Manucher J. Javid

High-dose multi-agent chemotherapy followed by bone marrow rescue for malignant astrocytomas of childhood and adolescence

Between April 1986 and March 1989, ten patients under 21 years of age with histologically confirmed malignant astrocytoma, received marrow-ablative chemotherapy with either thiotepa and Etoposide (five patients) or thiotepa, Etoposide and BCNU (five patients), followed by bone marrow ‘rescue’. Nine patients had glioblastoma multiforme (GBM), and one patient had an intrinsic brain stem anaplastic astrocytoma (AA). Seven patients were treated for recurrent tumor. Two patients who developed GBM as second malignancies were treated directly following surgical resection. One patient had received irradiation only for recently diagnosed cervical spinal cord GBM.Thiotepa was administered at a total dose of 600–900 mg/M2 over three days, Etoposide was administered at a total dose of 1500 mg/M2 over three days, and BCNU was administered at a total dose of 600 mg/M2 over four days. Non-hematopoietic toxicities have been mainly transient, predictable and acceptable, consisting of oropharyngeal mucositis, cutaneous hyperpigmentation, erythema and desquamation.Four patients achieved complete responses (CR), as determined by radiographic evaluation (CT and/or MRI) on day 28 post-marrow infusion. The mean remission duration of those with CR is 290 + days; two patients presently remain in remission. Two patients achieved partial responses (PR, greater than 50% tumor shrinkage) by day 28 post-marrow infusion; both developed disease progression, at day 61 and 94 post-marrow infusion, respectively. One patient, with a brain stem AA, had stable disease maintained for 13 months post-marrow infusion.With a total (CR + PR) response rate of 60%, these regimens merit evaluation in broader categories of recurrent brain tumor patients, as well as in patients with newly-diagnosed GBM.

Metrizamide--CSF contrast medium. Analysis of clinical application in 215 patients.

Two-hundred-fifteen patients were evaluated with metrizamide, a new water-soluble contrast agent for use in the subarachnoid spaces. Side effects were reported in 67% of these; 39% were moderate or severe. Cervical injections monitored by fluoroscopy provide the most precise positioning of the medium. The benefits of metrizamide use outweigh its risk.

Treatment of increased intracranial pressure: a comparison of different hyperosmotic agents and the use of thiopental.

Long term intracranial pressure (ICP) monitoring was carried out in over 200 patients with various intracranial abnormalities; a fiberoptic epidural intracranial pressure monitor was used. Ninety of these patients had significantly elevated ICP or exhibited pressure waves requiring therapy. Initial therapy consisted of hyperventilation with a respirator and administration of hyperosmotic agents. Comparison studies utilizing 30% urea, 20% mannitol, and furosemide intravenously and 30% urea and 10% glycerol orally were randomly done. In 45 patients two or more of these agents were used at different times in the same patient for comparison of effectiveness. When equimolar amounts of intravenous urea and mannitol were used, similar effects on increased ICP were obtained. There was no significant reduction of increased ICP with the use of furosemide alone. No rebound effect was observed with either mannitol or urea. Orally, urea was more effective than glycerol in equimolar amounts. Again no rebound was observed. In 14 patients who required doses of hyperosmotic agents more frequently than every 4 hours, continuous infusion of thiopental was used in conjunction with the hyperosmotic agents to control pressure. This regimen resulted in good ICP control in 12 patients. A rational protocol for the medical management of increased ICP utilizing hyperosmotic agents and, in refractory cases, hyperosmotic agents plus thiopental has resulted in effective control of ICP in 96% of our patients throughout their course without the need to resort to decompressive surgery. (Neurosurgery, 5: 570--575, 1979).

Nonsurgical Management of Spontaneous Intracerebral Hematoma

This report describes our experience with the use of osmotic diuretics, governed by continuous monitoring of intracranial pressure (ICP), as the primary treatment for 12 consecutive patients suffering from an acute, supratentorial intracerebral hematoma. In all cases the hematoma, as shown by computed tomographic scan, had a long axis of greater than 4.0 cm. ICP and cerebral perfusion pressure were successfully maintained within the assigned limits in all patients, and in none was surgical evacuation required. There was one death during the 6-month follow-up period. With appropriate weighting to differences in admission status, statistical comparison of the patient outcome in the present series with that reported by McKissock et al. suggests that ICP monitoring can improve the outcome of conservatively (and perhaps surgically) treated patients.

Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia

Thymidine kills cells by depleting dCTP stores. The present experiments tested whether deoxycytidine, by replenishing dCTP pools, could prevent thymidine cytotoxicity and thymidines enhancement of carboplatin killing in two human T-cell acute leukemia cell lines. MOLT3 and JM cells were exposed to combinations of thymidine, deoxycytidine, and carboplatin and then assessed for survival, the magnitude of thymidine-carboplatin chemosensitization, and changes in deoxyribonucleoside triphosphate pools. For both cell lines, deoxycytidine (up to 144.5 micrograms/ml x 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100-1000 micrograms/ml x 24 h) and thymidine-carboplatin sensitization (up to 60 micrograms carboplatin/ml during the last hour of thymidine). This contrasts with complete protection in prior studies using other cell types. Thymidine alone markedly increased dTTP and dGTP pools and decreased dCTP; dATP pools underwent a sharp decline which has not been observed before in any cell line. In subsequent studies 0.0336-137.3 micrograms deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 micrograms thymidine/ml. Together, deoxycytidine and deoxyadenosine completely prevented thymidine-carboplatin sensitization even though dATP and dCTP pools were not entirely returned to normal. These findings are discussed in regard to the unusual sensitivity of T-cell malignancies to thymidine toxicity, mechanisms of cytotoxicity and chemosensitization by thymidine, and the possibility of thymidine selectively sensitizing T-cell malignancies to killing by alkylating agents.

Suspected cancer-causing agents in the hospital environment.

Abstract Samples of articles, such as cleaning agents and personal hygiene products, found in patient hospital rooms or used in these areas were tested for their cancer-producing potential in a short-term, in vitro assay. The DNA cell-binding (DCB) test used to screen these articles was previously found accurate in indicating a chemicals potential to induce tumors in more than 95% of cases. Seventeen out of fifty-one articles tested in the present study were found to be positive; i.e., they should be considered potentially dangerous to humans. We believe that efforts should be made to eliminate, to the extent possible, such potential carcinogens from the hospital environment. Simple steps to accomplish this goal are suggested.