Expression of entry receptor nectin-1 of herpes simplex virus 1 and/or herpes simplex virus 2 in normal and neoplastic human nervous system tissues.

Herpes simplex virus 1 and/or Herpes simplex virus 2 (HSV) are important pathogens of human nervous system (NS) and genetically modified HSV strains have been proposed as vectors for gene therapy targeting the brain and brain tumors. Nectin-1 is an immunoglobulin-like adhesion molecule that participates in the formation of synapses and serves as an entry receptor for HSV. The expression pattern of nectin-1 in normal human NS and brain tumors is not well understood. To better understand the nectin-1 expression in normal and neoplastic human NS, immunohistochemistry was used to detect the nectin-1 expression in sections of normal human brain, spinal cord and trigeminal and dorsal root ganglia (n=10) and in sections of primary NS neoplasms (n=22). In normal human NS, nectin-1 was detected in the soma and processes of central and peripheral neurons, in ependymal cells, choroid plexus epithelial cells, vascular endothelial cells and meningothelial cells. Oligodendrocytes, astrocytes, vascular smooth muscle cells, and Schwann cells showed variable immunoreactivity. Among tumors, schwannoma, fibrous meningioma, and medulloblastoma were nectin-1 negative. Oligodendroglioma, ependymoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma multiforme and meningothelial meningioma showed weak focal nectin-1-positivity. Ganglion cells of ganglioglioma were strongly positive. These studies provide novel information about the expression of nectin-1 in normal and neoplastic NS, and thus may lead to a better understanding of cell targeting by HSV during HSV-induced neurological disease and during a HSV-based gene therapy.

Fibrinolytic therapy in intraventricular hemorrhage.

OBJECTIVE: To review the literature concerning intraventricular administration of fibrinolytic agents to treat patients with intraventricular hemorrhage (IVH). DATA SOURCES: An extensive literature search (MEDLINE, EMBASE, Conference Proceedings) was conducted to identify articles in English published between 1966 and May 2000 pertaining to the pathophysiology of IVH and its treatment by intraventricular administration of recombinant tissue plasminogen activator (alteplase) or urokinase (u-PA). The bibliographies of selected identified articles were also screened for publications not found in the computerized search. STUDY SELECTION: All pertinent publications were reviewed and considered. Those describing the intraventricular administration of fibrinolytic agents to patients with IVH were included. DATA SYNTHESIS: IVH has a poor prognosis, partly due to the mass effect of blood clots on the ventricular walls. The cerebrospinal fluid has a limited fibrinolytic system. Therefore, clots may remain in the ventricles for months after a hemorrhage. The management of IVH is primarily directed at controlling intracranial pressure through an external ventricular drain, but this catheter often becomes occluded by coagulated blood. To overcome this problem, and to dissolve the residual blood clot, investigators have administered alteplase or u-PA directly into the ventricles of patients with IVH. Complications of this therapy include infection and possible rebleeding. Clinical studies of fibrinolytic therapy for IVH have found a 30-35% reduction in mortality with treatment, but to date, have not clearly documented improved neurologic outcome of the survivors. CONCLUSIONS: Fibrinolytic therapy with alteplase or u-PA may be life-saving in severe cases of IVH. Yet many technical issues remain to be resolved, such as the optimal dose, frequency, method, timing, and duration of administration of the agent. Additional randomized, double-blind, placebo-controlled studies need to be performed so that the true value of this therapy can be assessed.

Progress in the diagnosis and treatment of patients with meningiomas. Part I: diagnostic imaging, preoperative embolization.

BACKGROUND: The clinical management of patients with meningiomas has changed over the past decade. Change has occurred because of a variety of factors including improved diagnostic imaging, better results with surgery and interventional neuroradiology, and the advent of radiosurgery. Recent clinical studies from several disciplines have provided new information on topics germane to the management of patients with meningiomas. Collecting this information into a series of review articles would have significant value, primarily for neurosurgeons. OBJECTIVE: The purpose of this first paper is to bring together and evaluate the available data on: 1) noninvasive diagnostic imaging of meningiomas, including magnetic resonance imaging (MRI), computed tomography (CT) scanning, and MR angiography, venography and spectroscopy; 2) the present role of cerebral angiography in patients with meningiomas; and 3) the current status of preoperative embolization for these tumors. RESULTS: With the advent of MR technology, the quality of diagnostic imaging for meningiomas has improved dramatically, and this is reflected in more sophisticated preoperative planning. MR imaging provides improved delineation of dura and sinus involvement, and even information about a tumor's consistency. Meningiomas have characteristic neuroimaging features, yet other lesions can still mimic a meningioma. MR venography can be used to demonstrate sinus patency, but intra-arterial cerebral angiography gives the most precise information concerning the degree of tumor involvement of critical vascular structures, and the anatomy of arterial feeders. In trained hands, superselective catheterization for preoperative embolization of meningiomas is feasible, and seems to be reasonably safe. CONCLUSIONS: MR imaging, CT scans, and cerebral angiography can currently be used in a complementary fashion to diagnose, evaluate, and treat patients with meningiomas, with a high degree of clinical certainty. Angiography is used to determine the sites of blood supply to the tumor, which can then be attacked first intraoperatively, making tumor removal easier. Preoperative embolization continues to have value in selected patients, including those in whom the blood supply to the tumor is difficult to access at the time of surgery.

