Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study.

BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population.

Retrospective review of MEG visual evoked hemifield responses prior to resection of temporo-parieto-occipital lesions.

Visual evoked cortical magnetic field (VEF) waveforms were recorded from both hemifields in 21 patients with temporo-parieto-occipital mass lesions to identify preserved visual pathways. Fifteen patients had visual symptoms pre-operatively. Magnetoencephalographic (MEG) VEF responses were detected, using single equivalent current dipole (ECD), in 17/21 patients studied. Displaced or abnormal responses were seen in 15 patients with disruption of pathway in one patient. Three of 21 patients had alterations in the surgical approach or the planned resection based on the MEG findings. The surgical outcome for these three patients suggests that the MEG study may have played a useful role in pre-surgical planning.

Therapy-related myelodysplastic syndrome (t-MDS) in a patient with anaplastic astrocytoma: successful treatment with allogeneic bone marrow transplant.

OBJECTIVE: and importance Therapy-related myelodysplastic syndrome (t-MDS) is a rare and typically fatal complication of therapy for cancer, including brain tumors. We report successful therapy of t-MDS that developed after treatment for an anaplastic astrocytoma. CLINICAL PRESENTATION: t-MDS developed four and one-half years after successful therapy (resection, radiation and chemotherapy) administered for a cerebral anaplastic astrocytoma in a 34-year-old patient. INTERVENTION: The patient was treated with allogeneic bone marrow transplant (BMT) for t-MDS. CONCLUSION: She is alive three years after BMT with no evidence of brain tumor and in complete remission from t-MDS. To our knowledge, this is the first report of allogeneic BMT administered for t-MDS in an adult brain tumor patient. Clinicians must be alert to the development of t-MDS following chemotherapy for brain tumors and initiate appropriate treatment promptly.

Historical perspective on the Department of Neurosurgery at the Henry Ford Hospital.

The Henry Ford Hospital (HFH) was founded in 1915 as a philanthropic gift from Henry Ford, the automobile magnate and inventor of the Model T. The hospital and its organizational structure represented a nonsectarian facility that would provide care for all members of society. The system was patterned after the newest and most modern medical centers at the time in Europe, Canada, and the United States, including the German Krankenhauser, the Johns Hopkins Hospital, the Mayo Clinic, and the Peter Bent Brigham Hospital in Boston. The HFH grew into the Henry Ford Health System in the 1970s to 1990s, with the acquisition of other hospitals, the development of a multiple-region-based clinic system through southeastern Michigan, and the development of comprehensive, vertically integrated health care systems. The Division of Neurosurgery at HFH was established by Albert Crawford in 1926. The tradition of training residents in neurosurgery began in 1946, and the residency training program was accredited by the American Board of Neurosurgery in 1954. In 1970, the Division of Neurosurgery of the Department of Surgery was combined with the Division of Neurology to create the joint Department of Neurology and Neurosurgery. A separate Department of Neurosurgery was established in 1981. Four individuals have served as chairmen of the Department of Neurosurgery at HFH, i.e., Albert Crawford (1926-1952), Robert Knighton (1952-1978), James Ausman (1978-1991), and Mark Rosenblum (1992 to the present). During the 1980s and 1990s, HFH evolved into the vertically integrated, regionally distributed Henry Ford Health System. Under the current direction of Dr. Rosenblum, the Department of Neurosurgery at HFH has grown to include 11 full-time neurosurgeons, 2 neuro-oncologists, and 3 investigators with Ph.D. degrees and has recently expanded into three additional hospitals in southeastern Michigan, paralleling the growth of the system. The faculty annually treats more than 2,000 cases in all neurosurgical subspecialties, ranging from neuro-oncological surgery, cranial base surgery, radiosurgery, cerebrovascular surgery, epilepsy surgery, treatment of movement disorders, pain and spasticity surgery, pediatric neurosurgery, and neurotrauma treatment to complex instrumentation of the spine. This article chronicles the history of the Henry Ford Health System and the Department of Neurosurgery, its research endeavors, and its residency training program.

Survival of patients with synchronous brain metastases: an epidemiological study in southeastern Michigan.

