myelin-basic-protein and Central-Nervous-System-Neoplasms

Schwannomas are peripheral nerve sheath tumors composed entirely of Schwann-lineage cells that cause pain and sensory-motor dysfunction through compression of peripheral nerves, the spinal cord, and/or the brain stem. Treatment of schwannoma is largely limited to resection which itself has limited value. The goal of this study is to establish a technique to identify the most efficient and tissue-specific promoter for use in a schwannoma gene therapy construct.. This work involves transfection of schwannoma cells with adeno-associated viral vector plasmids expressing GFP under different myelin cell specific promoters. The transfected cells were evaluated for green fluorescence intensity in vitro, and in vivo after implantation into sciatic nerves of nude mice.. Our data demonstrate that myelin protein zero (MPZ, P0) and peripheral myelin protein 22 (PMP22) promoters produce greater GFP expression in schwannoma cell lines than myelin basic protein (MBP) promoter. In vitro, P0 promoter activity in schwannoma cell lines was shown to be less active than the cytomegalovirus and chicken β-actin (CBA) promoter. However, we did not observe any significant difference between the activity of the CBA and P0 promoters in a xenograft schwannoma model.. We show here the influence of the peripheral nerve microenvironment on promoter efficacy in expressing transgenes using simple transfection by lipofection followed by prompt implantation of the transfected cells into the sciatic nerve of nude mice.. We demonstrate that of the myelin specific promoters evaluated, P0 is optimal for driving expression of transgenes in schwannoma cells.

Topics: Animals; Cell Line, Tumor; Central Nervous System Neoplasms; Genetic Therapy; Humans; Mice; Myelin Basic Protein; Myelin P0 Protein; Myelin Proteins; Neurilemmoma

Solitary fibrous tumor is a rare, spindle-cell benign mesenchymal neoplasm and has a high recurrence rate. In this study, we reviewed our experience in the diagnosis and treatment of 24 patients with central nervous system solitary fibrous tumors.. Clinical data were retrieved from the medical records. Prognosis was assessed by clinic service and telephone interview. The specimens were stained with hematoxylin and eosin. Immunohistochemistry for CD34, CD99, EMA, HMB-45, Bcl-2, vimentin, GFAP, S-100, MBP, CK and MIB-1 was performed in all cases. Distributions of time to progression and recurrence were estimated using the Kaplan-Meier method and compared using the log-rank test.. The 24 patients included 13 men and 11 women with a median age of 49.0 years. The most frequent initial symptoms were headache, dizziness, unstable walk and hearing loss. The most common location was cerebellar pontine angle (n = 6). Surgery reached gross total removal for 18 patients but subtotal removal for six patients on initial operation. Histopathologic examination showed spindle to oval cells were disposed in wavy fascicles between prominent, eosinophilic bands of collagen. Dense bands of collagen appeared in cross section as minute nodules that separated individual tumor cells. Cellular areas with a partial hemangiopericytoma pattern were noted in six cases. Atypical presentations were shown on initial operation in three cases. CD34, CD99 and vimentin were 100% positive; but EMA, CK, MBP, HBM-45 and GRAP were 100% negative. The positive in Bcl-2, RF and S-100 was 89%, 85% and 26%, respectively. Follow-up information was available for 23 patients. The median follow-up period was 36.0 months. Nine patients recurred and one patient died from the progression. Incomplete surgical resection was significantly associated with recurrence (p = 0.010). MIB-1 labeling index in recurrence was higher than in no recurrence (6.0% versus 3.4%, p = 0.029). All treated with subtotal removal only had subsequent tumor recurrence or progression; however, the two patients who were administered adjuvant radiosurgery after subtotal removal did not recur or progress. Adjuvant radiosurgery seemed to improve the prognosis (p = 0.028).. Solitary fibrous tumor is a rare mesenchymal tumor with a propensity to recur. The most affected area is the cerebellopontine angle. Immunohistochemistry should be used to differentiate solitary fibrous tumor from other tumors. The extent of resection, MIB-1 labeling index and some anaplastic features might be predictive for recurrence. Postoperative radiosurgery might be an option in incompletely resected solitary fibrous tumor. Regular and long-term follow-up remains mandatory to monitor recurrence.

