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PubMed1982

Malignant glioma. Results of combined modality therapy.

Multimodal treatment of malignant gliomas is routinely used at New York University Medical Center. Overall, our treatment program has resulted in survival rates of 78% at six months, 51% at one year, and 7% at five years for these high-grade brain tumors. However, various subgroups (based on tumor or host factors, or both) fared significantly better or worse than others. Particularly limited survival rates were found in patients who experienced paresis/paralysis or impaired mental function, who had tumors that were markedly anaplastic, who were elderly, or who for a variety of reasons did not receive the multimodal treatment we consider optimal.

Adult↗
PubMed1999

Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme: report from the Children's Cancer Group.

BACKGROUND: The survival of children with glioblastoma multiforme (GBM) remains poor. In an effort to improve the cure rate of children with this disease, high-dose chemotherapy followed by autologous stem cell rescue (ASCR) has been evaluated. We report the regimen-related toxicity (RRT) and survival seen in 11 children with newly diagnosed GBM treated with high-dose chemotherapy on a Children's Cancer Group study (CCG-9922). PROCEDURES: This phase II pilot study, intended to treat 30 patients, accrued 11 patients from July, 1993, to April, 1995. The pre-ASCR preparative regimen included BCNU 100 mg/m2 every 12 hr for a total of six doses on days -8, -7, -6; thiotepa 300 mg/m2/day on days -5, -4, -3; and etoposide 250 mg/m2/day on days -5, -4, -3. All patients received delayed radiotherapy at a dose of 5,400 cGy to the primary site commencing on approximately day +42 after ASCR. RESULTS: Five patients (45%) developed significant, nonfatal (grade III or IV) pulmonary and/or neurological toxicities. Three patients developed signs and/or symptoms of idiopathic interstitial pneumonitis. Eight patients (73%) have died, two (18%) of toxicity, and six (55%) of disease progression. Three patients (27%) achieved and remain in complete radiographic remission 2.9, 3.9, and 5.1 years from ASCR. One of these three, developed a lymphoblastic non-Hodgkins lymphoma (NHL) 3. 5 years post-ASCR. The survival rates for these 11 children at 1 year and 2 years are 73% +/- 13% and 46% +/- 14%, respectively. The progression-free survival rates at 1 year and at 2 years are 64% +/- 14% and 46% +/- 14%, respectively. CONCLUSIONS: We conclude that high-dose chemotherapeutic regimens followed by ASCR is a feasible treatment of childhood GBM. The BCNU-based preparative regimen utilized in this study was associated with prohibitive pulmonary toxicity.

Adolescent↗
PubMed1996

The sequential changes in DNA synthesis, glucose utilization, protein synthesis, and peripheral benzodiazepine receptor density in C6 brain tumors after chemotherapy to predict the response of tumors to chemotherapy.

BACKGROUND: Monitoring therapy in patients with brain tumors is very difficult and unreliable. It has been shown that there is no good correlation between tumor sensitivity measured in vitro and in situ tumor response to therapies. METHODS: Sequential changes in tumor size, number of DNA synthesizing cells (labelling index [LI]), glucose utilization (LCGU), protein synthesis (LCPS), and peripheral benzodiazepine receptor (PBR) density were examined after chemotherapy for seven days. This was done using antibromodeoxyuridine immunohistochemical stain and multiple tracer quantitative autoradiography in a C6 rat brain with an implanted glioma. On Day 10 after inoculation, the rats were divided into 5 experimental groups: (1) a nontreatment group (control Group 1); (2) a group received 5% dextrose intraarterial (IA) administration (control Group 2); (3) a group received 1,3-bis-(2-chloroethyl) nitrosourea (BCNU) intravenous (i.v.) administration (Group 3) (5% dextrose was solvent); (4) a group received BCNU IA administration (Group 4) (5% dextrose was solvent); and (5) a group received sarcosinamide chloroethyl nitrosourea (SarCNU) IA administration (Group 5) (solvent as for the BCNU group). RESULTS: Three treatments showed a significant decrease (P < 0.003) in tumor growth. The most effective treatment was BCNU IA and SarCNU IA was moderately effective. BCNU i.v. showed no effect on tumor growth when compared with the two control groups. The change in the peak LI correlated well with the peak LCGU. These parameters decreased markedly and significantly in both Group 4 and Group 5 from Day 1 after treatment. The rates of the decrease in these biologic factors also correlated well with a decrease in the tumor growth. The LCPS did not correlate with a decrease in the LI or LCGU. The dissociation constant (Kd) and densities of the receptors PBR (B max) did not change significantly in any of the treatment groups during the observation period. CONCLUSIONS: From the results presented, we concluded that changes in the LI and LCGU represent the most reliable parameters with which to predict the response or sensitivity of this glial tumor to the treatments applied. These data suggest that if changes in peak LCGU were measured in tumors using positron emission tomography, they might be instrumental in providing in vivo information about the sensitivity of a tumor to a given treatment without the need for repeated tumor biopsy.

Animals↗
PubMed1998

Assessment of pulmonary and cardiac function after high dose chemotherapy with BEAM and peripheral blood progenitor cell transplantation.