OBJECT: It has been suggested that synchronous brain metastases (that is, those occurring within 2 months of primary cancer diagnosis) are associated with a shorter survival time compared with metachronous lesions (those occurring more than 2 months after primary cancer diagnosis). In this study the authors used data obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results program to determine the incidence of synchronous brain metastases and length of survival of patients in a defined population of southeastern Michigan residents. METHODS: Data obtained in 2682 patients with synchronous brain metastases treated between 1973 and 1995 were reviewed. Study criteria included patients in whom at least one brain metastasis was diagnosed within 2 months of the diagnosis of primary cancer and those with an unknown primary source. The incidence per 100,000 population increased fivefold, from 0.69 in 1973 to 3.83 in 1995. The most frequent site for the primary cancer was the lung (75.4%). The second largest group (10.7%) consisted of patients in whom the primary site was unknown. The median length of survival was 3.2 months. There was no significant difference in the median survival of patients with primary lung/bronchus and those with an unknown primary site (3.3 months and 3.2 months, respectively). CONCLUSIONS: Patients who present with synchronous lesions have a poor prognosis, and the predominant cause of death, in more than 90% of cases, is related to systemic disease; however, despite poor median survival times, certain patients will experience prolonged survival.

The role of protein kinase Calpha in U-87 glioma invasion.

To investigate the hypothesis that protein kinase Calpha (PKCalpha) is functional glial tumor cell invasion, stable PKCalpha sense and antisense transfected U-87 cell lines were established and PKCalpha expression characterized by Western blot and PKC activity assays. Invasion assays including barrier migration (Koochekpour et al., Extracellular matrix proteins inhibit proliferation, upregulate migration and induce morphological changes in human glioma lines. Eur. J. Cancer, 1995, 31, 375-380; Merzak et al., CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res., 1994, 54, 3988-3992; Merzak et al., Cell surface gangliosides are involved in the control of human glioma cell invasion in vitro. Neurosci. Lett., 1994, 177, 11-16), and spheroid confrontation were used to study the relationship between PKCalpha expression and invasiveness. PKCalpha overexpressing clones show increased barrier migration (1.5x) relative to the control transfected clones. PKCalpha inhibited clones exhibited reduced invasiveness, to < 50%. In coculture with PKCalpha overexpressing clones, the remaining normal fetal rat brain aggregate volume was significantly decreased (up to 200%) but 90% of the initial brain volume was left in PKCalpha inhibited clone in the rat brain aggregate tumor spheroid confrontation. This effect was not associated with significant growth inhibition. We conclude that expression of PKCalpha in glioma-derived cell lines appears to be central to glioma invasion in vitro.

Role of extracellular matrix in tumor invasion: migration of glioma cells along fibronectin-positive mesenchymal cell processes.

OBJECTIVE: The major morbidity of glioma lies in its infiltrative growth. One of the major patterns of this invasive growth is the formation of Scherer's secondary structures associated with the blood vessels and the leptomeninges. To better understand the role of extracellular matrix (ECM) in glioma invasion, we investigated in vitro the interaction between glioma cells and the meningeal mesenchymal tissue from the brain. As an aid to this study, ECM in glioma cell line spheroids was compared with that in primary fetal brain aggregates. METHODS: To study the expression of ECM, four glioma cell lines (U-87 MG, U-251 MG, AN1/lac-z, and HF-66) and primary cells from fetal rat brain were grown as spheroids and monolayers. To sudy the role of ECM in glioma invasion, spheroids from the glioma cell lines were grown over established cultures of fetal meningeal and mesenchymal tissue. Expression of fibronectin, laminin, tenascin, collagen VI, and chondroitin sulfate proteoglycan was studied by immunofluorescence. RESULTS: Expression of ECM by the spheroids was variable. U-87 MG expressed most of the ECM components robustly, whereas AN1/lac-z expressed them all weakly. Fetal rat brain aggregates produced minimal ECM. In cocultures of glioma spheroids and fetal meningeal mesenchymal tissue, individual cells from the glioma spheroids that expressed least fibronectin (AN1/lac-z and U-251 MG) migrated along the fibronectin-positive mesenchymal cells in the culture dish. Cells from the other two lines (U-87 MG and HF-66) that expressed fibronectin strongly did not demonstrate such behavior. None of the other ECM components showed a similar association; mesenchymal cells did not express laminin as strongly as fibronectin, and glioma cells were not observed to align with the laminin-positive structures. CONCLUSION: This study suggests that fibronectin may play a key role in intracerebral invasion of glioma cells.

Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma.

