High-dose methotrexate for primary CNS lymphoma in the elderly.
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Primary central nervous system lymphoma (PCNSL) in the immunocompetent patient reaches a peak incidence in the sixth and seventh decades of life. This retrospective study reviewed the efficacy and tolerability of high-dose methotrexate (HDMTX) in an elderly patient population. Between May 1995 and September 1998, ten consecutive elderly patients with histologically proven PCNSL were treated with HDMTX. The median age was 72.5 years and eight patients (80%) were older than 70 years. HDMTX was well tolerated with no episodes of grade 4 toxicity nor febrile neutropenia. Toxicity included grade 3 nausea (1), grade 2 mucositis (2), and grade 2 asymptomatic elevation of liver transaminases (2). Grade 1 toxicity occurred in three patients with nausea, diarrhea, and mild reversible elevation in serum creatinine in one patient each. Six patients had a complete response and three patients achieved a partial response, giving an overall response rate of 90% (95% confidence interval, 56%-100%). The median overall survival for the cohort was 36 months (range 4-43 months). In summary, HDMTX is well tolerated in this elderly population with PCNSL and achieves response rates and median survival comparable with other chemotherapy or radiotherapy regimens. (+info)
SETA: a novel SH3 domain-containing adapter molecule associated with malignancy in astrocytes.
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Differential display polymerase chain reaction analysis was used to compare five differentiation states of the O-2A progenitor-like cell line CG4: progenitor cells and cells at 12 h or 4 days after the induction of differentiation into oligodendrocytes or astrocytes. This led to the identification of 52 sequence tags that were expressed differentially with cellular phenotype. One sequence was upregulated during differentiation of CG4 cells and represented a novel gene that we named SETA (SH3 domain-containing gene expressed in tumorigenic astrocytes). This gene encodes an SH3 domain-containing adapter protein with sequence similarity to the CD2AP (CD2 adapter protein) and CMS (Cas ligand with multiple Src homology) genes. SETA mRNA was expressed at high levels in the developing rat brain but was barely detectable in the normal adult rat or human brain. However, SETA mRNA was found in approximately one half of the human gliomas tested, including astrocytomas grades II, III, and IV, as well as oligodendrogliomas, mixed oligoastrocytomas, and human glioma-derived cell lines. A rat glioma generated by treatment with the alkylating carcinogen ethylnitrosourea on postnatal day 1 and a derived cell line also expressed SETA mRNA. Furthermore, in an in vitro model of astrocytoma progression based on p53-/- astrocytes, expression of SETA was restricted to cells that are tumorigenic. (+info)
Oncogenic potential of human neurotropic virus: laboratory and clinical observations.
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Cancer is a multi-step disease involving a series of genetic alterations that result in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has greatly increased through the use of DNA tumor viruses and their transforming proteins as a biological tool to decipher a cascade of events that lead to deregulation of cell proliferation and subsequent tumor formation. For the past ten years our laboratory has focused on the molecular biology of the human neurotropic papovavirus, JCV. This virus causes progressive multifocal leukoencephalopathy, a fatal neurodegenerative disease of the central nervous system in immunocompromised patients. JCV is a common human virus that infects more than 80% of humans but does not induce any obvious clinical symptoms. The increased incidence of acquired immune deficiency syndrome and the use of immunosuppressive chemotherapy have dramatically raised the incidence of PML. The coincidental occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-infected nonhuman primates, provides intriguing speculation on the association between JCV and CNS malignancies. In this report we discuss clinical data and laboratory observations pointing to the direct involvement of JCV in cancer. (+info)
Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study.
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The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70 years. (+info)
Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.
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PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome. (+info)
Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: from the First International CNS Germ-Cell Tumor Study.
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This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients. (+info)
The IGF/IGFBP system in CNS malignancy.
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The insulin-like growth factor (IGF) system includes IGF-I and IGF-II, the type I and type II IGF receptors, and specific IGF binding proteins (IGFBP-1 to IGFBP-6). These factors regulate both normal and malignant brain growth. Enhanced expression of IGF-I and IGF-II mRNA transcripts has been demonstrated in gliomas, meniningiomas, and other tumours. Abnormal imprinting of IGF-II occurs in gliomas, medulloblastomas, and meningiomas. Both types of IGF receptor are expressed in gliomas and, in particular, the type I IGF receptor appears to be upregulated in malignant brain tissue. Antisense IGF-I receptor mRNA induces an antitumour response, resulting in complete brain tumour regression. Clinical trials for the treatment of brain tumours in humans based on a gene transfer protocol using IGF-I receptor antisense are under way. All six IGFBPs are expressed to a variable extent in brain tumours. High concentrations of IGFBP-2 are found in cerebrospinal fluid from patients with malignant central nervous system tumours; therefore, IGFBP-2 might be a useful marker for these tumours. IGFBP-4 appears to be a negative regulator of tumour proliferation. Both in vitro and in vivo experiments suggest that the IGF system represents an important target for the treatment of malignant central nervous system tumours and the ongoing trials should provide valuable information for future therapeutic approaches. (+info)
Frequent alterations of the p14(ARF) and p16(INK4a) genes in primary central nervous system lymphomas.
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To elucidate the role of p53/p16(INK4a)/RB1 pathways in the tumorigenesis of primary central nervous system lymphomas (PCNSLs), we have analyzed p14(ARF), p16(INK4a), RB1, p21(Waf1), and p27(Kip1) status in a series of their 18 sporadic cases of diffuse large B-cell lymphoma, using methylation-specific PCR, differential PCR, and immunohistochemistry. Homozygous deletion or methylation of p14(ARF) was detected in 10 (56%) PCNSLs, and they were almost entirely deletions (except 1 case). A total of 11 (61%) PCNSLs demonstrated homozygous deletion (6 cases) or methylation (5 cases) of p16(INK4a). Six tumors showed both p14(ARF) and p16(INK4a) homozygous deletions. Hypermethylation of the RB1 and the p27(Kip1) promoter region was detected in 2 (11%) cases, whereas p21(Waf1) methylation was not detected in any. Immunohistochemistry revealed loss of p14(ARF) and p16(INK4a) expression in 10 (56%) samples, correlating with the gene status. Four cases showed independent negative immunoreactivity for pRB and p27(Kip1), and nearly one-half of cases (8 of 18; 44%) were characterized by lack of p21(Waf1) expression. These results indicate that inactivation of p14(ARF) and p16(INK4a) by either homozygous deletion or promoter hypermethylation represents an important molecular pathogenesis in PCNSLs. Hypermethylation of RB1, p21(Waf1), and p27(Kip1) appears to be of minor significance, these genes being independently methylated in PCNSLs. (+info)