BACKGROUND: Limited information is available regarding the cardiac and pulmonary effects of high dose chemotherapy (HDCT) and autologous peripheral blood progenitor cell (PBPC) transplantation. METHODS: The authors evaluated cardiac and pulmonary function after BEAM (BCNU 300 mg/m2, etoposide 400 mg/m2/day x 3 days, cytosine arabinoside 200 mg/m2/day x 4 days, and melphalan 140 mg/m2), HDCT, and PBPC transplantation in 26 patients with non-Hodgkin's lymphoma or Hodgkin's disease. Therapy prior to BEAM included doxorubicin (25 patients), bleomycin (6 patients), and mediastinal irradiation (4 patients). All patients had pulmonary function tests (PFTs) and equilibrium radionuclide angiography before and at a median of 57 weeks after transplantation. RESULTS: Prior to high dose therapy, 8 patients had abnormal PFTs, including 6 with a diffusing capacity of the lung for carbon monoxide (DLCO) <70% of predicted value. At the time of reevaluation after HDCT, all patients included in the study were in complete remission, and none had received additional therapy after transplantation. At a median of 77 weeks after transplantation, none of the patients had cardiac or pulmonary symptoms. Moreover, there were no significant changes in total lung capacity, forced vital capacity, forced expiratory volume in 1 second/forced vital capacity, DLCO, or left ventricular ejection fraction values when compared with baseline studies. CONCLUSIONS: The authors concluded that HDCT with BEAM and PBPC transplantation did not result in significant cardiac or pulmonary toxicity, even in patients with borderline pretransplantation PFT values. Further studies of patients undergoing HDCT and PBPC transplantation are needed.

Adult↗
PubMed1996

Human brain tumor O(6)-methylguanine-DNA methyltransferase mRNA and its significance as an indicator of selective chloroethylnitrosourea chemotherapy.

O(6)-methylguanine-DNA methyltransferase (MGMT) removes and repairs chloroethylnitrosourea (CENU)-induced O(6)-methylguanine-DNA by accepting the alkyl group at a cysteine moiety. MGMT activity is, therefore, predictive of resistance or sensitivity to CENU chemotherapy. We measured the levels of MGMT mRNA expression in human brain tumors using a reverse transcription-polymerase chain reaction (RT-PCR) method, and studied the significance of MGMT mRNA levels in CENU chemotherapy. The level of MGMT mRNA was represented as a percentage relative to the MGMT mRNA in U138MG brain tumor cells. Forty-three patients with brain tumors were entered into the study. High-grade gliomas had significantly lower levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (p < 0.05 determined by analysis of covariance). Out of 14 high-grade gliomas, 4 had a level of MGMT mRNA below 10%, indicating chemosensitivity to CENU. Out of 11 patients who received CENU chemotherapy, 3 had a partial response. All 3 responders had a low level of MGMT mRNA. The time to tumor progression (TTP) for 6 patients with a level lower than the median was short, but significantly longer than the TTP for 5 patients with a higher level (p < 0.05 determined by Gehan's Wilcoxon test). These results indicate that a fraction of brain tumors have a low expression of MGMT mRNA, and that the level of MGMT mRNA is a useful indicator of effectiveness in selective CENU chemotherapy.

Antineoplastic Agents, Alkylating↗
PubMed1999

O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation.

Repair of cytotoxic DNA damage by O(6)-methylguanine-DNA methyltransferase (MGMT) is a potentially important factor of chemoresistance to chloroethylnitrosoureas (CENUs), commonly used in the treatment of glioblastoma multiforme (GBM). The value of p53 as a prognostic factor in GBMs remains unclear, but a possible relationship between MGMT gene expression and p53 has been suggested. To further examine these GBM characteristics in vivo, we assessed MGMT gene expression using semi-quantitative RT-PCR and p53 alteration by immuno-histochemistry on a series of 39 GBMs. MGMT gene expression was inversely correlated with age (p < 0.03), consistent with the results of others. Interestingly, tumors from male patients had higher MGMT mRNA amounts than tumors from female patients (p < 0.03). No prognostic implication was observed either for MGMT gene expression or for p53 accumulation. However, MGMT gene expression was significantly lower in p53-altered GBM, regardless of the percentage of positive cells (p < 0.01). Our observation suggests that in human glial tumors, a low level of MGMT gene expression might promote p53 alteration, probably via mutation of its gene. Int. J. Cancer (Pred. Oncol.) 84:416-420, 1999.

Aged↗
PubMed1996

Evaluation of reactive oxygen species involvement in amiodarone pulmonary toxicity in vivo and in vitro.

Amiodarone (AM) is an effective antidysrhythmic agent, restricted in use by the development of adverse effects, including potentially fatal AM-induced pulmonary toxicity (AIPT). Although the pathogenesis of AIPT is unknown, an oxidant mechanism has been proposed. The present study evaluated the role of reactive oxygen species (ROS) in AM-induced toxicity. The effect of inhibiting lung antioxidant defense on in vivo development of AIPT was evaluated in hamsters. Lung glutathione reductase activity was inhibited by 66%, 6 hours following administration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (20 mg/kg i.p.). When AM (1.83 mumol) was administered intratracheally 6 hours after BCNU, toxicity was enhanced, as indicated by lung hydroxyproline content and histological evaluation 21 days later. However, BCNU treatment did not affect AM-induced alterations in lung glutathione, suggesting that the increased toxicity was not due to decreased antioxidant capacity following BCNU. The effect of BCNU on AM cytotoxicity in vitro was evaluated using rabbit lung alveolar macrophages. Incubation with 5 microM BCNU for 2 hours caused greater than 95% inhibition of glutathione reductase activity. However, BCNU treatment had no effect on 146 microM AM-induced cytotoxicity, as assessed by lactate dehydrogenase latency following 12 hours of incubation. Rabbit macrophages loaded with 2',7'-dichlorofluorescein, which is oxidized by ROS to fluorescent 2',7'-dichlorofluorescein (DCF), were used to evaluate ROS generation by AM. Incubation of macrophages with AM (73 or 146 microM) for 1 hour, with or without the catalase inhibitor sodium azide (1 mM), did not result in DCF formation. Overall, these results do not support the hypothesis that AIPT is due to ROS action.

Amiodarone↗