UNLABELLED: It has long been recognized that some patients with low-grade astrocytoma may survive for many years, whereas in others the disease follows a more malignant course resulting in a short survival time, usually due to malignant transformation into higher-grade tumors. OBJECT: The aim of this study was to investigate angiogenesis in the initial biopsy specimen of tumor tissue as a biological marker to identify patients with low-grade astrocytoma who are at high risk of malignant tumor transformation or death. METHODS: Tumor tissue was studied in 74 consecutively treated adult patients in whom a diagnosis of diffuse supratentorial hemispheric histologically proven fibrillary low-grade astrocytoma was made and who underwent surgery between January 1972 and January 1994. Studies were conducted using monoclonal antibodies to the antigens of the proliferation-associated Ki-67 (MIB-1), factor VIII, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF). The overall 5-year survival rate for the entire patient population was 65%, with a median survival time of 7.5 years. The total mean follow-up period was 6.1 years. All tumors showed a low proliferative potential at the time of the initial operation, as demonstrated by an MIB-1 labeling index of less than 1.5%. Patients with more than seven microvessels in tumor tissue (29 cases) had a shorter survival time (mean 3.8 years) than those with seven or fewer microvessels (mean survival 11.2 years). This difference in survival times was significant by univariate (p = 0.001) and stepwise multivariate analyses (p < 0.001). Tumors with a larger number of microvessels also had a greater chance of undergoing malignant transformation (p = 0.001). Similarly, significant staining for VEGF was correlated with shorter survival times when using univariate (p = 0.003) and multivariate (p = 0.008) analyses and with a greater chance of malignant transformation (p = 0.002). Patients with tumors staining positive for VEGF (39 individuals) had a median survival time of 5.3 years, and those with tumors negative for VEGF (35 patients) had a median survival time of 11.2 years. No association was observed between bFGF, EGF, and survival or malignant transformation. The stepwise multivariate analysis included histological and clinical variables simultaneously. CONCLUSIONS: The authors have shown that microvessel density and VEGF levels are independent prognostic markers of survival in fibrillary low-grade astrocytoma. This finding leads them to propose that fibrillary diffuse low-grade astrocytoma is not a single pathological entity but is composed of a spectrum of tumors with differing propensities to undergo malignant transformation that is at least partly based on their inherent angiogenic potential.

Neurocytoma in the cerebellum. Case report.

A neurocytoma is a central nervous system tumor composed of small cells with features of neuronal differentiation; it typically occurs in the periventricular region, close to the septum pellucidum and the foramen of Monro. In this article, the authors report the case of a neurocytoma located in the cerebellum, which to their knowledge is the first reported case of its kind. The finding of a neurocytoma at a nonclassic location refutes the theory that this tumor has its origins in subependymal progenitor cells, unless an ectopic location of progenitor cells is invoked to explain the occurrence of a neurocytoma away from the ventricles. On the basis of this case, the authors suggest that neurocytomas should be added to the differential diagnosis of mass lesions in the supratentorial intraventricular regions as well as in the posterior fossa.

Inhibitory effects of CAI in glioblastoma growth and invasion.

While distant metastases are rare in patients with primary brain malignancies, local growth and invasion are common and life-threatening. Regional infiltration is responsible for the failure of local therapies, resulting in tumor recurrence, progression, and death. The process of invasion requires cellular adhesion, local proteolysis and migration. CAI, carboxyamide-triazole, is an anticancer agent developed as an inhibitor of selected signal transduction pathways. Studies on the effects of CAI on human glioblastoma growth and invasiveness are presented. CAI inhibited proliferation of 6 of 8 cell lines tested in a dose-dependent fashion in vitro (IC50 range 1.5-44 microM), with no effect on the U373 line. Inhibition of adhesion to tissue culture plastic was observed for the H4, T98G, and U373 lines pretreated with CAI; H4 and T98G were inhibited in adhesion to collagen type IV. Incubation with CAI decreased production of the 72 kDa and 92 kDa type IV collagenases in all cell lines, ranging from 16 to 93% inhibition. These observations show that the effects of CAI on cell line behavior can vary between lines that are similar in origin. Despite variability in the inhibitory effects for proliferation and adhesion, CAI is consistently able to inhibit the invasive phenotype of all glioma cell lines in vitro using the Matrigel barrier assay (IC50 range 13-28 microM). These observations suggest that CAI may have benefit in the treatment of gliomas and high grade astrocytomas.

Spinal epidural abscess: evaluation of factors influencing outcome.

