p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency.

Mutations in the p53 gene were analyzed in 40 gliomas using the single strand conformation polymorphism assay together with restriction fragment length polymorphism analysis to assess loss of heterozygosity for 17p alleles in the same tumors. Mutations occurred in 40% of the gliomas and were found in exons 4-8 of the p53 gene. G:C to T:A transversions, which occur in high frequency in some lung (greater than 50%), liver (greater than 80%), breast (30%), and esophageal cancers (25%), were noted in greater than 25% of the gliomas studied here. These transversions were clustered in exon 5 from codons 156 to 168, a region of the p53 gene not previously associated with a high frequency of mutation, and may represent a new hot spot for mutations in certain cancers. The majority of gliomas (27 of 38) analyzed here retained both 17p alleles. The frequency of p53 mutations was 37% in this group of tumors and increased to 64% in tumors with one 17p allele. Allelic loss for chromosome 17p occurred in 4 of 11 gliomas independently of mutations in the p53 gene. Absence of p53 mutations in 36% of the tumors with one 17p allele suggests that a tumor suppressor gene other than p53 may be located on chromosome 17p and involved in progression to malignancy of some gliomas.

High frequency of p53 protein accumulation without p53 gene mutation in human juvenile pilocytic, low grade and anaplastic astrocytomas.

We analysed 31 non-glioblastoma astrocytomas for alterations in p53 protein expression and for mutations in the p53 gene. Immunohistochemistry detected p53 protein accumulation in 71% (five of seven) of juvenile pilocytic astrocytomas (WHO grade I), 63% (five of eight) of astrocytomas (WHO grade II), and 63% (10 of 16) of anaplastic astrocytomas (WHO grade III). The single strand conformation polymorphism (SSCP) assay of exons 2-11 of the p53 gene and direct DNA sequencing identified p53 mutations in 14% (one of seven) of grade I, 25% (two of eight) of grade II, and 19% (three of 16) of grade III astrocytomas. This is the first report of a p53 mutation in grade I juvenile pilocytic astrocytomas. Immunohistochemistry and SSCP analyses gave concordant results in 55% (17 of the 31) of the tumors. A total of 14 tumors, 60-80% within each grade, showed p53 protein accumulation in the absence of detectable mutations of the p53 gene. No mdm-2 gene amplification was found in these tumors. The similar frequency of p53 alterations in tumors of grades I-III suggests that the p53 gene plays a significant role early in the formation of astrocytomas rather than late in tumor progression to higher grade. The data suggest that mechanisms other than p53 gene inactivation by mutation or mdm-2 complex formation result in the accumulation of P53 protein in > 70% of non-glioblastoma astrocytomas.

A correlative study of p53 protein alteration and p53 gene mutation in glioblastoma multiforme.

The p53 tumor suppressor gene is frequently mutated in glioblastomas. Mutations within the p53 gene often result in aberrant expression of the p53 protein leading to protein accumulation within the nucleus of the cells which can be detected by immunochemistry. Many studies have correlated alterations of p53 protein expression with p53 gene mutations. Positive staining of tumor cells for p53 protein has been widely assumed, perhaps incorrectly, to signify the presence of p53 gene mutations. This study compared the immunostaining patterns for p53 protein in 37 glioblastomas with the molecular genetic data obtained by the single strand conformation polymorphism assay. p53 gene mutations were detected in 46% (17 of 37) of glioblastomas, while 65% (24 of 37) of glioblastomas were positive for protein accumulation by immunohistochemistry. Although 30 of 37 glioblastomas analyzed showed concordance for p53 protein expression and p53 gene mutations, a subset of seven glioblastomas showed discordant accumulation of the p53 protein in the absence of any detectable p53 gene mutations. The mdm-2 gene was assessed in 17 glioblastomas for gene rearrangements or amplification, but none were found. This result suggests that a mechanism other than p53 gene mutation can result in altered p53 protein expression.

Adrenal medullary transplants as a treatment for advanced Parkinson's disease.

