Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme.

Pathological findings in 20 cases of glioblastoma multiforme were correlated with clinical histories and computerized tomographic (CT) scans. This was done to define the neoplasm in three stages: before treatment, during remission, and during recurrence. The untreated lesions were markedly cellular neoplasms composed predominantly of small anaplastic cells. The radiographic central region of low density was necrosis, the enhancing rim was a cellular zone of viable neoplasm, and the perilesional low-density area was edema with infiltrating tumor. In these 20 cases, all of the identifiable neoplasms lay within the zone of peritumoral edema or contrast enhancement, although small anaplastic cells may have been present in more distant regions. The lesions in remission were remarkable for their minimal mass effect, discrete nature, extensive necrosis, and content of large bizarre glia. The large cells were confined to the original tumor bed and were consistent with neoplastic cells inactivated and immobilized by radio- and chemotherapy. These lesions were accurately localized by CT scanning. The recurrent lesions were heterogeneous, but most were formed of widely disseminated small anaplastic cells. The highly cellular regions of such lesions could be localized by CT scanning, but CT could not detect less cellular foci in the cerebrum, cerebellum, or brain stem. In one patient, the contrast-enhancing lesions of "recurrence," were foci of radionecrosis, underscoring the difficulty in distinguishing this entity from recurrent neoplasm.

Traumatic occlusion in fibromuscular dysplasia of the carotid artery.

A patient with fibromuscular dysplasia involving the cervical carotid artery developed subtotal occlusion after a trivial head injury. An association between occlusion in fibromuscular dysplasia-diseased carotid arteries and trivial blunt head injuries is suggested and appropriate treatment options are discussed.

Hydrolytic enzyme activities of the nervous system.

The activities of five hydrolytic enzymes (acid and alkaline phosphatase, hexosaminidase [N-acetyl-beta-D-glucosaminidase], beta-galactosidase, and beta-glucorinidase) were measured in reconstituted homogenates of lyophilized human brain tissue and primary and metastatic tumors. The linearity of reaction, with respect to incubation time, and optimal pH of each enzyme and in tumor tissues were comparable to those in normal brain tissue. Total enzyme activities of hexosaminidase, beta-glucuronidase, and beta-galactosidase were significantly higher in tumors than in normal cerebral white matter. The ratio of hexosaminidase activity to beta-glucuronidase activity was significantly lower for metastatic than for primary tumors or normal white matter. When histological observations do not clearly establish if a brain tumor is primary or metastatic, this ratio may help. Alteration of hydrolytic enzyme activities as demonstrated here may be indicative of "ket enzymes" that are essential for maintaining the metabolic advantages of tumors.

Hydrolytic enzymes in meningiomal subtypes.

Estimation of activity of five hydrolytic enzymes was made in foru histologically different types of human meningiomas derived from surgery. The hydrolytic enzymes examined in 13 tumors included four lysosomal enzymes: beta-glucuronidase, N-acetyl-beta-D-glucosaminidase (hexosaminidase), beta-galactosidase, and acid phosphatase. The fifth enzyme studied was alkaline phosphatase. The one papillary-type meningioma examined appeared to contain generally greater activities of the lysosomal enzymes than the other tumor types. Alkaline phosphatase was decidedly greater in transitional type meningiomas. The correlation of histological types with alkaline phosphatase activity is discussed with regard to previous observations.

Chemotherapy of recurrent medulloblastoma with combined procarbazine, CCNU, and vincristine.

Seventeen patients with recurrent medulloblastoma were treated with a combination of three drugs: procarbazine, CCNU, and vincristine (PCV). Tumor recurrence was documented at varying periods following surgery and radiotherapy. Among 16 evaluable patients, ten showed a response to PCV on the basis of subjective neurological improvement and a decrease in tumor size by radiological criteria. Five patients were designated as having stable disease on the basis of no change in neurological status and tumor size. One patient showed uninterrupted progression of disease. The median time to progression for all patients was 45 weeks. Significnat myelotoxicity, exacerbated by prior spinal irradiation, compromised therapy. After an initial response, it was often necessary to reduce the higher doses of CCNU and procarbazine that caused concomitant bone-marrow toxicity; as a consequence of the lowered doses, tumor progression was then frequently observed. The authors conclude that PCV is an effective form of palliative therapy for recurrent medulloblastoma.

Basis and results of chemotherapeutic treatment of gliomas.

