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Biomedical subjects

M Westphal

Publications and source records attributed to M Westphal.

At least 109 records · Page 6Linked to original sources
PubMed1996

Central neurocytoma: clinical, immunohistologic, and biologic findings of a human neuroglial progenitor tumor.

BACKGROUND: Central neurocytomas are rare brain tumors recognized by their typical radiologic and histologic features. In general, a good prognosis is achieved by total removal. The histogenesis is still under debate, but a neuronal origin is widely assumed. METHODS: This study presents the clinical and immunohistologic findings of five patients and the results of cell culture experiments of two patients with central neurocytoma treated surgically between 1983 and 1993. RESULTS: The patient age at diagnosis ranged from 21 to 30 years (mean, 25 years). The male-to-female ration was 1:4. Raised intracranial pressure due to hydrocephalus was the main cause of the clinical manifestations. Total resection was achieved in two cases. Four patients received radiotherapy. One patient suffered a recurrence 1 year after surgery, requiring a second resection and radiotherapy. Follow-up studies took place between 1 and 10.5 years (mean, 7.1 years). To date, all patients are free of their tumors. Two patients suffered from permanent memory disturbances after surgery. Immunohistochemistry confirmed the neuronal nature of the tumors. Cell-culture studies, which have been carried out for the first time, demonstrated concomitant expression of neuronal (synaptophysin) and glial (GFAP) markers. CONCLUSION: Total removal is the therapy of choice. In tumor recurrence or limited surgery (e.g. due to severe affliction of the fornical structures), radiotherapy has shown to be efficacious. The cell-culture experiments give new insight on the histogenesis of central neurocytoma, indicating that the tumor arises from an undifferentiated precursor cell with the capacity of bipotential neuroglial differentiation.

Adult↗
PubMed1996

Glioma invasion in the central nervous system.

Invading glioma cells seem to follow distinct anatomic structures within the central nervous system. Tumor cell dissemination may occur along structures, such as the basement membranes of blood vessels or the glial limitans externa, that contain extracellular matrix (ECM) proteins. Frequently, invasive glioma cells are also found to migrate along myelinated fiber tracts of white matter. This behavior is most likely a consequence of using constitutive extracellular ligands expressed along the pathways of preferred dissemination. The extracellular space in anatomic structures, such as blood vessel basement membranes or between myelinated axons, is profoundly different, thus suggesting that glioma cells may be able to use a multiplicity of matrix ligands, possibly activating separate mechanisms for invasion. In addition, enzymatic modification of the extracellular space or deposition of ECM by the tumor cells may also create a more permissive environment for tumor spread into the adjacent brain. Tumor cell invasion is defined as translocation of neoplastic cells through host cellular and ECM barriers. This process has been studied in other cancers, in which a cascade of events has been described that involves receptor-mediated matrix adhesion, degradation of matrix by tumor-secreted metalloproteinases, and, subsequently, active cell locomotion into the newly created space. Although some of these mechanisms may play an important role in glioma invasion, there are some significant differences that are mainly the result of the profoundly different composition of the extracellular environment within the brain. This review focuses on the composition of central nervous system ECM and the recent evidence for the use by glioma cells of multiple invasion mechanisms in response to this unique environment.

Central Nervous System↗
PubMed1996

Differential expression of novH and CTGF in human glioma cell lines.

Aims-(1) To investigate the expression in human derived glioblastoma cell lines of two structurally related genes, novH (nephroblastoma overexpressed gene) and CTGF (connective tissue growth factor), which encode putative insulin-like growth factor binding proteins of a novel type. (2) To investigate whether the same transcription factors regulate CTGF and novH expression.Methods-Expression of novH and CTGF was analysed in 24 glioblastoma derived cell lines by northern blotting. The CTGF promoter region was characterised by nucleotide sequencing, RNase protection experiments, by transient transfections, and CAT assays.Results-CTGF and novH mRNA levels differed in the glioma cell lines studied. NovH and CTGF genes were not co-expressed in all cell lines. The CTGF promoter region was highly conserved compared with the corresponding region in the mouse (FISP12) and exhibited in vitro transcriptional activity.Conclusions-Although the coding regions of novH and CTGF are highly homologous, their promoter regions are substantially different, suggesting that these two genes may be regulated by different mechanisms. Considering that novH and CTGF are likely to be, respectively, negative and positive regulators of growth and that some glioma cell lines expressing novH are not tumorigenic, expression of these two genes might represent a key element in determining the stage of differentiation or the malignant potential, or both, of some tumour cell lines.

