UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From May 1990 to November 1994, 70 consecutive patients suffering from glioblastoma multiforme were treated following surgery with conventional radiotherapy and adjuvant IV BCNU administered alone or in combination with tamoxifen. Twenty-five patients received BCNU alone (control group A) while 24 patients also received 40 mg of tamoxifen (TMX) PO daily (group B) and 21 received 100 mg of TMX PO daily (group C). There were no significant differences between the 3 groups concerning age, type of resection and median post-operative Karnofsky performance status (KPS). Blood toxicity over grade II occurred in 33.5% of patients receiving TMX versus 12% of patients treated with BCNU alone (p < 0.05). Deep venous thrombosis complications were observed in 4 patients of each TMX group, whereas they were not observed in the control group (p < 0.04). Median time to tumor progression (MTTP) was 35 weeks in the control group and 27 weeks in both TMX groups B and C. Median survival time (MST) was 56, 66 and 51 weeks, respectively. These results suggest that the addition of TMX to standard treatment of glioblastomas does not affect the time to tumor progression and overall survival but may increase the risk of deep venous thrombosis or nitrosourea-induced blood toxicity.
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PMID:Treatment of supratentorial glioblastoma multiforme with radiotherapy and a combination of BCNU and tamoxifen: a phase II study. 1084 93

The overall prognosis for patients with glioblastoma multiforme is extremely poor. However, a small proportion of patients enjoy prolonged survival. This study investigated retrospectively the extent to which erroneous histopathological classification may contribute to long-term survival of patients initially diagnosed with "glioblastoma multiforme." We compared two age- and gender-matched patient groups with different postoperative time to tumor progression (TTP), defined as "short-term" for TTP of less than 6 months (n = 54), and "long-term" for TTP of more than 12 months (n = 52). Histological specimens of the corresponding tumors, all primarily diagnosed as glioblastoma multiforme, were reevaluated according to the current World Health Organization (WHO) classification of central nervous system tumors, with the investigators being blinded to clinical outcome. Among the tumors from short-term TTP patients, one tumor (2%) was reclassified as anaplastic oligoastrocytoma (WHO grade III) while the remaining 53 were confirmed as glioblastoma multiforme. In contrast, 13 tumors (25%) from the long-term TTP patients were reclassified, mostly as anaplastic oligodendroglioma (WHO grade III; n = 7) or anaplastic oligoastrocytoma (WHO grade III, n = 2), respectively. In addition, three were reclassified as anaplastic astrocytoma (WHO grade III), and one was identified as anaplastic pilocytic astrocytoma (WHO grade III). Our data indicate that a sizable proportion of glioblastoma patients with long-term survival actually carry malignant gliomas with oligodendroglial features. The correct histopathological recognition of these tumors has not only prognostic but also therapeutic implications, since oligodendroglial tumors are more likely to respond favorably to chemotherapy.
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PMID:Long-term survival of glioblastoma multiforme: importance of histopathological reevaluation. 1092 75

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.
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PMID:Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. 1093 31

Extracellular matrix metalloproteinase inducer (EMMPRIN) also called CD147, basigin or M6 in the human is a member of the immunoglobulin superfamily that is enriched on the surface of tumor cells and stimulates adjacent stromal cells to produce several matrix metalloproteinases (MMPs). In this study, we have demonstrated that coculturing of EMMPRIN-expressing human glioblastoma multiforme cells (U251) with brain-derived human fibroblasts not only stimulates production, but also activation of pro-gelatinase A (proMMP-2), an enzyme that is enriched in malignant gliomas and most likely crucial to tumor progression. Production of membrane types 1 and 2-MMPs (MT1-MMP and MT2-MMP), which are activators of proMMP-2, was also stimulated in these cocultures. Stimulation of MMP-2, MT1-MMP and MT2-MMP production was inhibited by anti-EMMPRIN monoclonal antibody in a dose-dependent manner. Thus, we have shown, for the first time, that EMMPRIN causes increased expression of MT1-MMP and MT2-MMP, as well as increased production and activation of MMP-2.
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PMID:Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. 1093 78

