Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal metastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression.
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PMID:Neuraxis dissemination in pediatric brain tumors. Response to preirradiation chemotherapy. 173 73

Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis.
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PMID:Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. 785 49

p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236delta (deletion of codon 236). To test whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236delta, we generated transgenic mice expressing Y236delta in astrocytes using the regulatory elements of the glial fibrillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236delta transgenic p53-/- mice, while in p53+/- mice the incidence was 28% (11/40) (P>0.3). However, the mean tumor latency for GFAP-Y236delta/p53+/- mice was significantly shorter than for p53+/- mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell specific expression of Y236delta results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant effect of Y236delta provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This reflects well observations from human astrocytic neoplasms with p53 mutations.
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PMID:Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant. 1110 34

Tumors of the central nervous system (CNS) often have sustained expression of labile genes, including angiogenic growth factors and immunosuppressive cytokines, which promote tumor progression. Stabilization of the RNA transcripts for these genes, such as vascular endothelial growth factor (VEGF), is an important molecular pathway for this up-regulation. HuR, a member of the Elav family of RNA-binding proteins, has been implicated in this pathway through its binding to adenine and uridine (AU)-rich stability elements (ARE) located in the 3' untranslated regions (3'-UTRs) of the mRNA. Whereas three of the Elav family members (Hel-N1, HuC, and HuD) are restricted to young and mature neurons, HuR is more broadly expressed, including proliferating cells of the developing CNS. Because RNA stabilization of labile genes may promote tumor growth, we analyzed and compared the expression pattern of HuR in 35 freshly resected and cultured CNS tumors to determine whether there was any correlation with tumor grade or histological type. We found that HuR mRNA was consistently expressed in all of the tumors, regardless of cell origin or degree of malignancy. Using a novel HuR-specific polyclonal antibody, we found that strong HuR protein expression was limited to high-grade malignancies (glioblastoma multiforme and medulloblastoma). Within the glioblastoma multiforme, prominent HuR expression was also detected in perinecrotic areas in which angiogenic growth factors are up-regulated. To further define its role as a potential RNA stabilizer, we analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of cytokines and growth factors linked to brain tumor progression. We used a novel ELISA-based RNA binding assay and focused on the 3'-UTRs of angiogenic factors VEGF, COX-2, and (interleukin) IL-8 as well as the immunomodulating factors IL-6, transforming growth factor (TGF)-beta and tumor necrosis factor (TNF)-alpha as potential RNA ligands. Our results indicated overall a very high binding affinity to these RNA targets. A comparison of these ligands revealed a hierarchy of binding affinities with the angiogenic factors, and TGF-beta showing the highest (Kd of 1.8-3.4 nM), and TNF-alpha the lowest (Kd of 18.3 nM). The expression pattern of HuR, coupled with the RNA binding data, strongly suggests a role for this protein in the posttranscriptional regulation of these genes in CNS tumors.
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PMID:HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mRNAs. 1128 Jul 80

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that locate in peripheral organs. It has been thought that a systemic immune response does not play a role in regression of central nervous system (CNS) tumors, because the CNS is an immunologically privileged site. However, recent advances in immunology have led to the possibility of immunotherapy using peripheral DCs against CNS tumors. Here, we investigated whether DCs pulsed with tumor extract could induce an antitumor effect against malignant glioma. Furthermore, we also investigated whether the antitumor effect become higher by pulsation with tumor extract-liposome complex, compared to pulsation with tumor extract alone. As a liposome, we used cationic small unilamellar vesicles composed of N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate chloride (TMAG), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylethanolamine (DOPE) in a molar ratio of 1:2:2. After intracerebral inoculation of mouse malignant glioma GL261 cells into syngeneic C57BL/6 mice, DCs pulsed with extract from the glioma cells by sonication were administered intraperitoneally thrice weekly on days 7, 14 and 21. Tumor growth inhibition was evaluated by measuring the tumor size 1 month after the tumor inoculation. The group treated with DCs pulsed by tumor extract was inhibited in tumor progression compared with the control non-pulsed DCs group, and the group treated with DCs pulsed by tumor extract and liposomes showed substantial tumor volume reductions in all the mice. Among the mice, there were several with no visible masses in their brains. Immunohistochemical study showed that the CD8-positive cytotoxic T cells (CTLs) were strongly recognized among the almost disappearing tumor cells of pulsed DCs groups. The CTLs showed a specific antitumor activity for GL261 mouse glioma cells. These findings indicated that DCs pulsed with tumor extract and liposomes might play an important role in the activation of an immune response in malignant glioma.
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PMID:Dendritic cells pulsed with tumor extract-cationic liposome complex increase the induction of cytotoxic T lymphocytes in mouse brain tumor. 1176 40