Journal Article↗
PubMed1996

Migration of human glioma cells on myelin.

Histoanatomically invading astrocytoma cells appear to migrate along distinct structures within the brain. Astrocytoma invasion may occur along extracellular matrix (ECM) protein-containing structures, such as blood vessels, but most frequently occurs along tracts of myelinated fibers. This behavior most likely is a consequence of the use of constitutive extracellular ligands expressed along the pathways of preferred dissemination. Enzymatic modification of the extracellular space or deposition of ECM by the tumor cells may also create a more permissive environment. Established human glioma cell lines and two preparations of primary cells isolated from glioblastoma biopsies were studied with the use of cell adhesion and monolayer migration assays to investigate whether crude human central nervous system myelin extracts present specific cell adhesion ligands that promote glioma attachment and cell migration. Two cell lines showed high levels of adhesion and migration on central nervous system myelin similar to levels of migration on the ECM protein merosin, which has previously been shown to be a highly permissive substrate for cultured astrocytoma cells. Two other cell lines showed lower but specific migratory response; one cell line did not attach or specifically migrate on crude myelin extracts. For both glioblastoma primary cell preparations, myelin and merosin were the most permissive substrates for attachment and migration. Other ECM proteins (collagen type IV, fibronectin, and vitronectin) were moderate or nonpermissive substrates. Our findings indicated that astrocytoma cells may be able to use oligodendrocyte membrane-associated ligands as well as ECM proteins of the basement membranes for invasion of normal brain.

Astrocytoma↗
PubMed1995

pDcsA vectors for strictly regulated protein synthesis during early development of Dictyostelium discoideum.

Two expression vectors have been constructed to express proteins exclusively in developing cells of Dictyostellium discoideum. In these Escherichia coli/D. discoideum shuttle vectors, proteins are synthesized under control of the promoter of the contact site A (csA) gene, which is efficiently suppressed during growth and becomes strongly activated during early development of D. discoideum. The pDcsA vectors appear to be valuable tools for the production of proteins that are not compatible with growth of D. discoideum cells.

Ampicillin Resistance↗
PubMed1994

Human neurocytoma cells in culture show characteristics of astroglial differentiation.

Cultured human neurocytoma cells from two neurosurgical patients were analysed for their immunocytochemical staining patterns and growth characteristics. In both cases, the cells stained positive for glial acidic fibrillary protein (GFAP) within one day of tissue culture in medium, with and without fetal calf serum, whereas the histological tumor specimens were negative. Both cases contained cells concomitantly expressing GFAP and synaptophysin (SNP) in the primary cultures. Epidermal growth factor (EGF) was mitogenic for the cultured cells but not platelet derived growth factor alpha (PDGF AA) or nerve growth factor (NGF). It is concluded that the human neurocytomas may represent neoplasms of a pluripotent neuroglial cell which can provide an interesting model to study the determinants for human glial/neuronal differentiation in vitro.

Astrocytes↗
PubMed1994

Treatment of cerebral arteriovenous malformations by neuroradiological intervention and surgical resection.

We present the results of a series of 105 patients with cerebral arteriovenous malformations (AVMs) who were treated by a combined protocol including endovascular occlusive measures and open surgical resection. 25 patients were treated only by surgical intervention, 72 patients underwent preoperative endovascular embolization and 8 patients were treated only by embolization, seven of which were only treated for palliation. After superselective angiography the vascular territories suitable for endovascular or microsurgical approach were defined, and in most cases these territories were complementary to each other. In 56 cases, only one embolization was necessary and due to an advantageous co-localization of the departments the whole combined endovascular/neurosurgical procedure was done in one anesthesia. If several endovascular sessions were necessary (16 patients), the resection was mostly carried out immediately after the last neuroradiological session in the same anesthesia with total time of such combined procedure now averaging about 7 hours. According to the proposed grading system by Spetzler we treated 25 grade 1, 24 grade 2, 40 grade 3, 11 grade 4, and 5 grade 5 lesions. The overall success rate defined as complete resection without additional permanent neurological deficit was 89.6% (87 out of 97 surgical cases). The benefits of such combined approach to cerebral AVMs become apparent in shortened and safer surgical procedures as well as in a low complication rate.

Adolescent↗
PubMed1994

Cranio-cervical decompression for Chiari I malformation. A retrospective evaluation of functional outcome with particular attention to the motor deficits.