Open autologous adrenal medullary to caudate nucleus transplantation was performed in 12 patients with advanced Parkinson's disease (PD). Ten of these patients had diurnal response fluctuations including "wearing off" and "on/off" phenomena. All of the patients were no longer satisfactorily responding to levodopa/carbidopa and dopamine agonists. The mean age of the patients was 55.1 years (range 37-65 yrs); mean duration of PD was 11.7 years (range 4-40 yrs); mean stage "on" was 3.3 (range 2-4); mean stage "off" was 4.8 (range 4-5). Mean duration of follow up from surgery was 10.4 months (range 2-17 months). Three patients improved dramatically with major changes in their lifestyle. The course of improvement in these 3 patients was different in each, implying that different mechanisms were responsible for the improvement. One of the patients died unexpectedly. In this patient, there were no surviving adrenal cells. Three patients improved moderately. Patients reported that they were "on" longer and had to take medication less often and were less dependent on individual doses of levodopa/carbidopa. The improvement has been sustained in two patients. However, in one of these patients there had to be frequent changes in scheduling to maintain the improvement. Two patients after technically successful implants did not improve. One of these patients subsequently died. In this patient there were a few surviving adrenal medullary cells. Four patients suffered major complications. One patient had a cerebral infarction and two had cerebral hemorrhages. One of these patients has shown a good recovery. One patient with autonomic insufficiency had a cardiac arrest with cerebral anoxia one week after surgery. This patient has shown a partial recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Supraophthalmic intracarotid infusion of BCNU for malignant glioma.

We treated five patients with 11 supraophthalmic infusions of BCNU at 200 mg/m2 every 2 months. All three patients with residual tumors showed marked CT response after one infusion. Two patients with bilateral tumors had no response on the contralateral side. All four evaluable cases showed evidence of BCNU neurotoxicity. CT findings superficially resembled tumor recurrence, but white matter changes, nonspecific gyral enhancement, and delayed calcification were more indicative of neurotoxicity. There were no procedure-related complications. One autopsy suggested that direct parenchymal damage might be responsible for delayed neurotoxicity. Supraophthalmic BCNU infusion, at this dosage, is too toxic for cerebral tissue.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlining the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlinging the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Three-dimensional neuroanatomic images in CT-guided stereotaxic neurosurgery.

A technique is described for three-dimensional reconstruction of human diencephalic structures based on information contained in a widely used stereotaxic brain atlas. Various methods of graphically representing the obtained diencephalic volumes are discussed and examples are given. The anatomic information contained in the computerized atlas can be implemented with computed tomography performed under stereotaxic conditions. Volume data provided by the tomograms are used for three-dimensional "stretching" of the volumes presented in the atlas. Improved accuracy in identifying "invisible" diencephalic targets in functional stereotaxic neurosurgery is expected to result from this new technique.

Propionibacterium as a cause of postneurosurgical infection in patients with dural allografts: report of three cases.

OBJECTIVE AND IMPORTANCE: Although Propionibacterium acnes is a common inhabitant of human skin, it is an uncommon pathogen in postoperative infections. We report three cases of postoperative wound infection/osteomyelitis caused by P. acnes. CLINICAL PRESENTATION: Three patients underwent craniotomy for a supratentorial meningioma and had a dural allograft at the time of closure. The patients presented several weeks after surgery with clinical evidence of a wound infection. INTERVENTION: All patients were diagnosed with P. acnes infection and treated for this pathogen with appropriate antibiotics. The bone flap was removed in two patients. After antibiotic therapy, all patients demonstrated no further evidence of infection. CONCLUSION: To our knowledge, this is the first published report of P. acnes infection in patients with a dural substitute. The source of infection cannot be confidently ascertained; however, two patients had strains of P. acnes from one brand of graft, which were indistinguishable by pulsed field gel electrophoresis typing.

Posterior stabilization of cervical spine fractures and subluxations using plates and screws.

Posterior stabilization of cervical spine fractures and subluxations with metal plates and screws is commonly used in Europe, but has rarely been employed by neurosurgeons in North America, where stabilization has usually been achieved with wires supplemented by bone grafts or acrylic. The limitations of the more commonly used stabilization techniques include the failure to achieve rotational stability, the necessity for intact laminae, and the requirement for bone grafting. We therefore examined the efficacy of posterior cervical plating in 19 patients who had posttraumatic instability of the cervical spine between C3 and C7 without residual spinal cord compression and 1 patient who had a subluxation as a result of osteomyelitis. Two patients had no neurological deficit, 4 had partial deficits, and 14 had no neurological function below the level of injury. Operation was performed after patients were medically stable and maximal reduction of fractures was achieved (usually within 48 hours). The plates are made of vitallium and contain two or three holes 13 mm apart through which 16-mm screws are placed bilaterally into the center of the articular masses of two or three adjacent vertebrae to stabilize one or two motion segments. Bone grafting is not performed. Patients are mobilized on the day after operation in a Philadelphia collar, which is worn for 3 months. Fourteen patients had stabilization of one motion segment and 6 had stabilization over two motion segments. The mean follow-up is 9.2 months. In a single patient with ankylosing spondylitis, plate fixation failed when screws pulled out. No patient experienced neurological deterioration as a result of the operative procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Modern management of spinal tuberculosis.