Therapeutic effects of sodium butyrate on glioma cells in vitro and in the rat C6 glioma model.

OBJECTIVE: Preliminary in vitro studies have indicated that sodium butyrate inhibits the proliferation of cultured glioma cells and induces cellular differentiation, making it potentially useful as a therapeutic agent for patients with glioblastoma multiforme. The purpose of this study was to expand on the preliminary research by investigating the effects of sodium butyrate on multiple cell lines, explanted cells from glioblastoma tumor specimens, and in vivo in the rat C6 glioma brain tumor model. METHODS: Four malignant glioma cell lines (A-172, T98G, U118MG, and C6) and two primary cell cultures derived from human glioblastoma tumor specimens were treated with 2 mmol/L sodium butyrate for up to 72 hours. Sodium butyrate-induced effects on cell morphology, proliferation, cell cycle distribution, migration, glial fibrillary acidic protein staining, and S100beta protein content were determined. For in vivo studies, a total of 64 male Wistar-Furth rats underwent operations to implant C6 glioma cells stereotactically or were used as controls. The rats were treated with escalating doses of sodium butyrate by microinfusion with Alzet minipumps (Durect Corp., Cupertino, CA). RESULTS: Sodium butyrate treatment in vitro produced changes in morphology and glial fibrillary acidic protein expression indicative of cellular differentiation. In cell lines and explanted cells, sodium butyrate consistently inhibited glioblastoma cell proliferation (to 51 +/- 6% that of controls) and migration (to 46 +/- 17%). Intratumoral infusion of 40 mmol/L sodium butyrate prolonged the survival of Wistar-Furth rats with intracerebral C6 tumors (P = 0.013) without detectable toxicity. CONCLUSION: These data support further consideration of direct interstitial infusion of sodium butyrate in a Phase I clinical study for patients with recurrent glioblastoma multiforme.

Gene therapy for brain tumors.

"Gene therapy" can be defined as the transfer of genetic material into a patient's cells for therapeutic purposes. To date, a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer for modulating the immune system, enzyme prodrug ("suicide gene") therapy, oncolytic therapy, replacement/therapeutic gene transfer, and antisense therapy. For malignant glioma, gene-directed prodrug therapy using the herpes simplex virus thymidine kinase gene was the first gene therapy attempted clinically. A variety of different strategies have now been pursued experimentally and in clinical trials. Although, to date, gene therapy for brain tumors has been found to be reasonably safe, concerns still exist regarding issues related to viral delivery, transduction efficiency, potential pathologic response of the brain, and treatment efficacy. Improved viral vectors are being sought, and potential use of gene therapy in combination with other treatments is being investigated.

Gene therapy for brain tumors: the fundamentals.

BACKGROUND: Over the past two decades, significant advances have been made in the fields of virology and molecular biology, and in understanding the genetic alterations present in brain tumors. The knowledge gained has been exploited for use in gene therapy. OBJECTIVE: The purpose of this article is to present an introduction to the field of brain tumor gene therapy for the practicing clinician. RESULTS: A variety of gene therapy strategies have now been used in the laboratory and in clinical trials for brain tumors. They can be divided into five categories: 1) gene-directed enzyme prodrug ("suicide gene") therapy (GDEPT); 2) gene therapy designed to boost the activity of the immune system against cancer cells; 3) oncolytic virus therapy; 4) transfer of potentially therapeutic genes--such as tumor suppressor genes--into cancer cells; and 5) antisense therapy. GDEPT is the strategy that has been most extensively studied. CONCLUSIONS: To date, gene therapy has been found to be reasonably safe and concerns related to adverse events such as insertional mutagenesis have not been realized. Although patients have not been cured, the development of this therapy could still be considered to be at an early stage. Current research is addressing factors that could be limiting the successful clinical application of gene therapy, which remains an intriguing experimental option for patients with malignant brain tumors.

The role of interstitial BCNU chemotherapy in the treatment of malignant glioma.