We report a series of 26 patients affected by a Chiari I malformation treated at our department between 1987 and 1993. All patients underwent pre- and postoperative evaluation by magnetic resonance imaging (MRI). Sequential perioperative motor evoked potential (MEP) recordings were performed in 8 patients. The preoperative symptoms can be divided into four subgroups: cephalgias (84.6%), cranial nerve deficits (69.2%), motor deficits (76.9%), sensory deficits (73%). Twenty-five out of 26 patients underwent craniovertebral decompression, 1 a transoral anterior decompression. One patient died 2 months after surgery because of progressive pulmonary failure. We registered following postoperative complications transient hypoglossal palsy (1 case), vertigo (2 cases), meningitis (1 case), minor CSF leaks (3 cases). Cephalgias subsided in 17 and improved in 4 out of 22 patients. Cranial nerve deficits improved in 8 and were stabilized in 7 out of 18 patients. A limited recovery of trigeminal function was possibly due to nuclear lesions. Five patients whose vestibular disturbances were not relieved by surgery were put on a course of carbazepine. Vertigo resolved in one case and in two others improved. While hypesthesia improved after decompression, the other sensory deficits were stabilized in 5% of the patients. Spasticity improved in 12 out of 18 patients, but weakness only in 7 out of 17 patients. Motor disturbances were always detected by MEP-recording. MEP-characteristics were not specific, resembling those of patients with other intra-, extramedullary myelopathies. Functional recovery was not matched by an improvement of the MEP parameters. MEP may be used as tool for surveillance of patients whose clinical findings are not progressive and are not at first surgical candidates.

Adult↗
PubMed1994

Karyotype analyses of 20 human glioma cell lines.

Human malignant gliomas are frequently associated with loss of gonosomes and chromosomes 13, 17, and 22. Their progression from anaplastic glioma to glioblastoma is marked by additional loss of chromosome 10. In addition, structural and numerical aberrations of chromosome 7 are frequently found. We report on the karyotypes of a series of 20 human gliomas of which 11 were analysed as established cell lines; 9 cases were investigated in early culture, 5 of which later also became established lines. In addition to the frequently reported overrepresentation of chromosome 7, four cell lines with polysomy for chromosome 22 were seen. A high incidence of structural chromosomal aberrations was present in early cultures as well as in cell lines after various in vitro passages. We found that the general characteristics of karyotypic aberrations found in early cultures or direct preparations of dispersed tumour material were reflected in the pattern of aberrations present in cell lines at much later time points. Thus it appears as if no systematic changes can be attributed to long-term cultures. Suspicious losses of chromosomes 14, 18, and 19 or gain of chromosome 22 indicate that individual cases may have originated due to other mechanisms than the ones already hypothesized, i.e., different suppressor genes or amplification of genes other than the EGF-R-gene. None of the established cell lines had a genomic rearrangement of c-erbB 1, c-erbB 2 or of the p 53 gene.

Adult↗
PubMed1994

Treatment of nongerminomatous germ-cell tumors of the pineal region.

Germ-cell tumors can be subdivided into germinoma, embryonal carcinoma, choriocarcinoma, endodermal sinus tumor (yolk-sac tumor), and teratoma. They are also distinguished by their production of secreted markers such as alpha-fetoprotein produced in endodermal sinus tumors and embryonal carcinoma or beta-human chorionic gonadotropin, produced by choriocarcinoma and embryonal carcinoma. Germinoma and teratoma produce none of the markers. Because it has been proposed that teratomas may differentiate from multipotent stem cells contained in embryonal carcinoma and are thus lineage related, the presence of markers indicates the presence of a nongerminomatous germ-cell tumor. Nongerminomatous germ-cell tumors are an invariably fatal subgroup within the pediatric pineal region germ-cell tumors. There is no effective, established therapeutic regimen. We report the treatment regimen for three children diagnosed with this highly aggressive tumor entity. The children were first given a course of chemotherapy with bleomycin, etoposide, and cisplatin. This resulted in the normalization of markers and the shrinkage of tumors. These were then removed by the infratentorial supracerebellar approach. Removal was followed by a second course of chemotherapy with vinblastine, ifosfamide, and cisplatin; after which the children underwent radiotherapy. All three children are well and without evidence of residual or recurrent disease 20, 30, and 32 months after surgery, respectively. We propose this therapy regimen for children in whom the markers are positive.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

p53 protein accumulation and gene mutations in human glioma cell lines.