Brain tumor chemotherapy has improved in recent years with increasing knowledge of the requirements for effective drugs (such as lipophilicity and low molecular weight in order to enter brain tissue, and ability to kill proliferating and non-proliferating cells) and the evolution of criteria for statistically evaluable studies. In Phase II studies BCNU is the best single agent so far, giving a response rate of 51 per 100 for a median duration of 9 months. CCNU and procarbazine are also effective, while epipodophyllotoxin, DTIC, BIC, methotrexate and vincristine are somewhat less so. Recent Phase III studies have shown unequivocally that radiotherapy is effective; BCNU and radiation therapy together appear at present the best available treatment following surgery. Combinations of drugs as well as new drugs are a major source of hope for the future in these tumors with their still inexorably fatal courses.

Current status of population kinetics in gliomas.

One must know tumor cell kinetics in order to devise a rational drug regimen for gliomas. With tritiated thymidine, the Labelling Index of astrocytomas is less than 1 per 100; of glioblastomas from 5-10 per 100. The duration of S phase is fairly constant, ranging from 7 to 10 hours. Double radioautography reveals a cell cycle time of 2 to 3 days and a Growth Fraction of 10 to 30 per 100 in glioblastomas. Calculations based on volume of tumor at recurrence after a gross total resection, analysis of primer dependent D.N.A. polymerase (P.D.P.), and analysis of cells by Flow Microfluorometer, all confirm these approximate figures. Thus most of the cells of a glioma are not sensitive to a cell-cycle phase specific drug. Such an agent, if given, should be administered over a 2 to 3 day period, in order to affect as many cells as possible. The most important part of a drug regimen should be an agent which attacks non-proliferating as well as proliferating cells, such as an alkylating agent. The effects of various drugs and schedules can be examined by animal models with the technqiue of colony forming efficiency.

Intracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys.

Intracarotid artery (ica) BCNU was given at doses of 1-20 mg/kg/week for 4 weeks in six rhesus monkeys. Vascular, neurologic, and ophthalmic toxic effects were minor. The monkey receiving a dose of 15 mg/kg had transient left hemiparesis and slowing in her electroencephalogram which cleared 1 week after the third ica infusion of BCNU. At autopsy no vascular, neural, or ophthalmic lesions were found. At doses of 20 mg/kg for two injections, one monkey developed fatty metamorphosis of the liver and Alzheimer II glia in the brain, yet did not develop arteriolitis, corneal damage, or neurologic deficit. It is concluded that reasonable doses of BCNU (less than the systemic maximum tolerated dose) should be well tolerated by ica administration in man.

BCNU (NSC-409962) and procarbazine (NSC-77213) treatment for malignant brain tumors.

Sixty-five patients with malignant brain tumors were treated with a combination of BCNU (100 mg/m2 qd X 1) and procarbazine (100 mg/m2 qd X 14); the cycle was repeated in 1 month and then on a 6-week schedule with procarbazine being given for 21 days. Forty-five patients had malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma, malignant glioma, or gemistocytic astrocytoma) and were evaluated as a group. All patients had either shown evidence of tumor regrowth after previous surgery and/or radiotherapy, or had deep unbiopsied tumors presumed to be malignant gliomas. Of these 45 patients, 13 of 45 (30%) were judged to be unequivocal responders and an additional eight of 45 (17%) were designated as probable responders. The median duration of clinical response was 34 weeks for responders and 20 weeks for probable responders. The combination of BCNU and procarbazine, therefore, was somewhat inferior to a previous combination of procarbazine, CCNU, and vincristine.

The relationship of polyamines in cerebrospinal fluid to the presence of central nervous system tumors.

Cerebrospinal fluid (CSF) polyamine concentrations were assayed in patients with and without central nervous system tumors, using a high-pressure liquid chromatographic technique. Definite elevations were found in the CFS polyamine concentrations of patients with untreated malignant central nervous system tumors when compared with those concentrations observed in the CSF of patients without neoplasia. Patients undergoing successful tumor therapy for malignant central nervous system tumors showed CSF polyamine concentrations that closely approximated the concentrations found in the CSF of patients without tumor.

Long-term survival of patients treated with BCNU for brain tumors.

The authors present three patients who, after excision and irradiation of their brain tumors, were treated with BCNU for recurrence. All three patients responded well and now are without evidence of tumor, 37, 30, and 36 months after BCNU was stopped. Although these patients represent only a small fraction of those treated with BCNU, they indicate the potential role of chemotherapy in the management of glial tumors.