BACKGROUND: Use of interstitial BCNU wafers in the treatment of malignant glioma is currently a controversial topic among neurosurgeons. Initial clinical studies indicated implantation of BCNU wafers into the postoperative tumor bed to be an acceptably safe, partially effective treatment for glioblastoma multiforme. Yet a more recent study has put the efficacy of this treatment in doubt, and there are potential complications associated with BCNU wafer use. OBJECTIVE: This article presents a review of the information presently available on BCNU wafers-both pro and con-to aid in the clinical decision-making process. The article focuses on studies of clinical efficacy (for initial use as well as in the setting of recurrent tumor), complications associated with BCNU wafers, and the experimental data, particularly related to BCNU penetration into the brain. RESULTS: Animal studies and computer simulations have shown that the depth of penetration of BCNU from wafers is limited. Yet in actual clinical use, the interstitial pressure within the wafer-laden tumor bed might be higher, convective flow greater, and delivery of BCNU to the brain more significant than predicted. CONCLUSION: Based on current information, use of interstitial BCNU wafers continues to be an option for treating malignant glioma. Additional clinical studies of BCNU wafers are currently underway.

Tumor bed cyst formation after BCNU wafer implantation: report of two cases.

BACKGROUND: Interstitial implantation of BCNU wafers is currently used to treat glioblastoma multiforme. Known complications of BCNU wafer implantation include abnormalities of wound healing (including CSF leak), edema formation, and intracranial infection. The purpose of this report is to alert neurosurgeons to an additional potential side effect: formation of a cystic mass within the implanted tumor bed. CASE PRESENTATIONS: Two patients are described: a 54-year-old male, who presented with a large right parieto-occipital mass, and a 47-year-old woman with a large right frontal lobe tumor. Both tumors were found on initial craniotomy to be glioblastoma multiforme; both recurred rapidly despite radiation therapy. Patients were treated with a second craniotomy for tumor resection and placement of BCNU wafers. After implantation, the first patient did well for 6 weeks, then developed lethargy, headaches, and vomiting. CT scan showed a large cyst at the craniotomy site; this required reoperation for drainage. The second patient had a seizure, deterioration of mental status, and progressive hemiparesis 10 days after wafer implantation. CT scan again showed that a large cyst had formed in the area of the previous surgery; she also required reoperation. In each case, minimal tumor and no evidence of infection were found. Within a few more weeks, each patient succumbed to progressive disease. CONCLUSIONS: The hypodense, roughly spherical cysts clearly demonstrated clinically significant mass effect, and required reoperation despite treatment with high-dose corticosteroids. Neurosurgeons should be alert to the possibility of tumor bed cyst formation in patients treated with interstitial BCNU wafers.

The history of neurological surgery at Northwestern University.

The residency program in neurological surgery at Northwestern University was founded in 1924 by Loyal Davis and was formally accredited by the American Board of Neurological Surgery in 1946. Allen Kanavel, mentor to Davis, was one of the original members of the Society of Neurological Surgeons. Five individuals have served as chief of neurosurgery at Northwestern: Davis, Paul Bucy, Anthony Raimondi, Albert Butler, and H. Hunt Batjer. Davis was the first surgeon west of the Appalachians to limit his work to neurosurgery. Between 1954 and 1963, there were two independent neurosurgery residency programs at Northwestern, one headed by Davis and the other by Bucy. A master surgeon and superb teacher, Bucy trained more than 65 residents and became one of the greatest authors and leaders in the field of neurosurgery. Neurosurgical training at Northwestern has traditionally emphasized excellence of patient care, strong resident and student teaching, and basic science research. Through the years, a major strength of the program has been its clinical volume and diversity. Four hospitals have played major roles in the program: Northwestern Memorial Hospital (created by the merger of Chicago Wesley Memorial Hospital and Passavant Memorial Hospital), Children's Memorial Hospital, Evanston Hospital, and the Veterans Administration Lakeside Hospital. This article traces the development of neurological surgery at Northwestern, with an emphasis on its historical background and the contributions of Kanavel, Davis, and Bucy. The present philosophy and structure of the training program and the program's future under the direction of Batier are also described.

Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells.

