The course of seizure disorders in patients with malignant gliomas.

OBJECTIVE: To describe the morbidity associated with seizures and the efficacy of anticonvulsant therapy in adult patients with malignant gliomas (MGs). STUDY DESIGN: A retrospective review of charts was performed to determine the occurrence of seizures at diagnosis, the frequency and character of subsequent seizures, and the use and toxic side effects of anticonvulsants. PATIENTS: Sixty-five consecutive adult patients with supratentorial MGs who were examined in the neurooncology clinic at a university medical center were studied. The diagnosis was glioblastoma in 47 of the patients, and it was anaplastic astrocytoma in 18 patients. The mean age of the patients was 49.5 years. The median Karnofsky status score was 80. The median survival was 18 months. RESULTS: Twenty-nine patients presented with seizures, and 21 of these had subsequent (eg, "recurrent") seizures while they were receiving anticonvulsant therapy. Ten of 36 patients who were free of seizures at diagnosis experienced seizures after diagnosis (eg, "late onset") while they were being treated with anticonvulsants, including five patients who had single seizures. Long-term seizure frequency in excess of one per month was observed in 13 patients. Ten patients had episodes of partial motor status epilepticus. Most recurrent and late-onset seizures occurred despite therapeutic anticonvulsant levels, and without evidence of tumor progression. Rash associated with anticonvulsants was observed in 26% of the patients. Other clinically important toxic side effects were observed in 14% of the patients who were receiving long-term anticonvulsant therapy. CONCLUSIONS: Seizures contributed substantially to the neurologic morbidity of MGs in at least 25% of these patients. The occurrence of seizures at diagnosis was a strong predictor of subsequent seizures, and in many patients, seizures proved to be refractory to standard anticonvulsant therapy. Long-term anticonvulsant toxic side effects are relatively common in patients with MGs. The use of long-term seizure prophylaxis for patients with MGs who are free of seizures at presentation is not clearly beneficial and should be studied in a prospective trial.

Synthesis of heat shock proteins following oxidative challenge: role of glutathione.

The relationship between glutathione metabolism, menadione sodium bisulphite oxidation of protein thiols, and the synthesis of hsc70 was investigated using CHO cells. A 30-min/37 degrees C exposure to menadione, a compound which redox cycles to produce superoxide anion radicals and hydrogen peroxide, resulted in rapid accumulation of hsc70 mRNA. PAGE and Western blot analysis indicated increased synthesis such that accumulation of hsc70 occurred. These changes were preceded by rapid oxidation of GSH to GSSG, followed by GSH depletion, and subsequent protein thiol oxidation. As a test of whether a correlation existed between GSH oxidation and depletion, protein thiol oxidation and hsp synthesis, cells were exposed to menadione in the absence and presence of glucose. Synthesis of hsc70 was increased in cells exposed to menadione in the absence of glucose compared with its presence. As a further test, cells were exposed to BSO/DEM in order to deplete GSH and then exposed to menadione. The synthesis of hsc70 following exposure to menadione was greatly increased in GSH-depleted cells compared with GSH-replete cells. Experiments were conducted to determine if electroporation of cells in GSSG containing buffer affected hsp synthesis. Electroporation in glucose-free buffer containing 3 mM GSSG did not affect hsp synthesis. We interpret these results to indicate that the inability to maintain glutathione in a reduced form during menadione redox cycling resulted in protein thiol oxidation. This, in turn, resulted in accumulation of hsc70 mRNA with a subsequent increase in the synthesis of hsc70.

Synthesis of hsp-70 is enhanced in glutathione-depleted Hep G2 cells.

