Differential gene expression profiling in human brain tumors.

Gene expression profiling of three human temporal lobe brain tissue samples (normal) and four primary glioblastoma multiforme (GBM) tumors using oligonucleotide microarrays was done. Moreover, confirmation of altered expression was performed by whole cell patch clamp, immunohistochemical staining, and RT-PCR. Our results identified several ion and solute transport-related genes, such as N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-2 receptors, GABA(A) receptor subunits alpha3, beta1, beta2, and beta3, the glutamate transporter, the glutamate/aspartate transporter II, the potassium channel K(V)2.1, hK(V)beta3, and the sodium/proton exchanger 1 (NHE-1), that are all downregulated in the tumors compared with the normal tissues. In contrast, aquaporin-1, possibly aquaporins-3 and -5, and GLUT-3 message appeared upregulated in the tumors. Our results also confirmed previous work showing that osteopontin, nicotinamide N-methyltransferase, murine double minute 2 (MDM2), and epithelin (granulin) are upregulated in GBMs. We also demonstrate for the first time that the cytokine and p53 binding protein, macrophage migration inhibitory factor (MIF), appears upregulated in GBMs. These results indicate that the modulation of ion and solute transport genes and heretofore unsuspected cytokines (i.e., MIF) may have profound implications for brain tumor cell biology and thus may identify potential useful therapeutic targets in GBMs.

Transcriptional patterns of growth factors and proto-oncogenes in human glioblastomas and normal glial cells.

To document over-expression of proto-oncogenes in tumors, it is necessary to determine the level of expression in the progenitor normal tissue. These studies compare the levels of nuclear transcription of a series of growth-factor related genes and proto-oncogenes in human glioblastoma cell lines with those in three normal glial cell populations. The unusual finding was that levels in the three normal glial cell populations varied considerably for several genes and thus overexpression of a specific gene in a tumor cell when compared to just one normal glial cell population would not necessarily represent overexpression. In this study, we compared the level of 17 genes in 7 tumors to the highest level of each gene found in any of three normal glial cell populations. Over-expression of PDGF-B in 4/7 glioblastoma cell lines, EGFR in 1/7, neu in 1/7 IGF-2 in 1/7 and ros in 2/7 was observed. The variation observed in the normal glial cell populations emphasizes the possibility that the normal glial cell populations represent different glial cell lineages and/or stages of differentiation and that the tumors could have arisen from different normal glial cells. Matching lineages of normal and tumor cells, probably by monoclonal antibody reactions, may be required to accurately define over-expression.

Urologic consequences of myelodysplasia and other congenital abnormalities of the spinal cord.

Spina bifida and other congenital abnormalities of the spinal cord are relatively common (1 per 1000 births). Early urologic evaluation to determine the extent of neurologic involvement of the lower urinary tract is essential. Urodynamic studies are important in determining voiding pressure and leak pressure and in classifying the type of detrusor and sphincter dysfunction. Therapy is directed toward preservation of the upper tracts. Many nonsurgical (clean intermittent catheterization and anticholinergic drugs) and surgical procedures allow the child to be continent and maintain a normal upper urinary tract. The importance of follow-up is stressed because neurourologic changes frequently occur, and prompt treatment or change of therapy is essential. Today, children with spina bifida are leading healthy, productive lives. A continued multidisciplinary approach to their care is important.

Intracranial tumor in infants: characteristics, management, and outcome of a contemporary series.

