotic medications generally penetrate the cerebrospinal fluid (CSF) poorly, the authors investigated, in a controlled study, whether the addition of intraventricular antibiotic treatment decreases the incidence of perioperative infection in adult patients. METHODS: Data pertaining to all CSF shunt procedures conducted at the authors' institution during an 11-year period were reviewed. Perioperative infection was defined as culture-positive CSF and the clinical presence of infection-related symptoms occurring within 90 days of surgery. All patients underwent intraoperative systemic antistaphylococcal antibiotic therapy. Before May 16, 1999, the senior author (R.H.S.) also administered 4 mg of gentamicin intraventricularly at surgery (Group I); thereafter, 10 mg of vancomycin was additionally administered (Group II). Other neurosurgeons at this institution did not use intraventricular antibiotic therapy, and their patients served as additional controls in identical time periods (Groups III and IV). A total of 802 shunt procedures were performed in 534 patients. Control infection rates were 5.4% (eight of 147) in Group I; 6.2% (nine of 145) in Group III; and 6.7% (18 of 267) in Group IV. With the combination of systemic antibiotic and intraventricular gentamicin and vancomycin (Group II), the infection rate fell significantly to 0.4% (one of 243). No complications were noted in association with intraventricular antibiotic administration. CONCLUSIONS: The combination of intraventricular gentamicin and vancomycin with systemic antibiotic therapy significantly decreased the incidence of perioperative shunt infection. It is presumed that intraventricular antibiotic therapy extends prophylactic antibiotic coverage into the CSF and prevents bacterial seeding.

Adolescent↗
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

Intraventricular tanycytic ependymoma: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Tanycytic ependymomas are a rare ependymoma subtype showing a marked predilection for the spine, with only a few reports of supratentorial tumors. We present a case of a tanycytic ependymoma arising from the lateral and third ventricle. CLINICAL PRESENTATION: The patient was a 55-year-old woman who complained of intermittent, progressively worsening dysequilibrium for several months. The neurologic exam in the neurosurgery clinic was without deficit. INTERVENTION: MRI of the brain revealed a 3-cm, minimally enhancing lesion centered in the superior aspect of the third ventricle. The tumor involved the left wall of the third ventricle, the septum pellucidum, and the anterior horn of the left lateral ventricle. Surgery was recommended for diagnosis and to prevent obstructive hydrocephalus. A gross total resection was achievedvia a transcallosal approach. Postoperatively, the patient remained neurologically intact. CONCLUSION: The long-term prognosis for tanycytic ependymomas is the same or slightly better than for other ependymoma subtypes. The current treatment plan includes gross total resection followed by radiologic surveillance. Repeat resection or radiation treatment will be recommended in the event of recurrence.

Cerebral Ventricle Neoplasms↗
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

Prophylaxis for deep venous thrombosis in neurosurgery: a review of the literature.

The incidence of deep venous thrombosis (DVT) and subsequent pulmonary embolism (PE) in patients undergoing neurosurgery has been reported to be as high as 25%, with a mortality rate from PE between 9 and 50%. Even with the use of pneumatic compression devices, the incidence of DVT has been reported to be 32% in these patients, making prophylactic heparin therapy desirable. Both unfractionated and low-molecular-weight heparin have been shown to reduce the incidence of DVT consistently by 40 to 50% in neurosurgical patients. The baseline rate for major intracranial hemorrhage (ICH) following craniotomy has been reported to be between 1 and 3.9%, but after initiation of heparin therapy this rate has been found to be as high as 10.9%. Therefore, neurosurgeons must balance the risk of PE against the increased risk of postoperative ICH from prophylactic heparin for DVT. The authors review the literature on the incidence of DVT and PE in neurosurgical patients, focusing on the incidence of ICH related to the use of unfractionated and low-molecular-weight heparin in this patient population.

Heparin↗
PubMed2004

Pituitary carcinoma: a review of the literature.

Pituitary carcinomas, defined as distant metastases of a pituitary neoplasm, are rare; fewer than 140 reports exist in the English literature. The initial presenting pituitary tumor is usually a secreting, invasive macroadenoma, with adrenocorticotropic hormone (ACTH)--and prolactin (PRL)--secreting tumors being the most common. The latency period between the diagnosis of a pituitary tumor and the diagnosis of a pituitary carcinoma is 9.5 years for ACTH-producing lesions and 4.7 years for PRL-secreting tumors. Survival after documentation of metastatic disease is poor; 66% of patients die within 1 year. Treatment options include additional surgery, radiotherapy, and chemotherapy, all of which are associated with poor results. Future studies will focus on identifying those invasive pituitary tumors most likely to metastasize and treating them aggressively before they progress to pituitary carcinomas.

Adrenocorticotropic Hormone↗