The question of whether depletion of glutathione (GSH) could affect the synthesis of stress proteins was investigated in Hep G2 cells. Cells were exposed to BSO/DEM at 37 degrees C to deplete glutathione. When 95% of the glutathione was depleted cells were washed, and BSO was added to cells previously exposed to BSO/DEM; then the cells were incubated at 37, 38.5, or 39 degrees C for 4 h. Two-dimensional PAGE analysis of GSH-depleted cells incubated at 37 degrees C indicated increased synthesis of heme oxygenase and a polypeptide tentatively identified as hsp-70B'. Depletion of GSH did not affect the cellular concentration of hsp-70 as assessed by Western immunoblotting, yet Northern blot analysis indicated that hsp-70 mRNA was increased in GSH-depleted cells. Incubation of GSH-replete cells at 38.5 degrees C did not appear to enhance the amount of hsp-70 mRNA or the relative rate of hsp-70 synthesis. In contrast, incubation of GSH-depleted cells at 38.5 degrees C elevated steady-state hsp-70 mRNA levels and the rate of hsp-70 synthesis relative to total protein synthesis. Depletion of GSH also increased the relative rate of hsp-70 synthesis at 39 degrees C. These results suggest that the synthesis of stress proteins can be affected by glutathione concentrations.

Depletion of glutathione after gamma irradiation modifies survival.

The relationship between the intracellular glutathione (GSH) concentration and the aerobic radiation response was studied in Chinese hamster ovary cells. Various degrees of GSH depletion were produced by exposure to buthionine sulfoximine (BSO) and/or diethyl maleate (DEM). Diethyl maleate did not act as a classical radiosensitizer under the experimental conditions employed, nor did exposure to DEM/BSO nonspecifically affect protein thiols as measured by thiol blotting. Dose-response curves were obtained using cells irradiated in the absence or presence of DEM/BSO, which decreased GSH levels by 90-95%. Exposure to DEM/BSO did not affect the formation of DNA single-strand breaks or DNA-protein crosslinks measured immediately after irradiation performed at ice temperatures. Analysis of survival curves indicated that the Dq was decreased by 18% when GSH depletion occurred prior to, during, and after irradiation. The DEM/BSO exposure did not affect D0. To study postirradiation conditions, cells were exposed to 10 microM DEM prior to and during irradiation, which was performed at ice temperatures. Levels of GSH were depleted by 75% by this protocol. Immediately after irradiation, the cells were rapidly warmed by the addition of 37 degrees C growth medium containing either 10 or 90 microM DEM. Addition of 10 microM DEM after irradiation did not affect the degree of depletion, which remained constant at 75%. In contrast, GSH depletion was increased to 90% 10 min after addition of the 90 microM DEM. Addition of 90 microM DEM after irradiation produced a statistically significant difference in survival compared to addition of 10 microM DEM. In a second depletion protocol, cells were exposed to 100 microM DEM at room temperature for 5 min, irradiated, incubated at 37 degrees C for 1 h, washed, and then incubated in 50 microM BSO for 24 h. This depletion protocol reduced survival by a factor of 2.6 compared to cells not exposed to the combination of DEM/BSO. Survival was not affected if the cells were exposed to the DEM or BSO alone. This was interpreted to indicate that survival was not affected by GSH depletion occurring after irradiation unless depletion was rapid and sustained. The rate of repair of sublethal and potentially lethal damage was measured and found to be independent of the DEM/BSO exposure. These experimental results in addition to previous ones (Freeman and Meredith, Int. J. Radiat. Oncol. Biol. Phys. 13, 1371-1375, 1987) were interpreted to indicate that under aerobic conditions GSH depletion may alter the expression of radiation damage by affecting metabolic fixation.

Failure of chronic glutathione elevation to reduce cytotoxicity produced by exposure to cis-diamminedichloroplatinum(II), ionizing radiation, or hyperthermia.

Chinese hamster ovary (CHO) cells cultured in vitro were continuously exposed to increasing concentrations of diethylmaleate (DEM). Chronic exposure of these cells (designated CHO/DEM) to 80 microM diethylmaleate resulted in an increase in cystine transport, a decrease in glutathione inhibition of the enzyme gamma-glutamylcysteine synthetase, elevation of intracellular glutathione levels to 4.3 times control, and elevation of glutathione-S-transferase activity by 6.6 times. Yet, CHO/DEM and control CHO cells exhibited the same ability to synthesize protein as measured by two-dimensional electrophoresis, the same cell cycle distribution, and the same population doubling times. CHO/DEM cells are resistant to DEM and diamide cytotoxicity, compared to control CHO cells. CHO/DEM cells were used to address the question of whether chronic elevation of glutathione, above control concentrations, reduced the cytotoxicity produced by exposure to cisplatin, gamma-radiation, or hyperthermia. The resulting dose-response curves obtained with CHO/DEM and control CHO cells indicated that chronic exposure to DEM, which resulted in chronic elevation of glutathione, did not provide protection against any of the three toxic treatments.

