Paul L. Kornblith

Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography

Positron emission tomography was used to measure local cerebral glucose utilization by the 2-[18F]fluoro-2-deoxy-D-glucose technique in 23 patients with cerebral gliomas. All 10 high-grade (III and IV) astrocytomas demonstrated a region of high activity with a glucose consumption of 7.4 ± 3.5 (SD) mg/100 gm per minute. The 13 low-grade (I and II) gliomas had a glucose metabolic rate of 4.0 ± 1.8 mg/100 gm per minute, with no distinctly visible hot spot. Thus, we found a correlation between rate of glycolysis and malignancy in primary cerebral tumors. Cerebral cortical glucose utilization was often depressed in areas adjacent to or neurally connected to the tumor site, and there was focal irregular delta wave EEG activity in these areas.

A Phase I study of intermittent intravenous bromodeoxyuridine (BUdR) with conventional fractionated irradiation.

A Phase I trial of intravenous bromodeoxyuridine (BUdR) and conventional fractionated radiation therapy was performed in 14 patients with glioblastoma multiforme and 7 patients with other poorly radioresponsive tumors. The BUdR was given as a constant intravenous infusion for 12 hr/day for up to 14 days. Thirteen patients received a second 14 day infusion following a 10 to 14 day interruption for bone marrow recovery. Local toxicity (within the radiation field) was minor, with 7 of the 21 patients requiring a brief treatment break for moist skin desquamation. There was no significant CNS toxicity noted clinically nor by autopsy examination. Additionally, no significant enhancement of radiation injury was noted to bowel or liver. However, one patient treated for multiple pulmonary metastases experienced a clinical and radiographic pattern consistent with radiation pneumonitis. Dose-dependent systemic toxicity occurred in bone marrow and skin. Moderate myelosuppression, especially thrombocytopenia, was found following a 14 day cycle of BUdR at and above 650 mg/m2/12 hr infusion. Approximately one-third of patients developed a maculo-papular erythematous rash to the scalp, neck and upper chest. In two patients, the rash became generalized with evidence of epidermolysis on skin biopsy. Pharmacology studies revealed steady-state arterial plasma levels of 2 X 10(-6) M/1 during the 12 hr infusion of 650 to 700 mg/m2. Radiosensitization was measured by a change in the D0 of radiation survival curves of human bone marrow CFUc prior to and following the 14 day infusion in 4 patients. A trend of increasing radiosensitization was noted in most patients as the infusion rate of BUdR was increased from 500 to 870 mg/m2/12 hr. We conclude that the maximum tolerable dose of BUdR is 650 to 700 mg/m2/12 hrs when given as a 2 week intermittent intravenous infusion. Local toxicity is acceptable. The major systemic toxicities are myelosuppression and a maculopapular skin rash.

Depressed cerebellar glucose metabolism in supratentorial tumors

Fifty-four patients with supratentorial tumor and one with brainstem tumor were examined with positron emission tomography (PET) using [18F]fluoro-deoxyglucose (FDG). Twenty-one of these cases had satisfactory studies of the cerebellum. Of these, 12 showed significant metabolic asymmetry between the two cerebellar hemispheres, with the rate of glucose utilization in the hemisphere contralateral to the cerebral tumor being 8-34% lower than on the ipsilateral side, as compared with a right-left asymmetry of only--1.6% +/- 2.1% standard deviation for a group of 5 normal subjects. In these 12 cases the tumor involved the sensorimotor cortex and/or the thalamus with varying degrees of hemiparesis being present. For the remaining 9 patients with no significant cerebellar metabolic asymmetry, the tumor involved regions other than the sensorimotor cortex, and unilateral motor dysfunction was not a prominent clinical feature. The correlation between cerebellar metabolic suppression and unilateral motor dysfunction observed in our cases appears to be due to impairment or interruption of the cortico-thalamo-ponto-olivo-cerebellar circuitry by either the tumor itself or by edema. These results illustrate the ability of FDG-PET scans to detect metabolic changes, not apparent on CT scans, in areas of the brain remote from the primary lesion.

Radiosensitization of hematopoietic precursor cells (CFUc) in glioblastoma patients receiving intermittent intravenous infusions of bromodeoxyuridine (BUdR)

The potential use of bromodeoxyuridine (BUdR) as a radiosensitizer given by an intermittent intravenous route is being studied in a Phase I/II trial at the National Cancer Institute. In order to assess the extent of radiosensitization, we have studied the radiation response of human bone marrow cells CFUc taken from 6 patients prior to and after a 14-day infusion of BUdR. Varying concentrations (1000-1500 mg) of BUdR were infused for 12 hours every 24 hours for up to 14 consecutive days. Cell survival was determined by colony formation of CFUc in soft agar suspension. X ray survival curves were generated over a dose range of 0-300 rad and the slopes of the survival curves (DO) before and after BUdR infusion were compared. Radiation enhancement ratios (ER) (DO pre-BUdR/DO post-BUdR) ranged from 1.0-2.2 and appeared to be BUdR dose dependent. Above 650 mg/m2, the radiation ER was greater than or equal to 1.5. Dose dependent systemic toxicity to bone marrow and skin was also observed with intermittent intravenous infusions of BUdR. From our study, it appears that an intravenous dose of less than 700 mg/m2/12 hours is well tolerated and may result in radiosensitization of CFUc in man.