OBJECTIVE: The goal of this study was to critically evaluate the predictive efficacy of various clinical factors in spinal epidural abscess influencing outcome after surgical and/or medical treatment. METHODS: A retrospective analysis of 41 cases of spinal epidural abscess treated at Henry Ford Hospital between 1984 and 1992 was performed. RESULTS: Thirty patients underwent open surgery and received antibiotic therapy, and 11 patients received medical treatment alone. After a mean follow-up period of 20.9 months (range, 4-45 mo), 24 patients (58.5%) had no or minimal deficits, 9 patients (22%) had severe paresis or plegia and/or bowel/bladder dysfunction, and 8 patients (19.5%) died. Univariate analysis revealed patient age, degree of thecal sac compression, spinal location, surgical findings, and septic presentation to be significantly associated with outcome. In multiple logistic regression analysis, increasing age and degree of thecal sac compression were the only factors with significant independent association with poor outcome (P = 0.01 for both). A simple grading system (Grades 0-III) was developed, with patient age, degree of thecal sac compression, and duration of symptoms as the determining criteria. The incidence of poor outcome for patients with Grade 0 was 0%, compared to 85.7% for patients with Grade III. CONCLUSION: We conclude that long-term outcome after treatment of spinal epidural abscess can be predicted with the use of the proposed grading scheme. Surgical drainage plus parenterally administered antibiotics remains the recommended treatment, although medical treatment alone can also be used for certain patients.

Migratory patterns of lac-z transfected human glioma cells in the rat brain.

Malignant brain tumors are characterized by extensive tumor-cell infiltration into the normal brain tissue. The present work describes the migratory behavior of human glioma cells transplanted into the adult rat brain with the aim of exploiting the extent of active cell migration and passive cell displacement within the central nervous system. To detect every transplanted tumor cell, a stably bacterial beta-galactosidase (lac-z) transfected human glioma cell line was used. To distinguish between an active cell migration process and passive cell displacement, rat brains were also implanted with inert fluorescent polystyrene microspheres and the distribution of tumor cells and microspheres was studied 1 hr and 3 days after implantation. One hour after implantation the tumor cells were strictly localized at the implantation site. However, 3 days after implantation, both tumor cells and microspheres showed an extensive distribution within the brain. Confirming earlier neuropathological and experimental studies, it is shown that the lac-z-transfected glioma cells had the capacity to move within the Virchow-Robin and subarachnoid spaces. However, since fluorescent microspheres were also found in these areas, this spread of tumor cells may be primarily mediated by the extensive cerebrospinal fluid flow that exists within the brain. Three days after implantation, the glioma cells also showed an active migration over the corpus callosum. In comparison, the fluorescent microspheres showed only limited spread along the callosal body. It is concluded that the bacterial lac-z gene can be stably transfected into human glioma cells and, since every tumor cell can be visualized within the brain, this model provides a tool for studying the mechanisms behind tumor-cell invasion of the brain.

Cavernous malformation of the mammillary bodies: neuropsychological implications. Case report.

The authors present the first documented case of a cavernous malformation of the mammillary bodies. A 34-year-old woman presented with a 2-month history of headaches and acute memory changes. Magnetic resonance imaging studies demonstrated a retrochiasmatic interpeduncular lesion that was initially thought to be a craniopharyngioma. Operative resection confirmed the diagnosis of a cavernous malformation. This particular case is unique in its destruction of the mammillary bodies and presents further evidence of the relationship of these regions to memory. This report is also the first to document results of pre- and postoperative neuropsychological evaluations that specifically address the memory deficits created by destruction of the mammillary bodies.

Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis.

The poor prognosis of patients with malignant gliomas is at least partially due to the invasive nature of these tumors. In this study, the authors investigated the possibility that the cysteine protease cathepsin B (CB) is a participant in the process of glial tumor cell invasion. To accomplish this, an immunohistochemical analysis was made of the localization of antibodies to CB in biopsies of five specimens of normal brain, 16 astrocytomas, 33 anaplastic astrocytomas, and 33 glioblastomas multiforme. Staining was scored according to the percentage of positive cells and the intensity of the stain, graded from 0 to 3+. Staining for CB was not seen in any of five samples of normal brain except for occasional neuronal cell bodies and microglia. Only five (31%) of 16 astrocytomas showed a small percentage of positive cells (0.01%-3%) that were stained in a light, diffuse cytoplasmic pattern (1+). Twenty-nine (87.8%) of 33 anaplastic astrocytomas showed positive light, granular staining in 2% to 40% of cells. In anaplastic astrocytoma, the staining within a tumor was heterogeneous with intensities of 1+ (17%), 1+ to 2+ (29%), or 2+ (55%). In contrast, all 33 (100%) glioblastomas were positive in 10% to 90% of cells. The staining was present in a coarse, granular pattern with an intensity of 2+ (12%) or 3+ (88%). Tumor cells infiltrating into brain adjacent to malignant gliomas stained positively in 26 cases that could be evaluated for glioblastoma multiforme; these invading cells frequently followed penetrating blood vessels as typical "secondary structures of Scherer." Moderate to intense CB staining associated with endothelial proliferation in high-grade tumors was also observed, especially in regions of tumor infiltration into adjacent normal brain. These results provide evidence consistent with the hypothesis that CB is functionally significant in the process of tumor invasion and angiogenesis in the clinical progression of the malignant phenotype in astrocytes.