Since 1980, 22 patients less than 2 years of age have been treated for intracranial tumors at our institution. The most common presentation was elevated intracranial pressure associated with ventriculomegaly (73%). The diagnosis was made by computed tomography or magnetic resonance imaging and confirmed surgically in every case. In 68% of cases, the tumor involved midline structures in the central nervous system. Tumors were infratentorial in 29% of patients less than 1 year of age and in 60% of those more than 1 year of age. Most tumors were either primitive neuroectodermal tumors (41%, 7 of 9 located in midline posterior fossa structures) or astrocytomas (27%, 5 of 6 located in the hypothalamus, chiasm, or optic nerve). Twenty patients had gross or subtotal tumor resection. Surgical mortality and neurological morbidity were 10% and 5%, respectively. Of 5 patients who underwent a second operation for tumor recurrence, 3 demonstrated a change in the pathological features of the tumor from those of the original diagnosis. Of 10 surgical survivors with malignant tumors, 8 received chemotherapy and 5 radiation therapy. Radiation was not administered before 1 year of age. The overall 1-year survival was 70%, and 2-year survival was 58%. Two-year survival for benign and malignant tumors was not significantly different. We think that the interdisciplinary efforts directed toward the treatment of these tumors has improved survival and that all children should be offered entry to a research protocol and aggressive treatment.

Quadriplegia secondary to hematoma after lateral C-1, C-2 puncture in a leukemic child.

Epidural, subdural, and intramedullary hemorrhage developed after lateral cervical (C-1, C-2) puncture in a thrombocytopenic patient with meningeal leukemia and increased intracranial pressure. Aggressive platelet support before the procedure did not prevent the hemorrhagic complication. Complete recovery from total motor paralysis with respiratory arrest followed immediate surgical decompression and continuing platelet support. The potential dangers of otherwise minor procedures in compromised patients are reiterated. Neurological recovery as seen here argues for immediate surgical intervention with the development of such potentially life-threatening events.

Small bowel obstruction secondary to incomplete removal of a ventriculoperitoneal shunt: case report.

Small bowel obstruction and partial enteral loss secondary to entrapment by an incompletely removed ventriculoperitoneal shunt is a previously unreported hazard.

Ventral brain stem compression in pediatric and young adult patients with Chiari I malformations.

OBJECTIVE: The purposes of this study were as follows: 1) to determine the incidence and degree of ventral brain stem compression (VBSC) in pediatric and young adult patients with Chiari I malformations, and 2) to correlate VBSC with other imaging and clinical factors to help determine what amount of VBSC is successfully treated with a posterior decompressive procedure alone. METHODS: The magnetic resonance images and clinical histories of 40 pediatric and young adult patients with Chiari I malformations were analyzed for subjective grade of VBSC, distance of tonsillar descent, odontoid's relation to Chamberlain's and Wackenheim's line, clival length, foramen magnum diameter, syringomyelia, scoliosis, hydrocephalus, presenting clinical status, treatment, and outcome. To objectively measure the amount of ventral cervicomedullary encroachment by the odontoid and its investing tissues into the rostral spinal canal, a line (B-C2) was drawn between the basion and posteroinferior aspect of the C2 body on a sagittal magnetic resonance image. A line perpendicular to this line, pB-C2, was drawn through the odontoid tip to the ventral dura, and a distance (representing the amount of ventral canal encroachment) was measured. RESULTS: Flattening and distortion of the ventral brain stem were present in 48 and 28% of the patients, respectively. Only two patients had basilar invagination by traditional definitions. pB-C2 measurements correlated with the subjective grade of VBSC (P < 0.05), age, and distance of tonsillar descent (P < 0.05). Eye motion abnormalities and upper cervical osseous anomalies were associated with higher pB-C2 measurements. All patients with a pB-C2 measurement of less than 9 mm were treated successfully with posterior fossa decompression alone despite any subjective VBSC. Some patients with pB-C2 measurements greater than 9 mm had either preoperative neurological deficits or neurological worsening after posterior fossa decompression referable to VBSC. CONCLUSION: Patients with a pB-C2 measurement of less than 9 mm do not require treatment directed at VBSC. In select patients with pB-C2 measurements of 9 mm or greater, reduction of VBSC may be prudent before posterior fossa decompression.

Neonatal ventriculosubgaleal shunts.