Biophysical properties of cultured human glial cells

Summary Biophysical studies were performed on cultured human fetal brain cells identified by morphologic, cytologic and biochemical characteristics as astrocytic glia. Resting potentials were low (¯X= −7.7mV) because of the temperature during examination and because of an altered intracellular Na K ratio attributed to the culture metabolic conditions. Low resting potential appears unrelated to membrane biophysical properties and does not block the cells ability to divide and grow although the growth rate is reduced 15 . The cells displayed no spontaneous electrical activity nor were regenerative responses seen despite large membrane potential displacements. The astrocytic membranes were non-rectifying to imposed current pulses. The glial cells time constant averaged 311 μsec, 1/26 that of the feline Betz cell 35 but less than one standard deviation smaller than that found for in vivo feline astrocytes 56 . Membrane specific capacitance was found to be about 1 μF/sq.cm, a value common to many biological membranes. Membrane specific resistance averaged 327 ω·sq.cm, a very low value compared to that of neurons but in accord with calculations from other glial (astrocyte) studies. These biophysical values allow rapid transfer of large amounts of potassium.

Response of cultured human brain tumors to nitrosoureas: Correlation with clinical data

An in vitro microcytotoxicity assay was utilized to determine the sensitivity of 58 cultured human malignant gliomas to the chemotherapy agent 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU). Of 58 such tumors, 42 (72%) showed a statistically significant cytotoxic response to BCNU in this assay. For those responding tumor lines, the cytotoxic index ranged from 0.25 to 0.76, with most clustered at the 0.40 level.

Human astrocytoma: serum-mediated immunologic response.

An in vitro microcytotoxicity assay has been used to study the humoral immune response to human astrocytomas. Sera of 17 of 26 patients with these tumors produced significant cytotoxicity when tested against allogeneic astrocytoma cells. The cytotoxic response was found to occur both preoperatively and postoperatively without obvious relationship to the histologic grade of the patients tumor. Three of 46 sera from normal controls and 1 of 12 sera from patients with non‐neoplastic nervous system diseases were also cytotoxic in this test. Sera from each of 3 patients with non‐astrocytic neuroectodermal tumors were significantly cytotoxic, while none of 4 serums from meningioma patients was positive. These results indicate that a humoral immunologic response directed against antigens present on the astrocytoma cell surface occurs in most astrocytoma patients. The use of this microcytotoxicity assay may prove helpful in the preoperative diagnosis of this tumor. Cancer 33:1512–1519, 1974.

In vitro cellular radiosensitivity of human malignant tumors

Abstract Cells from four human tumors considered to be either clinically curable by radiation therapy (medulloblastoma) or non-radiocurable (osteogenic sarcoma, glioblastoma multiforme) were grown in tissue culture and the in vitro X-ray survival curve parameters determined. These were compared with the survival parameters for normal human diploid skin fibroblasts grown and irradiated under identical conditions. There were no significant differences in response among the tumor cell lines: the D o values ranged from 130 to 144 rads, and n from 1·4 to 1·9 . For normal lcells, D o = 132 rads, and the n = 0·95 . These results suggest that the wide range of clinical radiocurabilities found among various human tumors cannot be explained on the basis of the results of the in vitro survival curve parameters.

Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme

Sixty patients with high-grade gliomas (including 50 patients with glioblastoma multiforme) were entered on four sequential Phase I trials combining continuous intravenous infusions of halogenated pyrimidines and high-dose brain irradiation. Patients received two 14-day infusions of bromodeoxyuridine (BUdR) or iododeoxyuridine (IUdR) during the initial wide field and later reduced field radiation treatment (total radiation dose 65–70 Gy). All patients were followed a minimum of 6 months or until death. The actuarial median survival was 13 months for the entire group, with an 18-month survival of 24%. No significant survival differences were observed based on BUdR versus IUdR, 12-h versus 24-h infusion schedule, degree of surgical resection, or sex. Good performance status and age under 50 years were significant favorable prognostic factors. Of interest, the 48 patients who completed planned treatment had a 14-month median survival, with a 30% 18-month survival. These survival observations are at least comparable to other combined modality trials in patients with glioblastoma multiforme. Ongoing and planned clinical trials using the halogenated pyrimidine analogs as radiosensitizers in patients with glioblastoma multiforme are discussed.

Corticotropin releasing factor administered into the ventricular CSF stimulates the pituitary-adrenal axis.

Ovine corticotropin releasing factor (CRF) given intracerebroventricularly to rhesus monkeys at doses of 0.1-1 microgram/kg activates the pituitary-adrenal axis. The increases of plasma cortisol concentrations after intraventricular injection of CRF were similar to those observed after intravenous administration of this releasing factor and occurred without elevation of plasma concentrations of CRF, measured by radioimmunoassay. Thus, the cerebrospinal fluid (CSF) can serve as a conduit for delivery of CRF to the pituitary gland.