Improved management of multiple brain abscesses: a combined surgical and medical approach.

Bacterial brain abscesses occur in approximately 1500 to 2500 patients each year in the United States. Multiple abscesses have been noted in 10 to 50% of these patients. The goal of this study was to better define the roles of surgery and medical management in patients harboring multiple brain abscesses and to develop an algorithmic approach to the treatment of these complex patients. Between 1976 and 1992, 16 patients with multiple brain abscesses were treated by a single physician (M.L.R.). The ages of the patients ranged from 1.5 to 73 years (median, 47 yr). In all patients, a diagnosis of multiple abscesses was made by computed tomography (15 patients) or magnetic resonance imaging (1 patient) brain scans. The number of abscesses per patient ranged from 2 to 30, and the abscesses were located in all regions of the brain. Thirteen received a combination of antibiotics and surgical drainage, and three received antibiotics only. Surgery was performed on abscesses larger than 2.5 cm or on those situated in critical areas of the brain or causing significant mass effect. Excision and open aspiration via craniotomy and stereotactic aspiration were analyzed on the basis of the location of the lesion and infecting organism. Any abscess that enlarged after 2 weeks of antibiotics or that failed to shrink after 3 to 4 weeks of antibiotics was again aspirated or excised. Forty-three surgical procedures were performed in 13 patients, and 8 (62%) of the patients operated on required more than one surgical procedure. No significant morbidity was observed in any of the surgical procedures. Antibiotics were administered intravenously for an average of 6 to 8 weeks and were adjusted according to organism type and sensitivity to antibiotics. One patient (6%) died, and the remaining 15 patients had resolution of all abscesses and good neurological recovery within 6 months. On the basis of these results, we propose a combined surgical and medical approach to the treatment of patients with multiple brain abscesses. We recommend the aggressive surgical drainage of all abscesses larger than 2.5 cm in diameter, combined with 6 to 8 weeks of intravenous antibiotics. Biweekly computed tomography or magnetic resonance imaging is necessary to closely monitor patients for evidence of abscess growth or failure to resolve despite antibiotics, prompting another operation. The application of this combined approach should yield cure rates of more than 90% in patients with multiple brain abscesses, a result similar to that expected when treating patients with solitary lesions.

Cathepsin B expression and localization in glioma progression and invasion.

The poor prognosis of human malignant gliomas is due to their invasion and recurrence, the molecular mechanisms of which remain poorly characterized. We have accumulated substantial evidence implicating the cysteine protease cathepsin B in human glioma malignancy. Increases in cathepsin B expression were observed throughout progression. In primary brain tumor tissue, transcript abundance (Northern blot analysis) increased in low-grade astrocytoma to high-grade glioblastoma from 3- to 6-fold, respectively, above normal brain levels. This increase correlated with increases in protein abundance (from + to ) as measured by immunohistochemistry. Furthermore, in glioblastoma cell lines increases in transcript abundance (ranging from 3- to 12-fold) were accompanied by increases in enzyme activity (44-133 nmol/min x mg protein). Altered subcellular localization was observed both immunohistochemically and by indirect immunofluorescence confocal microscopy and was found to correlate with increased grade. In addition, this increase in cathepsin B expression and altered subcellular localization correlated with histomorphological invasion and clinical evidence of invasion as detected by magnetic resonance imaging. These data support the hypothesis that cathepsin B plays a role in human glioma progression and invasion.

Development of an in vitro extracellular matrix assay for studies of brain tumor cell invasion.