The purpose of this study was to characterize the effects of sodium 4-phenylbutyrate (phenylbutyrate) on the proliferation, morphology, migration and invasiveness of malignant glioma cells in vitro. Phenylbutyrate is a novel differentiating and cytotoxic compound used clinically with low toxicity in the treatment of beta-thalassemia, sickle cell anemia and urea cycle disorders. Preliminary clinical trials testing phenylbutyrate as an anti-cancer agent have included patients with malignant glioma. However, little information is available regarding the effects of phenylbutyrate on glioma cells, particularly with respect to the expression of genes important in the pathogenesis of glial malignancy. In experiments reported here, glioma cell lines and explant cells from a tumor patient were exposed to 2, 4 and 8 mM phenylbutyrate and compared to untreated control cells. The effect on cellular proliferation was assessed using cell counts and DNA flow cytometry. Changes in morphology were evaluated using vimentin staining. Scratch and Matrigel assays were performed to assess changes in cellular migration and invasiveness. Finally, Northern blot analysis was used to study c-myc and urokinase expression. Phenylbutyrate was found to have dose-dependent inhibitory effects on glioma cell proliferation, morphology, migration, invasiveness and c-myc and urokinase expression. Mean growth-inhibitory (IC50) phenylbutyrate concentrations ranged from 0.5 mM for T98G cells to 5.0 mM for explant cells. Phenylbutyrate treatment reduced % S phase cells, increased % G0/G1 cells, and produced morphologic changes consistent with induction of differentiation. 24 hours of treatment with 4 mM phenylbutyrate resulted in a 50% reduction in migration and invasiveness. Northern blots showed a decrease in urokinase and c-myc expression at non-cytotoxic doses. We conclude that phenylbutyrate is a promising candidate compound for treating patients with malignant glioma.

Molecular characterization of glioblastoma cell differentiation.

OBJECTIVE: Induction of cellular differentiation continues to be an attractive therapeutic strategy for malignant glioma. The purpose of this study was to develop a convenient in vitro model system for glioblastoma differentiation and to then characterize it using conventional techniques and flow cytometry. METHODS: A subline of U138 MG cells ("U138B") was treated with 0 to 4 mmol/L sodium butyrate (or serum deprivation) for up to 96 hours. Cells were initially studied for effects on proliferation, morphology, and glial fibrillary acidic protein (GFAP) staining. Northern blot and immunoblot analyses of c-myc expression were performed. Multiparameter flow cytometry was then used to analyze GFAP, c-myc protein, and total cellular protein fluorescence and to relate them to changes in cell cycle distribution. RESULTS: Butyrate treatment produced a dose-dependent inhibition of cellular proliferation and changes in morphology, GFAP staining, and c-myc expression consistent with a differentiation response. Detailed flow cytometric studies, including subpopulation analysis, showed that during 72 hours of treatment with 2 mmol/L butyrate, mean GFAP fluorescence increased to 420%, whereas c-myc protein decreased to 45 +/- 13% and total cellular protein increased to 181 +/- 17%. The effects of butyrate were distinct from those of serum deprivation and were not simply the result of cells shifting into Gzero/G1. CONCLUSION: The butyrate-induced responses of the U138B cell line provide a convenient model system for studying the molecular events accompanying the differentiation of glioblastoma cells. Multiparameter flow cytometry is a useful technique for characterizing such differentiation.

Current status of radiation therapy and radiosurgery in the treatment of intracranial meningiomas.

Complete surgical removal, including resection of involved bone and dura, is curative of intracranial meningiomas in approximately 90% of cases. However, complete removal may entail unwarranted risk if the tumor involves or is adjacent to critical vascular or neural structures. In addition, it is possible for fragments of tumor to "evade" resection, even with the use of meticulous microsurgical technique. Because of this, clinicians may be faced with the decision of whether to offer or recommend radiation therapy or radiosurgery to a patient with a residual or recurrent meningioma. For many years, it has been recommended that external-beam radiation therapy be considered in the treatment of incompletely resected or malignant meningiomas. More recently, the role of radiosurgery as adjuvant or even primary therapy for meningiomas has attracted considerable attention. This article presents a review of the literature on postoperative radiotherapy of intracranial meningiomas.

Flow cytometric applications of Sulforhodamine 101 as a fluorescent stain for total cellular protein.

In this paper, the use of Sulforhodamine 101 (SR 101; C.I. 14318) as a fluorescent stain for flow cytometric determinations of total cellular protein (TCP) is described. Flow cytometric quantification of TCP fluorescence can provide a valuable analytical parameter for assessing both changes occurring in overall cellular protein content, such as in response to blast transformation, and heterogeneity in cellular size within a specimen, such as a tumor. Very little information is available in the literature pertaining to the use of SR 101 as a protein stain. Like fluorescein isothiocyanate (FITC), SR 101 can be excited at 488 nm; however, it binds ionically and has an emission maximum at 600 nm, which is advantageous in certain staining and filter combinations. In this report, the utility of SR 101 staining is demonstrated using pokeweed mitogen-stimulated lymphocytes and cycloheximide- and dimethylsufloxide-treated cells. Single, two- and three-color flow cytometric applications are possible, using SR 101 in combination with 4',6-diamidino-2-phenylindole (DAPI) and/or FITC.