This is a pilot study performed to determine the maximum tolerated number of courses of high-dose thiotepa and carboplatin with autologous peripheral blood progenitor cell (PBPC) transplantation in poor-risk pediatric central nervous system (CNS) tumor patients. Twelve patients were enrolled and a total of 24 PBPC transplants were performed. The median age was 7.7 years. All patients had CNS tumors: 4 relapsed CNS PNET, 2 high-risk PNET in first remission, 2 relapsed/progressive brainstem tumor, 2 relapsed/progressive anaplastic astrocytoma, 1 relapsed GBM, and 1 recurrent ependymoma. The regimen consisted of thiotepa 250 mg/m2/day x 3 days and carboplatin 400 mg/m2/day x 3 days. No toxic deaths occurred. All patients were hospitalized for a median duration of 17 days. The median number of CD34 cells infused was 5.4 x 10(6)/kg (2.1-29.7 x 10(6)/kg) per course. Median time to ANC > 0.5 x 10(9)/L was 9 days, and platelets > 20 x 10(9)/L was 13.5 days. Four patients came off protocol after only one course of PBPC (2 had tumor progression, 2 parental choice); 4 patients underwent two, and 4 patients three courses of PBPC. Major nonhematologic complications were mucositis that necessitated infusion of narcotics (11/24 courses), fever of unknown origin (12/24), documented infection (9/24), and hemorrhagic cystitis (3/24). TPN was administered during 22 of 24 courses with a median duration of 15 days. It isfeasible to administer 2-3 courses of tandem high-dose thiotepa and carboplatin with PBPC transplant with prompt engraftment and manageable toxicities in pediatric CNS tumor patients.
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PMID:A pilot trial of tandem autologous peripheral blood progenitor cell transplantation following high-dose thiotepa and carboplatin in children with poor-risk central nervous system tumors. 1562 20

Central nervous system (CNS) cancers are the second most frequent malignancy (and the most common solid tumor) in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment. Advances in the understanding of the nature of the blood-brain/tumor barrier, chemotherapy resistance, tumor biology, and the role of angiogenesis in tumor progression and metastases have led to the advent of newer therapeutic strategies that circumvent these obstacles or target specific receptors that control signal transduction and/or angiogenesis in tumor cells. Ongoing clinical trials will determine whether these novel treatment modalities will improve outcomes for children with brain tumors.
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PMID:Recent advances in the treatment of pediatric brain tumors. 1564 97

The inclusion of neurocognitive end points in clinical trials of patients with CNS tumors is increasing. Neurocognitive end points are used to understand what cognitive problems exist before treatment to establish a baseline by which the effect of treatment is judged, and to determine whether different treatment regimens improve neurocognitive function due to better tumor control, slow expected neurocognitive deterioration due to the tumor, or have more or less short- and long-term neurotoxicity. However, the use of neurocognitive end points in clinical trials for patients with CNS tumors is in its infancy, so that long-term outcomes are difficult to predict and the ability to determine the effects of different agents and treatment approaches is scant. Including this aspect of patient evaluation in addition to survival and time to tumor progression will yield better risk-versus-benefit assessments as well as provide a basis for improving interventions.
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PMID:Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. 1652 86

Ependymomas are CNS tumors that originate from the spinal canal and walls of the ventricular system. Considerable controversy continues to exist with regard to their prognostic factors; age and extent of resection are the only statistically significant prognostic factors yet identified. The authors report a retrospective study of a homogenous population of 119 patients harbouring ependymomas between 1991 and 2002. All clinico-radiological and follow-up data were analyzed and a pathologic review was performed by two pathologists. Immunohistochemical staining for MIB-1, Topo IIalpha, p53 and MDM2 was performed. Histopathologic grades show relationship with MIB1 and Topo IIalpha labelling indices and cut-off values of 5% can differentiate between anaplastic and lower grades. p53 and MDM2 proteins expression are not common in ependymomas; however, they are seen in higher grades only and may be involved in the tumor progression.
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PMID:A study of proliferative markers and tumor suppressor gene proteins in different grades of ependymomas. 1872 Dec 29

Regulatory T cells (CD4+CD25+FoxP3+, Treg) have been shown to play a major role in suppression of the immune response to malignant gliomas. In this study, we investigated the kinetics of Treg infiltration in metastatic brain tumor models, including melanoma, breast and colon cancers. Our data indicate that both CD4+ and Treg infiltration are significantly increased throughout the time of metastatic tumor progression. These findings were recapitulated in human CNS tumor samples of metastatic melanoma and non-small cell lung carcinoma. Collectively, these data support investigating immunotherapeutic strategies targeting Treg in metastatic CNS tumors.
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PMID:Regulatory T cells actively infiltrate metastatic brain tumors. 1942 70


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