melphalan and Glioblastoma

Thirty-seven patients with recurrent primary brain tumors were treated with oral melphalan at a dose of 8 mg/m2/day for 5 days every 4-6 weeks. All patients had failed prior nitrosourea-based chemotherapy. Oral melphalan had no activity against glioblastoma, and minimal activity against other anaplastic astrocytomas. One recurrent medulloblastoma did have a clinical and radiographically sustained response that continued for greater than 14 months. We concluded that oral melphalan was not effective in the treatment of recurrent astrocytomas, but might have efficacy in medulloblastoma.

Topics: Administration, Oral; Astrocytoma; Brain Neoplasms; Clinical Trials as Topic; Glioblastoma; Humans; Medulloblastoma; Melphalan; Neoplasm Recurrence, Local

The tyrosine kinase receptor c-Met has been suggested to be involved in crucial parts of glioma biology like tumor stemness, growth and invasion. The aim of this study was to investigate the prognostic value of c-Met in a population-based glioma patient cohort. Tissue samples from 238 patients with WHO grade I, II, III and IV tumors were analyzed using immunohistochemical staining and advanced image analysis. Strong c-Met expression was found in tumor cells, blood vessels, and peri-necrotic areas. At the subcellular level, c-Met was identified in the cytoplasm and in the cell membrane. Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0.03). However the prognostic effect of c-Met in glioblastomas was time-dependent and only observed in patients who survived more than 8.5 months, and not within the first 8.5 months after diagnosis. This was significant in multivariate analysis (HR 1.99, 95 % CI 1.29-3.08, p = 0.002) adjusted for treatment and the clinical variables age (HR 1.01, 95 % CI 0.99-1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17-1.53, p < 0.001), and tumor crossing midline (HR 1.28, 95 % CI 0.79-2.07, p = 0.29). In conclusion, this study showed that high levels of c-Met holds unfavorable prognostic value in glioblastomas.

Topics: Brain Neoplasms; Cell Line, Tumor; Cephalosporins; Cohort Studies; Community Health Planning; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Proportional Hazards Models; Severity of Illness Index

Despite the male preponderance for developing glial tumors and a body of published literature that suggests a female gender advantage for long term survival in both human and animal studies, there have been relatively few rigorous investigations into the hormonal effects on glial tumor growth. In a previous study, we concluded that estrogen played a major role in the female survival bias seen in an intracerebral nude rat model of glioblastoma multiforme. Here we explore the potential therapeutic effect of exogenous estradiol delivery in nude rats with orthotopic glioblastoma tumors and examine the mechanism of action of estradiol on reducing tumor growth in this animal model. We administered estradiol, in several dosing regimens, to male, female and ovariectomized nude rats in a survival study. Brain sections, taken at various time points in tumor progression, were analyzed for estrogen receptor protein, proliferative index and apoptotic index. Estradiol increased survival of male, female and ovariectomized nude rats with intracerebral U87MG tumors, in a gender specific manner. The estradiol mediated effect occurred early in tumor progression, and appeared to be caused in-part by an increase in apoptotic activity. It remains unclear if estradiol's effect is direct or indirect and if it is estrogen receptor mediated. Estradiol-based or adjunctive therapy may be beneficial in treating GBM and further study is clearly warranted.

Topics: Animals; Apoptosis; Astrocytes; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Estradiol; Female; Glioblastoma; Humans; Immunoglobulin G; Male; Melphalan; Microglia; Neoplasm Transplantation; Ovariectomy; Rats; Rats, Nude; Receptors, Estrogen; Survival Analysis; Time Factors; Xenograft Model Antitumor Assays

The DNA repair and detoxifying enzymes, O(6)-methylguanine-DNA-methyltransferase (MGMT) and glutathione-S-transferase (GST), may be responsible fpr poor response to alkylating agents in glioblastoma treatment. The methylation of MGMT promoter and the expression of MGMT and GST were highly heterogeneous in surgical specimens of human glioblastoma and in established human glioblastoma cells under 2-D and 3-D culture conditions, suggesting an intrinsic property of these cells. MGMT and GST expression did not predict the sensitivity of glioblastoma cells to alkylating agents. Combination of alkylating agents with inhibitors of GST disclosed additive effects, suggesting that inhibition of GST should be considered in glioblastoma therapy.

Topics: Alkylating Agents; Brain Neoplasms; Carmustine; Cell Line, Tumor; Cell Proliferation; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; DNA Replication; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethacrynic Acid; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioblastoma; Glutathione S-Transferase pi; Glutathione Transferase; Guanine; Humans; Melphalan; Promoter Regions, Genetic; Tumor Suppressor Proteins

Rapid growth of a glioblastoma during therapy for multiple myeloma is reported. A 53-year-old man was admitted to our hospital with a right costal tumor, which was resected. The diagnosis was plasmocytoma. Urine protein electrophoresis showed a monoclonal peak in the region of gamma-globulin, and examination of the bone marrow revealed 17.8% of atypical plasma cells. Brain magnetic resonance (MR) imaging detected two small lesions, but these could not be identified as brain tumor. He received chemotherapy (melphalan 10 mg/day and predonin 30 mg/day for 4 days) and was discharged. Two weeks after discharge, he was readmitted because of left hemiparesis. T1-weighted MR imaging showed two large hypointense lesions in the right frontal lobe, with ring-like enhancement following Gd-DTPA infusion. 1H-MR spectroscopy showed typical findings of tumor with increased choline and lactic acid peaks. 201Tl SPECT revealed high accumulation in both early and delayed images. Right carotid angiography showed a hypervascular tumor with venous filling and mass effect. The lesions were resected via right frontal craniotomy, followed by intraoperative radiation and placement of an Ommaya reservoir. Histological examination showed the tumors were glioblastoma. The brain between the tumors also showed the typical appearance of glioblastoma, suggesting that the lesions were continuous. Postoperatively, the patient's left hemiparesis disappeared. He received local irradiation and chemotherapy and was then discharged. Coexistence of glioblastoma and multiple myeloma is rare. The cause may be genetic abnormality, but immunodeficiency due to multiple myeloma, surgical damage, or chemotherapy may have contributed to the rapid growth of the glioblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Prednisolone

We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens.. Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care.. Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation.. The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Brain Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Ependymoma; Female; Fibrosarcoma; Glioblastoma; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Medulloblastoma; Melphalan; Neoplasm Recurrence, Local; Pinealoma; Transplantation, Autologous; Treatment Outcome