Adult-onset presentation of Dandy-Walker variant in siblings.

BACKGROUND: The Dandy-Walker syndrome and Dandy-Walker variant usually present as isolated cases of hydrocephalus in pediatric patients. METHODS AND RESULTS: THis paper consists of a case report of the adult onset of symptoms in two sisters having Dandy-Walker variant. Such an occurrence has never before been reported in the medical literature. Both patients presented with headaches and progressive neurologic deficit. On computed tomography (CT scan) of the head, both were found to have hydrocephalus, with hypoplasia of the inferior vermis. Both patients were treated successfully with ventriculoperitoneal shunting. A third sister, with a similar history, elected not to undergo CT scanning or surgical treatment. CONCLUSIONS: Variants of the Dandy-Walker syndrome may occasionally present clinically in the adult age group. Such an occurrence in siblings is consistent with an underlying genetic etiology.

Analysis of c-erbB2 protein content of human glioma cells and tumor tissue.

This study was designed to determine whether or not overexpression of the c-erbB2 protein plays a role in the etiology of human gliomas. The c-erbB2 gene codes for a 185 kDa cell membrane glycoprotein (gp185c-erbB2), which is similar to the receptor for epidermal growth factor. In initial studies, four human glioma cell lines (A-172, U118MG, U138MG and SW608) were used to develop techniques for detecting and quantifying gp185c-erbB2, using immunofluorescence microscopy, immunoblot analysis and flow cytometry. A-172 cells were found to have the highest content of gp185c-erbB2. More detailed studies utilizing A-172 cells indicated that cellular gp185c-erbB2 content changed little in response to conditions affecting cellular proliferative status, including serum deprivation, growth in low glucose medium and treatment with dimethyl sulfoxide. Ten human glioma specimens were then analyzed for cellular gp185c-erbB2 fluorescence and DNA content, using A-172 cells as a biological standard. Results indicated that gp185c-erbB2 was expressed at levels comparable to that of A-172 cells in many specimens, and at a very high level in one specimen. These data reiterate the problem of the molecular heterogeneity of human gliomas and indicate that gp185c-erbB2 may have a role in at least a subset of malignant glial tumors.

A quantitative analysis of modulations occurring in cellular c-myc protein content, %S phase and growth balance under growth-inhibitory conditions.

The c-myc protein was one of the first proto-oncogene products to be linked to the increased proliferative activity of neoplastic cells. However, few studies have attempted to quantify changes occurring in cellular c-myc protein content in response to growth-inhibitory conditions, or to relate such changes to total cellular protein (TCP) levels, %S phase cells and/or cellular growth balance. Knowledge of such relationships is important for determining the biological relevance of the c-myc protein as a marker for proliferating cells. In this study, a dual-laser flow cytometric technique employing three fluorescent dyes was used to quantify cellular changes in c-myc protein, TCP, DNA and growth balance in exponentially-growing and serum deprived U118MG, A-172 and HL-60 cells. Results obtained by flow cytometry were verified using other techniques. Changes in c-myc protein content were found to occur independently of changes in TCP, %S phase or cellular growth balance, and varied between cell lines. These results indicate that cellular c-myc protein determinations convey information that is unique from other indicators of cellular growth and proliferation. Such information may be linked, however, to the nutritional status and origin of the cells being assayed.

Evaluation of the Pelorus Stereotactic Surgical System for CT-guided stereotactic brain biopsy.

The Pelorus Stereotactic Surgical System is a relatively new, commercially available device that can be used to perform computed tomography (CT)-guided stereotactic brain biopsy. It has been promoted as being a relatively simple and inexpensive system that is more rapid, less cumbersome, and generally easier to use than conventional stereotactic frames. In this paper, we describe the Pelorus System, and report on its diagnostic accuracy and associated morbidity, based on our experience with 49 consecutive patients in two institutions. Patients ranging from 7 months to 85 years of age had CT-guided stereotactic biopsy, primarily for diagnosis of lesions deep within the cerebral hemispheres. Two transfrontal biopsies of the lateral pons were also done. Satisfactory tissue for histologic diagnosis was obtained in 42 of 49 patients (86%). In this series, there were two deaths in the immediate postoperative period, unrelated to the use of the Pelorus System. One patient suffered a transient neurologic deficit, which resolved over a period of 3 days. Although the Pelorus System has some limitations, we found it easy to use, well-tolerated by patients, and useful for performing CT-guided stereotactic biopsy.