Topics: 12E7 Antigen; Adolescent; Adult; Aged; Antigens, CD; Antigens, CD34; Biomarkers, Tumor; Cell Adhesion Molecules; Central Nervous System Neoplasms; Child; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Ki-67 Antigen; Male; Middle Aged; Myelin Basic Protein; Neoplasm Recurrence, Local; Prognosis; Proto-Oncogene Proteins c-bcl-2; S100 Proteins; Solitary Fibrous Tumors; Vimentin; Young Adult

Central nervous system prophylaxis of childhood acute lymphoblastic leukemia has dropped rates of relapses but has been associated with neurotoxicity and imaging abnormalities. Predictors of neurotoxicity are lacking, because of inconsistency between clinical symptoms and imaging. Some have suggested that cerebrospinal fluid myelin basic protein (MBP) levels to be of potential interest. A retrospective analysis of MBP levels in correlation with clinical and radiologic data is presented.. MBP levels obtained at the time of intrathecals, charts, and neuroradiology reports were retrospectively analyzed. Academic achievement data were obtained from phone contacts with patients and families.. We retrieved 1248 dosages of MBP in 83 patients, 381 neurologic examinations in 34 patients and 69 neuroradiologic investigations in 27 patients. Fifty-two patients had abnormal MBP levels. Radiologic anomalies were present in 47% of those investigated, 14% of them having school difficulties. Proportions of patients with school difficulties in the groups with abnormal MBP levels but no radiologic anomalies or with no radiologic investigations were 0% and 3%, respectively, which was lower than in the group of patients with normal MBP levels (100%, 22%, and 5%, respectively).. Notwithstanding the retrospective character of our study, we conclude that there is limited usefulness of systematic dosage of MBP as indicator of treatment-induced neurotoxicity in acute lymphoblastic leukemia patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Neoplasms; Child; Child, Preschool; Cognition Disorders; Combined Modality Therapy; Cranial Irradiation; Female; Humans; Infant; Infant, Newborn; Injections, Spinal; Male; Myelin Basic Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma

While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras*GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their effect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its effect. L-744,832 demonstrates both cytostatic and cytotoxic effects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in high-grade astrocytomas (EGFRvIII/p140EGF-R) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchorage-dependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G1/M and G2/S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21WAF1/CIP1, but this induction is not necessary for the cell cycle inhibitory effects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic effects.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Astrocytoma; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Bromodeoxyuridine; Cell Cycle; Cell Division; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; ErbB Receptors; Farnesyltranstransferase; Genes, ras; Growth Inhibitors; Humans; Lymphokines; Membrane Proteins; Methionine; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myelin Basic Protein; Neovascularization, Pathologic; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We compared the molecular phenotypes of central nervous system tumors arising in four different lines of transgenic mice (TGM) carrying the Simian virus 40 large T antigen driven by different promoters or enhancers. Two of the four lines developed primitive neuroectodermal tumors (PNETs) in the brain stem or pineal gland. A third TGM line developed retinoblastomas (a PNET-like tumor of the retina) as well as PNETs in the mesencephalon, while the fourth TGM developed retinoblastomas and adrenal pheochromocytomas.. The expression of developmentally regulated polypeptides specific for the neuronal or glial lineage was examined in these PNETs using immunohistochemistry and Western blotting.. Neoplastic cells in all of the PNETs exhibited neuronal, but no glial specific markers as evidenced by the invariable expression of synaptophysin, but no detectable glial fibrillary acidic protein or myelin basic protein. PNETs with a more differentiated neuronal phenotype expressed multiple neuronal polypeptides. The phenotypic properties of these PNETs closely resembled those found in human brain PNET biopsy samples and cell lines derived therefrom.. We conclude that Simian virus 40 T antigen-induced PNETs in TGM exhibit the molecular phenotype of developing neurons or neuronal progenitor cells. Although many factors could influence the phenotype of these experimental PNETs (e.g., promoter, site of integration of the transgene) these PNETs appear to be suitable TGM models of human PNETs of the central nervous system.

Topics: Adrenal Gland Neoplasms; Animals; Antigens, Polyomavirus Transforming; Blotting, Western; Central Nervous System Neoplasms; Disease Models, Animal; Eye Neoplasms; Glial Fibrillary Acidic Protein; Immunohistochemistry; Mice; Mice, Transgenic; Microscopy, Electron; Myelin Basic Protein; Neuroectodermal Tumors, Primitive; Neurofilament Proteins; Phenotype; Pheochromocytoma; Promoter Regions, Genetic; Retinoblastoma; Synaptophysin; Tumor Cells, Cultured