Primary malignant extragonadal germ cell tumors. An analysis of the effect of the effect of radiotherapy.

A retrospective analysis was performed on all patients diagnosed with biopsy-proven extragonadal germ cell tumors at the University of Virginia (Charlottesville, VA), The Medical University of South Carolina (Charleston, SC), the Bethesda Naval Hospital (Bethesda, MD), and The Medical College of Virginia (Richmond, VA) for the time period of January 1965 to December 1984. A total of 54 patients were treated with the initial sites of presentation observed: mediastinum, 26; central nervous system, 14; retroperitoneum, eight; and sacrococcygeal region, six. Megavoltage irradiation was used in 44 patients with a dose range of 2400 to 5580 cGy (mean, 4213 cGy). With a minimum follow-up of 4.0 years and a mean follow-up of 10.8 years, the 5-year actuarial survival for the entire population was 57.8%. Local control was achieved in 26 of 44 (59%) of the irradiated population. Factors of prognostic significance included histologic type at presentation, site of presentation, and radiation doses greater than or equal to 4000 cGy. Radiotherapy appears to be an effective modality in patients with extragonadal seminomas; however, the nonseminomatous tumors do not appear to be as radioresponsive.

Total lymphoid irradiation in heart transplantation: adjunctive treatment for recurrent rejection.

In the face of recurrent heart transplant graft rejection refractory to all conventional immunotherapy, retransplantation is customary treatment. The case of a heart transplant recipient unsuitable for retransplantation whose recurrent rejection was successfully treated with postoperative total lymphoid irradiation is described.

Primary central nervous system germ cell tumors. Effect of histologic confirmation on radiotherapy.

Primary malignant intracranial germ cell tumors are rare lesions responsible for only 0.5% of all central nervous system (CNS) malignancy. With stereotactic localization these lesions can be safely biopsied, and histologic confirmation will affect the ultimate prognosis. This report is a multi-institutional retrospective analysis of 33 patients diagnosed with a primary CNS germ cell tumor. Tumors in 14 patients (42%) were histologically confirmed (13 germinoma and one embryonal cell carcinoma); 19 patients were treated with a presumptive diagnosis. All patients were irradiated with a dose range of 3950 cGy to 6000 cGy to the primary lesions. Eight patients received craniospinal irradiation, and 25 patients were locally treated. The 5-year actuarial survival for the entire population was 64%. The survival rate in patients with histologic confirmation was 79% versus 53% in the unbiopsied population. Radiation doses greater than 5000 cGy, radiotherapy volume, and age were prognostic factors in determining survival.

1986 Association of Residents in Radiation Oncology Survey.

Two simultaneous surveys were conducted by the Association of Residents in Radiation Oncology (ARRO). A survey of all residents in Radiation Oncology was conducted to obtain information on trends in residency training. A simultaneous survey of Chief Residents was obtained to determine more specific information on current training programs. Over one-half of residents responded. Eighty-eight percent of respondents were graduates of a North American medical school. Most did at least an internship prior to entering Radiation Oncology and 3/4 of those who did not do a separate internship rotated through other areas at a later time to broaden their knowledge. One-half are Board certified or Board eligible in another specialty or hold a Masters or Ph.D. degree. Three-quarters of all residents had authorship of at least one paper during training and one-half were primary authors. Eighty percent felt adequately prepared for practice after residency. One-half plan at least an initial post-residency affiliation with an academic center. Many were concerned that Radiation Oncologists are not afforded respect equivalent to that of other specialties. Ninety-eight percent favored departmental status for Radiation Oncology. Resident recommendations for improving the image of Radiation Oncology are presented.

Primary malignant mediastinal germ-cell tumors and the contribution of radiotherapy: a southeastern multi-institutional study.