OBJECTIVE: We report on 32 neonates treated with ventriculosubgaleal (VSG) shunts to determine VSG shunt survival and associated complications. METHODS: Between 1993 and 1997, 37 VSG shunts were placed in 32 neonates when the cerebrospinal fluid (CSF) or the abdomen was considered unsuitable for ventriculoperitoneal shunt placement. In each child, a ventricular catheter was attached to 3 cm of a closed-end peritoneal tube via a right-angle connector, which drained into a surgically created subgaleal pocket. RESULTS: The causes of hydrocephalus were as follows: intraventricular hemorrhage (IVH) in 20 neonates, meningitis/ventriculitis in 6, IVH and infection in 2, and other causes in 4. The mean postconception age at the time of VSG shunt insertion was 37.2 weeks (33.1 wk in the IVH group), and the mean weight was 2227 g (1724 g in the IVH group). The average preoperative head circumference was 33.6 cm. The average survival of these 37 VSG shunts (five children had two VSG shunts) was 35.1 days. The complications were as follows: one CSF leakage occurred when sutures were removed; one catheter fell into the ventricle and required removal, and one child died immediately after VSG shunt revision. There were no VSG shunt infections. All surviving children followed for a minimum of 4 months after insertion of a VSG shunt (n = 24) have required a ventriculoperitoneal shunt. Mean follow-up from the time of first VSG shunt insertion was 21.6 months. Four children died as a result of causes unrelated to the VSG shunt. CONCLUSION: VSG shunts offer a simple, effective, and relatively safe means of temporizing hydrocephalus, and they avoid the need for external drainage or frequent CSF aspiration in these medically unstable infants until the CSF characteristics and abdomen are acceptable for ventriculoperitoneal shunting.

Nonaccidental pediatric head injury: diffusion-weighted imaging findings.

OBJECTIVE: Diffusion-weighted imaging (DWI) reveals nonhemorrhagic posttraumatic infarction hours to days before conventional computed tomographic scanning or magnetic resonance imaging (MRI). We evaluated the diagnostic utility of DWI in children with nonaccidental head trauma. METHODS: The medical records and imaging examinations obtained between January 1998 and May 2000 for all children less than 2 years of age with presumed or suspected nonaccidental head injury were reviewed retrospectively. Twenty children who had undergone DWI within 5 days of presentation were included in the study. Computed tomographic scans, conventional MRI sequences, and DWI combined with apparent diffusion coefficient (ADC) maps were evaluated. RESULTS: Eleven girls and nine boys (median age, 5 mo) were studied. Eighteen children had presumed nonaccidental head trauma, and two children had suspected nonaccidental head trauma. Of the 18 children with presumed nonaccidental trauma, 16 (89%) demonstrated abnormalities on DWI/ADC, as compared with neither of the two children with suspected nonaccidental trauma. In 13 (81%) of 16 positive cases, DWI revealed more extensive brain injury than was demonstrated on conventional MRI sequences or showed injuries not observed on conventional MRI. DWI combined with ADC maps allowed better delineation of the extent of white matter injury. DWI/ADC abnormalities in the nonaccidental head-injured children were likely to involve posterior aspects of the cerebral hemispheres, with relative sparing of the frontal and temporal poles. Severity on DWI correlated significantly with poor outcome (P < 0.005). CONCLUSION: DWI has broad applications in the early detection of infarction in children with nonaccidental head injury and enhances the sensitivity of conventional MRI. In the patients in this study, early DWI provided an indicator of severity that was more complete than any other imaging modality. The use of DWI may help to identify children at high risk for poor outcome and to guide management decisions.

Expression of platelet-derived growth factor and transforming growth factor and their correlation with cellular morphology in glial tumors.

This study was undertaken to evaluate the role of two sets of growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), in the induction and maintenance of glial tumors and their phenotypic expression. Explants from eight malignant tumors, five benign tumors, and two nontumor glial cells were analyzed for levels of messenger ribonucleic acid (mRNA) expression of PDGFA, PDGFB, TGF-beta 1, and TGF-beta 2. Results were normalized to the mRNA expression of tubulin, a "housekeeping" gene present in glial cells. Of the 15 explants tested, PDGFB was seen in six, all of which were malignant tumors; PDGFA was seen in all 15 with much higher levels expressed in malignant tumors; and TGF-beta 1 and TGF-beta 2 were seen in all 15 without a clear difference between cell types, although expression tended to be higher in malignant tumors. This project supports the theory that the induction and maintenance of glial tumors is likely to be a multifactorial phenomenon.