EMMPRIN (extracellular matrix metalloproteinase inducer), also called CD147, basigin or M6 in the human, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). In our study, we investigated expression of EMMPRIN in human normal brain and gliomas, since mouse basigin and chicken HT7, the species homologues of human EMMPRIN, are associated with neuronal interactions and normal blood-brain barrier function, respectively. EMMPRIN expression was detected in all samples of non-neoplastic brain and glioma tissues examined. However, expression levels of EMMPRIN mRNA and protein were significantly higher in gliomas than in non-neoplastic brain. Moreover, levels of mRNA expression and immunohistochemical staining correlated with tumor progression in gliomas: They were highest in the most malignant form of glioma, glioblastoma multiforme, followed by anaplastic astrocytoma and then low-grade astrocytoma. Also, immunolocalization revealed quite different distributions in non-neoplastic brain and glioma: EMMPRIN was demonstrated only in vascular endothelium in non-neoplastic regions of the brain, whereas it was present in tumor cells but not in proliferating blood vessels in malignant gliomas. These data indicate that an MMP inducer molecule EMMPRIN is differently expressed in human normal brain and gliomas and could be associated with astrocytoma progression. Possible mechanisms whereby glioma cell EMMPRIN could influence tumor progression will be discussed.
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PMID:Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. 1096 35

Recent publications support the use of preradiation chemotherapy in the treatment of selected primary brain tumors. In the pediatric population, this treatment strategy often delays radiotherapy and may improve the outcome in patients. This manuscript describes the use of a preradiation chemotherapy approach for adult patients with newly diagnosed glioblastoma multiforme. The main objective of this trial was to determine the feasibility of delivering up to 3 monthly cycles of a 72 h continuous simultaneous intravenous infusion of BCNU (40 mg/m2/day) and cisplatin (40 mg/m2/day). Patients were evaluated for tumor response or progression after each cycle. Following the completion of the chemotherapy treatments or evidence of tumor progression, patients underwent external beam radiotherapy. A dose of 45 Gy was delivered to the pretreatment tumor volume plus surrounding edema and a margin of 3.0 cm. An additional 14.4 Gy was delivered to the preoperative volume plus a 2 cm margin. Fifty patients were enrolled, 47 were eligible and analyzable. Overall, 79% of patients were able to complete at least 2 cycles of treatment, exceeding the predefined measure of feasibility. One patient achieved a complete response, 10 patients a partial response and 18 patients had stable disease at completion of the chemotherapy treatments. Twenty-four patients experienced grade 4 toxicity, mostly hematologic. All patients were able to undergo radiotherapy following chemotherapy. These results indicate that a preradiation strategy is feasible. Although responses to the chemotherapy were seen, a phase III trial is needed to determine whether this approach provides an advantage over standard treatment; such a phase III trial has been undertaken by ECOG.
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PMID:A phase II study of preradiation chemotherapy followed by external beam radiotherapy for the treatment of patients with newly diagnosed glioblastoma multiforme: an Eastern Cooperative Oncology Group study (E2393). 1098 56

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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PMID:Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. 1105 Dec 33