The resurgence of pulmonary tuberculosis in the United States has been paralleled by a concomitant rise in tuberculosis of the spine (Pott's disease). The appearance of drug-resistant strains of tuberculosis, infection in large numbers of immunocompromised hosts, newer imaging modalities, and the development of more effective spinal reconstruction techniques have raised important issues regarding the management of Pott's disease. In spite of this, there has been little published recently on the modern management of Pott's disease in developed countries. We report our experience with the management of 20 patients with Pott's disease in the past 5 years, 16 of whom were admitted during the last 18 months of this retrospective study. The mean patient age was 49 years. Sixteen (80%) were men. Nineteen (95%) had a positive tuberculin skin test, and 13 (65%) had pulmonary tuberculosis. Symptoms consisted of spinal pain, weakness, sensory complaints, and flank mass in order of decreasing frequency. Ten patients were neurologically intact; the remainder had motor deficits of variable severity. The thoracic spine was involved in 13 patients, the lumbar spine was involved in 4, the cervical spine was involved in 2, and the thoracolumbar spine was involved in 1. Spinal deformity was present in 11 patients, spinal epidural compression was present in 13, and a paraspinal mass was present in 18. Operative indications included motor deficits, spinal deformity, nondiagnostic computer tomographic-guided needle biopsy, and noncompliance with, or lack of, response to medical therapy. Eleven patients underwent operations. Six patients had vertebrectomy and bone grafting with posterior instrumentation when indicated; three had laminectomy, debridement, and abscess drainage; one had laminectomy and posterior instrumentation; and one had paraspinal abscess drainage. Two patients have died; the remainder have been monitored for at least 1 year and are neurologically improved or normal without residual infection. The average angulation decreased from 31 to 24 degrees by the follow-up examination. In selected patients, early operative treatment with instrumentation, when indicated, minimizes neurological deterioration and spinal deformity, allows early ambulation, and results in excellent neurological outcome.

Stereotactic surgical system controlled by computed tomography.

The three-dimensional data obtained by computed tomographic (CT) scanning offer an advantage in using this imaging technique for stereotactic surgical procedures. This requires interfacing of CT image data with a stereotactic guide. In the performance of functional procedures where the surgical target must be identified from brain landmarks, such as the anterior and posterior commissures, an image reconstruction technique that presents in an image high spatial resolution structural information must be used. The description of a fully hardware- and software-interfaced CT-directed stereotactic surgical system is presented. The logic of operation and examples of images reconstructed with a high spatial resolution algorithm are illustrated. The experimentally determined measurement of an electrode tip localization with this system is within 1 pixel or +/- 0.5 mm in any direction.

Neurological manifestations of primary rhabdomyosarcoma of the head and neck in children.

The authors describe four of their own cases of primary rhabdomyosarcoma (RMS) of the head and neck and summarize an additional 25 cases collected from the world literature, each manifesting neurological involvement. The need for early diagnosis and radical surgery is stressed.

Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors.

To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes. The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.

Cytologic findings in progressive multifocal leukoencephalopathy. Report of two cases.

Cytologic preparations from two cases of progressive multifocal leukoencephalopathy (PML) were obtained by stereotactically guided needle biopsies using computerized tomograms of the brain. Case 1 was a 32-year-old man with an acquired immunodeficiency syndrome-related complex. Case 2 was a 71-year-old man with chronic lymphocytic leukemia. Smears showed moderate cellularity, consisting of moderately to markedly atypical cells with enlarged hyperchromatic nuclei. The chromatin pattern showed smudging, with or without clumping, similar in pattern to the human polyomavirus-infected "decoy" cells seen in urine cytology. Nuclei were predominantly round to oval, smoothly contoured and often stripped of cytoplasm. Occasional bizarre lobulated or multinucleated forms were seen. Some atypical cells had abundant cytoplasm exhibiting stellate projections. Histologic sections of the biopsy material confirmed the diagnosis in each case. In both cases, electron microscopy demonstrated intranuclear polyoma-type virus particles. The present findings suggest that PML should be considered in the differential diagnosis of marked cytologic atypia in brain aspirates from immunocompromised patients.

An unusual CT presentation of cerebral toxoplasmosis.

Intracranial opportunistic infections have been widely reported in patients with acquired immune deficiency syndrome (AIDS). We report an unusual presentation of Toxoplasma gondii infection in a patient with AIDS.

A fully interfaced computerized tomographic-stereotactic surgical system.

A fully interfaced computerized tomographic system has been designed and constructed. A prototype Philips Medical Systems Inc. translate-rotate body scanner has been modified to accommodate a specially designed head holder and stereotactic guide. A high resolution partial scanning algorithm is used to achieve improved spatial resolution in comparison to conventional algorithms. Integration of scanning data with the geometry of the guide system is achieved with software control.