Invasion of brain by tumor cells is an inherent feature of the malignant phenotype. Assays to quantitate invasiveness should provide a powerful tool to investigate this phenomenon. We have developed a modified in vitro assay to measure tumor cell invasion, attachment, and chemotaxis using a barrier of the complex basement membrane Matrigel on gelatin-coated filters. Within 5 hours, 7.8% of U251MGp and 2.6% of SF126 human malignant glioma cells invaded the Matrigel and filter, compared with 0.8% of normal human leptomeningeal cells. The extent of invasion was directly proportional to incubation time and filter pore size and inversely proportional to the Matrigel concentration. Cells from exponentially growing U251MGp cultures invaded more readily (10.9%) than cells from plateau-phase cultures (2.3%); however, labeling studies with bromodeoxyuridine showed that quiescent cells and rapidly dividing cells were equally capable of invading. This suggests that the mechanisms underlying invasion by malignant glioma cells are distinct from those underlying proliferation and indicates the need for therapy aimed specifically at invasive behavior. In a practical application of this assay to test a potential anti-invasive strategy, monoclonal antibodies to the beta subunit of an integrin receptor mediating attachment to the extracellular matrix inhibited invasion by U251MGp cells in a dose-dependent manner. This assay should allow evaluation of the cellular and molecular basis of brain tumor progression and perhaps aid the development of rationally designed drugs that limit tumor invasion. It may also allow prediction of the clinical behavior of neoplasms in individual patients.

AIDS and the neurosurgeon--an update.

Over the past decade, acquired immunodeficiency syndrome (AIDS) has become the leading public health crisis in the United States, Western Europe, and Africa. Despite improvements in the diagnosis and treatment of AIDS-related disorders, the number of people infected with the human immunodeficiency virus (HIV-1) continues to grow, requiring a greater proportion of limited financial, medical, and human resources. Since nearly one half of symptomatic AIDS patients have neuropathologic disease, clinicians must be aware of the myriad neurologic manifestations of AIDS and use the most effective methods to diagnose and treat them. The work-up of the AIDS patient with neurologic symptoms includes a careful history and physical examination, laboratory studies, and radiographic imaging. Gadolinium-enhanced magnetic resonance (MR) imaging has become the radiographic screening study of choice. MR imaging can be used to predict which patients should undergo stereotactic biopsy before an empirical trial of antitoxoplasmosis therapy. Any patient with a mass lesion that does not respond to empirical therapy for toxoplasmosis should also undergo biopsy to exclude another treatable disorder. While the number of patients with neurological complications can be expected to increase in the near future, better imaging techniques may obviate the need for biopsy in many of these patients. The increasing threat of HIV-1 infection in the workplace requires meticulous care both in and out of the operating room to minimize accidental exposure of health-care workers.

Effect of pharmacologic doses of zinc on the therapeutic index of brain tumor chemotherapy with carmustine.

To evaluate the potential differential effect of pretreatment with pharmacologic doses of the trace element zinc on the chemosensitivity of glioma cells and bone marrow cells for carmustine (BCNU), we performed in vitro and in vivo studies of zinc toxicity as well as of the combined treatment with zinc and the anticancer drug. We studied the in vitro effects on established human and rat glioma cell lines using a microcolorimetric growth assay and on murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage. Zinc exposures of up to 100 microM for 120 h did not influence the growth of six of seven human glioma cell lines. Only U87MG demonstrated statistically significant toxicity during high zinc exposure (100 microM over 120 h). Dose-response growth curves generated for BCNU did not show protection against the anticancer agents by a 48-h pretreatment with different zinc concentrations. The clonogenic capacity of bone marrow cells was slightly reduced by in vitro culture for 24 and 48 h. Although this effect appeared to be more prominent in the presence of zinc supplementation, overall a statistically significant inhibition was seen only after exposure to a concentration of 100 microM zinc over 48 h. As compared with chemotherapy alone, in vitro pretreatment with 50 microM zinc over 48 h followed by chemotherapy resulted in an increased number of colony-forming unit-granulocyte monocyte (CFU-GM): CFU-GM increased by a factor of 2 for BCNU (60 microM x 2 h). This statistically significant in vitro chemoprotection would translate into a dose-protection factor of 1.5, i.e., for the same level of myelosuppression, zinc pretreatment would allow administration of a 50% increased dose of BCNU. The in vivo studies were performed in an s.c. xenograft model of the human glioma cell line U87MG in athymic mice. The maximal tolerable pretreatment with zinc was determined to be a 10-day course of daily i.p. injections of 10 mg/kg ZnCl2. The subsequent i.p. administration of the dose lethal to 10% of the mice (LD10) and of a 1.5 x LD10 dose of BCNU resulted in less bone marrow toxicity in pretreated animals than in non-zinc-pretreated mice as determined in a CFU-GM assay. Glioma colony-forming efficiency (CFE) assays, on the other hand, did not show any zinc-related difference in the BCNU sensitivity of U87MG.(ABSTRACT TRUNCATED AT 400 WORDS)