A retrospective review was performed by a multi-institutional study group to determine the contribution of radiotherapy to the management of primary malignant mediastinal germ-cell tumors. Twenty-seven patients diagnosed with a primary mediastinal germ-cell tumor between January 1965 and July 1985 form the basis of this study. Twenty-five of the 27 patients were male. Thirteen patients' tumors were diagnosed as seminoma and the remaining 14 patients' tumors had other germ-cell histologies. The single most important prognostic factor was histology, with a 5-year actuarial survival of 100% for the seminomas and only 8.8% for the remaining germ-cell varieties. If total surgical extirpation is not possible, biopsy may be adequate. Of the patients with seminoma, 11 of 12 had local control, and 3 of the 12 patients were treated with doses between 3,000 and 3,100 cGy. High doses for this variety of mediastinal germ-cell tumor might not be required. For the germ-cell tumors other than seminoma, no patient had local control with doses over the range of 3,000-4,750 cGy.

An excess of uterine sarcomas after pelvic irradiation.

The Ohio State University Registry recorded 1208 uterine corpus malignancies between 1940 and 1983. Thirty cases occurred in women with a history of pelvic irradiation. Eight patients had previously been irradiated for pelvic malignancy, four of whom presented with advanced stage sarcomas and died of their disease within 14 months. This represents an increase over the expected sarcoma prevalence which is less than 5%. In contrast, the majority of women (20 of 22) previously irradiated for benign conditions were diagnosed with endometrial adenocarcinoma. In 18, the adenocarcinoma was diagnosed as Stage I, and the prognosis was only slightly less favorable than for nonirradiated women. No significant effect of age at the time of irradiation was apparent. This study of women with a history of pelvic irradiation who later developed uterine cancer demonstrates a tendency for patients previously irradiated for pelvic malignancy to present with advanced stage, extremely aggressive uterine tumors compared to those previously irradiated for benign conditions.

Malignant thymoma: role of radiation therapy in management.

Malignant thymoma is a rare tumor generally seen as an anterior mediastinal mass. Radiation therapy in ten patients with malignant thymoma diagnosed in 1968-1983 was reviewed retrospectively. Surgical therapy consisted of subtotal resection in four patients and biopsy only in six. Megavoltage irradiation in the dose range of 4,600-5,250 cGy was employed. In all symptomatic patients, palliation of presenting symptoms was achieved. In seven patients, a greater than 50% reduction in tumor mass followed radiation therapy. Local control was achieved in six patients. Three patients show no evidence of disease clinically, after a minimum follow-up study of 1 year. Radiation therapy is an important therapeutic modality in the control of malignant thymoma.

Management of locoregional recurrent oropharyngeal carcinoma.

Sixty-seven patients with recurrent locoregional squamous cell epithelioma of the oropharynx were reviewed to determine the curative potential of secondary therapy for recurrent carcinoma. Of the 37 patients in whom recurrent carcinoma developed after radical surgery, only 11 percent (4 of 37) had a 2 year disease-free survival following secondary treatment. Recurrence developed in 30 patients after radiation therapy. Surgical resection of the recurrent carcinoma was possible in 13 of the patients, 38 percent (5 of 13) of whom were free of disease for a minimum of 2 years. Though treatment results in patients with recurrent oropharyngeal carcinoma are discouraging, secondary therapy in selected patients can yield 2 year disease survival in over a third of cases. Favorable prognostic factors included the development of recurrent carcinoma following radiation therapy and a tumor initially classified as stage I or II, irrespective of the initial mode of therapy.

Dose-time relationships and the local control of small cell carcinoma of the lung.

Since 1971, 66 patients with small cell carcinoma of the lung--32 with limited and 34 with disseminated disease--have received irradiation to the primary tumor. There were 20 local failures, 90% of which were apparent within 30 weeks of the start of irradiation. Patients were treated with local irradiation only (32), irradiation plus combination chemotherapy (25), or local plus total body irradiation (9). With local irradiation alone, tumor control increased with increasing biologic dose. When chemotherapy or total body irradiation was added, doses of irradiation that were otherwise insufficient for local control proved to be effective.