Intradural chordoma without bone involvement: nuclear magnetic resonance (NMR) appearance. Case report.

This paper presents a rare case of intradural chordoma which involved the pons but had no radiological or surgical evidence of bone involvement. The appearance of this tumor on nuclear magnetic resonance imaging is presented.

TPA-mediated regulation of osteopontin in human malignant glioma cells.

Malignant gliomas are the most common primary intracranial neoplasms in adults and are largely refractory to post-surgical therapy despite intensive therapeutic efforts. Using a number of different brain tumor-derived cell lines we have demonstrated that the mRNA for osteopontin (OPN), which is substantially over-expressed by some tumors in comparison with normal tissues, is preferentially expressed in high grade and metastatic brain tumors compared to low grade brain tumors. One glioma-derived cell line, U105MG, which does not express significant amounts of OPN mRNA, could be induced dose-dependently by the tumor-promoting and PKC-activating phorbol ester, TPA, to over-express OPN mRNA in a PKC-dependent manner. Unexpectedly, treatment of U105MG cells with Ca2+ ionophore (A23187) completely inhibited TPA-mediated induction of OPN while treatment with the intracellular Ca2+ antagonist TMB-8 had no significant effect. Elucidation of regulatory mechanisms for OPN induction in glioma cells should facilitate rational design of novel therapeutics for human malignant gliomas.

Neurofibromatosis and central nervous system tumors in childhood.

Neurofibromatosis is a multifaceted disease that often results in tumors of the central nervous system. As our understanding of the molecular biology of the disease improves along with better neuroradiology imaging, surgical instrumentation, and adjunctive care, the management schemes for these patients are evolving. This article reviews what is known about neurofibromatosis, common management problems with respect to the central nervous system, and an approach to the handling of these issues.

Cavum septi pellucidi as a cause of shunt dysfunction.

Cavum septi pellucidi and cavum vergae are generally asymptomatic fluid collections between the leaves of the septum pellucidum and are present in approximately 15% of adult brains. There are occasional reported cases of symptomatic cysts arising in this area. This paper reports a case in which a cavum septi pellucidi was a cause of shunt malfunction. On an air ventriculogram this condition was initially confused with a subdural collection.

Anterior sacral meningocele.

A case of anterior sacral meningocele is presented emphasizing early diagnosis based on recurring functional complaints and employing appropriate radiological studies. The appropriate use of computerized tomography (CT) scanning and the proper surgical management utilizing laminectomy and obliteration of the communicating channel of the meningocele are discussed.

Ventral brain-stem compression from a subarachnoid ependymal cyst.

A case of ventral brain-stem compression by a congenital subarachnoid ependymal cyst in an infant is presented. Marsupialization of the cyst provided effective decompression and clinical improvement. Immunohistochemical staining demonstrated the glial nature of the epithelium. The fact that these cysts may be congenital, as demonstrated here, supports the hypothesis that they arise from glial elements that have been displaced during development.

Expression of glial fibrillary acidic protein, vimentin, fibronectin, and N-myc oncoprotein in primary human brain tumor cell explants.

Cultured cells of explants from 23 human gliomas (seven astrocytomas, eleven anaplastic astrocytomas, three ependymal tumors and two medulloblastomas) were studied to examine cell morphology and expression of glial fibrillary acidic protein (GFAP), vimentin, fibronectin, and N-myc oncoprotein. The most common antigenic phenotype consisted of cells that were GFAP-positive and fibronectin-positive. Both low and high grade astrocytomas retained GFAP expression after several passages in vitro. The establishment of glial tumors in vitro may not necessarily result in loss of GFAP expression early in passage nor is expression of GFAP and fibronectin mutually exclusive. N-myc oncoprotein was seen in only two specimens, one anaplastic astrocytoma and one ependymoma.