Despite multimodal therapy, glioblastoma multiforme (GBM) is associated with a poor prognosis with a median survival of less than 1 year. However, a small number of patients with GBM shows survival times of several years. Although clinical features like age and performance status at diagnosis are well known prognostic parameters, molecular markers for prognosis of overall survival are still lacking. Therefore, we compared 2 age- and gender-matched groups of GBM patients with different post-operative time to tumor progression (TTP), defined as 'short-term' for TTP of less than 6 months (n = 21), and 'long-term' for TTP of more than 24 months (n = 21) for genetic alterations of the PTEN, CDKN2A and TP53 genes as well as overexpression of the EGFR, p53 and Mdm2 proteins. For the GBMs with 'short-term' TTP vs. 'long-term' TTP, the studies revealed PTEN mutations in 4/21 vs. 2/21, TP53 mutations in 5/21 vs. 8/21, homozygous deletion of the CDKN2A gene in 5/21 vs. 6/21, overexpression of EGFR in 7/20 vs. 10/20, accumulation of p53 protein in 9/20 vs. 7/20 and of Mdm2 protein in 0/20 vs. 1/20 cases studied. Taken together, our data indicate that mutations of the PTEN and TP53 tumor suppressor genes, homozygous deletion of the CDKN2A gene as well as overexpression of the EGFR, p53 and Mdm2 proteins lack prognostic significance for overall survival time in patients with GBMs.
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PMID:Molecular analysis of the PTEN, TP53 and CDKN2A tumor suppressor genes in long-term survivors of glioblastoma multiforme. 1108 71

Activation of telomerase may allow unlimited cell proliferation and immortalization. One of the telomerase protein subunits has a reverse transcriptase (hTERT) activity that is essential for telomerase function and regulation. In human gliomas, telomerase is frequently associated with malignant tumor progression. In our study, we investigated the expression of hTERT at the cellular level in 34 primary de novo glioblastoma multiforme (GBM) by in situ hybridization (ISH). The expression of hTERT in tumor tissue was also assessed by RT-PCR. In addition, telomerase activity measured by telomeric repeat amplification protocol (TRAP) and telomere length polymorphism assayed by telomere restriction fragment (TRF) Southern blot were investigated. We found that all GBM, including those with negative TRAP reaction, contained abundant amounts of cytoplasmic hTERT mRNA. Interestingly, the ISH analysis revealed that the hTERT mRNA was homogeneously expressed by the whole tumor cell population in about 60% of the GBM. In the remaining cases, hTERT was absent in subsets of tumor cells. TRF analysis, which shows that both TRAP-positive and TRAP-negative de novo GBM have elongated telomeres, further supports that telomerase activity is present in all de novo GBM. Correlations with tumor size and extent of necrosis suggest that hTERT reactivation is an early event in GBM development and that telomerase activity may be lost in subpopulations of neoplastic cells during tumor progression. Finally, ISH analysis of hTERT mRNA seems to provide a prognostic parameter for primary de novo GBM.
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PMID:In situ detection of telomerase catalytic subunit mRNA in glioblastoma multiforme. 1109 11

Previous uncontrolled clinical trials have shown the in vivo retrovirus (RV)-mediated transduction of glioblastoma cells with the herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent systemic treatment with ganciclovir to be feasible and well tolerated. However, because of continued tumor progression in most patients, the antitumor effect could not be determined using historical controls. Here, we describe a phase III, multicenter, randomized, open-label, parallel-group, controlled trial of the technique in the treatment of 248 patients with newly diagnosed, previously untreated glioblastoma multiforme (GBM). Patients received, in equal numbers, either standard therapy (surgical resection and radiotherapy) or standard therapy plus adjuvant gene therapy during surgery. Progression-free median survival in the gene therapy group was 180 days compared with 183 days in control subjects. Median survival was 365 versus 354 days, and 12-month survival rates were 50 versus 55% in the gene therapy and control groups, respectively. These differences were not significant. Therefore, the adjuvant treatment improved neither time to tumor progression nor overall survival time, although the feasibility and good biosafety profile of this gene therapy strategy were further supported. The failure of this specific protocol may be due mainly to the presumably poor rate of delivery of the HSV-tk gene to tumor cells. In addition, the current mode of manual injection of vector-producing cells with a nonmigratory fibroblast phenotype limits the distribution of these cells and the released replication-deficient RV vectors to the immediate vicinity of the needle track. Further evaluation of the RV-mediated gene therapy strategy must incorporate refinements such as improved delivery of vectors and transgenes to the tumor cells, noninvasive in vivo assessment of transduction rates, and improved delivery of the prodrug across the blood-brain and blood-tumor barrier to the transduced tumor cells.
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PMID:A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. 1109 43

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