Mutations in, and aberrant expression of, the p53 tumor suppressor gene were assessed in 17 cell lines derived from human malignant brain tumors (glioblastoma multiforme). Exons 5 through 8 were screened by single strand conformational polymorphism analysis (SSCP), followed by direct DNA sequencing. Mutations were found in 6 of 17 glioma cell lines, i.e., at a frequency similar to that found in primary malignant gliomas. Loss of the wild type allele was observed in 4 of the mutated cell lines. Two cell lines had the same mutation (CGG-->TGG; Arg-->Trp) in codon 248. Five of 6 mutations were transitions, 4 of which occurred at CpG dinucleotides. In one cell line a 10-bp deletion at the intron 4/exon 5 junction was found. Five of 6 glioma cell lines contained a mutation identical to that in the respective primary tumor despite prolonged in vitro culture (140-221 passages). Thus, the acquisition of p53 mutations during culture appears to be infrequent. Two cell lines derived from heterozygous tumors maintained the wild type p53 allele during long term culture. p53 protein levels were assessed by immunofluorescence cytochemistry and immunoprecipitation followed by Western blot analysis and revealed elevated levels of the p53 protein, although to a variable extent, in all cell lines with p53 mutations. A marked p53 protein accumulation was also observed in two cell lines lacking p53 mutations in exons 5 through 8, indicating that a prolonged half life of the gene product is not solely dependent on an aberrant coding sequence. The remaining cell lines had either low levels or no detectable p53 protein; one of the latter contained a gross rearrangement of the p53 gene. Our results suggest that with respect to p53 gene status, glioma cell lines usually resemble the original tumors and may, therefore, be suitable for studying the biological changes associated with p53 mutations in glial tumors.

Base Sequence↗
PubMed1993

Neurotrophin gene expression by cell lines derived from human gliomas.

The expression of neurotrophin (NGF, BDNF, and NT-3) mRNAs in 24 cell lines derived from human malignant gliomas was studied by Northern analysis. Widespread expression of neurotrophin genes was found with BDNF being the most abundantly expressed. Nearly all cell lines expressed BDNF, and about two-thirds of the cell lines expressed NGF and NT-3. Half of the cell lines analyzed expressed all three neurotrophins. Secretion of NGF into the medium of several cell lines could be detected by ELISA and a PC12 neurite outgrowth assay. Immuno- and bioactive NGF was isolated from conditioned medium of one cell line. No evidence of expression of the neurotrophin receptors trk and trkB by Northern analysis was found. Receptor crosslinking with radiolabeled cognate ligands failed to detect functional receptors in all but one cell line. In this cell line a receptor complex for BDNF was found that corresponded to truncated trkB receptors that lack the signal transducing tyrosine kinase domain. Neurotrophins did not stimulate mitosis of the glioma cultures. The findings suggest that production of neurotrophins by glioma cells is a general phenomenon, although neurotrophins made by gliomas lacking their receptors may not play an autocrine but rather a paracrine role.

Blotting, Northern↗
PubMed1993

Loss in expression of the retinoblastoma gene product in human gliomas is associated with advanced disease.

The retinoblastoma susceptibility gene (RB), the prototype of the class of tumor suppressor genes, is inactivated in a number of human malignancies. We investigated a possible role of RB in human brain tumors. Immunoprecipitation revealed frequent loss of RB protein expression in glioma cell lines (8/24), which was accompanied by lack of RB encoded transcripts. Among seventeen primary brain tumors studied by Western blotting, loss of Rb protein expression was observed in WHO grade 3 and 4 gliomas (3/10). However, none of the low grade gliomas and the other primary brain tumors investigated lacked RB protein expression. These data suggest a role for RB in glial malignancy, and loss of Rb expression appears to be associated with glial tumor progression.

Adult↗
PubMed1993

A joint protocol for the neurosurgical and neuroradiologic treatment of cerebral arteriovenous malformations: indications, technique, and results in 76 cases.

We report on a group of 76 patients who had been treated during a period in which preoperative embolization using interventional neuroradiologic technique was standard procedure. During this time, 20 consecutive patients were operated on without embolization, eight patients were treated with embolization only, and 48 patients were operated on after embolization. In 35 cases surgery immediately followed the last embolization procedure. All arteriovenous malformations (AVMs) were classified and the outcome analyzed according to Spetzler [J Neurosurg 1986; 65: 476-83]. Those lesions treated with a combination of embolization and surgery had higher Spetzler grading than those that had been operated without previous embolization. The overall recovery rate was 82.9%. In 7.9% of the cases the AVMs were not totally extirpated. The overall complication rate was 9.2%. It is concluded that preoperative embolization facilitates surgery and reduces the risk of severe morbidity and mortality, especially in high-grade lesions. In addition to the clinical results, the application and usefulness of Ethibloc as an embolizing agent is reported.

Adolescent↗