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Jeffrey N. Bruce, Gregory R. Criscuolo, Marsha J. Merrill, Ross R. Moquin, J. Bob Blacklock and Edward H. Oldfield

✓ Serum-free conditioned medium derived from confluent monolayer cultures of malignant human astroglial tumors contains a substance that rapidly increases capillary vascular permeability after intradermal injection into guinea pigs. Accumulation of vascular permeability factor (VPF) activity occurs with increasing duration of tumor incubation in vitro. Expression of this activity is inhibited by incubation of cell cultures with cycloheximide or dexamethasone. This VPF is an acid-stable heat-labile macromolecule that is inactivated by trypsin and pepsin and binds immobilized heparin. Activity is retained by ultrafiltration with 30,000-dalton cut-off microconcentrators. Pretreatment of test animals with systemic dexamethasone prior to intradermal injection of VPF diminishes microvascular permeability. Furthermore, VPF activity is not inhibited by antihistamines. Secretion of VPF may cause the vasogenic brain edema that is frequently associated with malignant primary and metastatic intracerebral tumors. Inhibition by dexamethasone of both VPF expression in tissue culture, and VPF activity at the microvascular level in test animals, is in keeping with the known efficacy of this agent in treating the vasogenic edema associated with brain tumors.

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Stephen C. Saris, Daniel R. Shook, Ronald G. Blasberg, Robert L. Dedrick, John L. Doppman, Krzysztof S. Bankiewicz, J. Bob Blacklock and Edward H. Oldfield

✓ Focal injury to the brain or retina is a frequent complication of drug delivery to the internal carotid artery (ICA) and may be due to poor mixing of the drug with blood at the infusion site. Rhesus monkeys were studied to determine whether phased drug delivery during diastole from a modified pulsatile angiographic injector would improve drug mixing in vivo. A radiolabeled flow tracer, carbon-14-iodoantipyrine (14C-IAP), was injected into the ICA of three monkeys in 80-msec pulses, each ending at least 50 msec before the end of local diastole. Local isotope concentration in the brain was determined by quantitative autoradiography. The ratio of highest to lowest concentration was 1.86 ± 0.26 (mean ± standard deviation) in the frontoparietal cortex, 1.65 ± 0.42 in the frontoparietal white matter, 1.89 ± 0.28 in the temporal cortex, and 1.39 ± 0.17 in the basal ganglia. These results were similar to recordings in three control animals that received intravenous 14C-IAP to demonstrate complete drug mixing ( 1.37 ± 0.12, 1.41 ± 0.11, 1.70 ± 0.08, 1.22 ± 0.24, respectively), and contrasted to findings in five animals which received continuous intracarotid infusions to demonstrate standard ICA drug delivery (4.54 ± 2.07, 2.94 ± 1.45, 5.43 ± 3.57, 3.60 ± 2.90, respectively). Pulsed intra-arterial infusion during diastole provides a technically simple method for improving intravascular drug mixing, and results in drug delivery to tissue capillaries that is proportional to blood flow.

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J. Bob Blacklock, Edward H. Oldfield, Giovanni Di Chiro, Dung Tran, William Theodore, Donald C. Wright and Steven M. Larson

✓ Glucose utilization by normal and neoplastic cerebral tissue can be measured in humans using positron emission tomography (PET) with fluorine-18-labeled 2-deoxy-D-glucose (FDG). Malignant gliomas are known to exhibit hypermetabolic glucose consumption compared to normal brain. Barbiturate-sensitive cerebral glucose utilization is coupled to neuronal activity, and lesions lacking neuronal activity should be relatively insensitive to barbiturate suppression of glucose utilization. In a study to examine this phenomenon, three patients with cerebral gliomas underwent FDG-PET while awake and during deep barbiturate coma. Cerebral glucose utilization was measured in normal brain, tumor, and a homologous, non-neoplastic control site in the contralateral hemisphere. A glucose utilization ratio for tumor/control tissue was calculated.

The mean reduction of glucose utilization during barbiturate coma was: gray matter 67%, white matter 47%, basal ganglia 66%, thalamus 57%, cerebellar cortex 55%, tumor 32%, and the contralateral control site 64%. The mean tumor glucose utilization ratio was 1.48:1 in the awake state and 2.69:1 during barbiturate coma. The changes in gray matter, basal ganglia, thalamus, cerebellar cortex, and tumor/control tissue ratio were significant (p < 0.05). In one patient, deep tumor invasion not evident on computerized tomography, magnetic resonance imaging, or baseline FDG-PET was apparent during barbiturate-enhanced FDG-PET scanning.

The study findings suggest that gliomas resist suppression of glucose utilization by barbiturates; this supports the hypothesis that barbiturates reduce neuronal metabolism by blocking synaptic activity. This differential effect on normal brain and gliomas enhances the capability to assess the extent of neoplastic tissue in brain and may represent the basis for novel therapeutic strategies.

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J. Bob Blacklock, Donald C. Wright, Robert L. Dedrick, Ronald G. Blasberg, Robert J. Lutz, John L. Doppman and Edward H. Oldfield

✓ Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo, the authors examined the distribution of drug delivery after internal carotid artery (ICA) infusion in rhesus monkeys. Carbon-14 (14C)-labeled iodoantipyrine was delivered into the ICA of eight monkeys at slow infusion rates (1% to 2% of ICA flow) or at fast infusion rates (20% of ICA flow) combined with additional techniques to promote mixing with ICA blood. Two monkeys received intravenous (IV) 14C-antipyrine. Uniformity of delivery was assessed by comparing high-to-low ratios of isotope concentration in four brain regions evaluated by quantitative autoradiography.

There was striking non-uniformity of drug delivery in the slow IA infusion group, with as much as 13-fold differences in drug concentration in anatomically contiguous areas. The values of high-to-low concentration ratios (mean ± standard deviation) in individual autoradiographic planes were: 1) frontoparietal cortex: slow IA infusion 4.54 ± 2.07, fast IA infusion 1.71 ± 0.31, IV infusion 1.30 ± 0.174; 2) frontoparietal white matter: slow IA infusion 2.94 ± 1.45, fast IA infusion 1.59 ± 0.41, IV infusion 1.34 ± 0.21; 3) temporal cortex: slow IA infusion 5.43 ± 3.57, fast IA infusion 1.69 ± 0.24, IV infusion 1.67 ± 0.25; 4) basal ganglia: slow IA infusion 3.6 ± 2.9, fast IA infusion 1.18 ± 0.10, IV infusion 1.09 ± 0.04. Differences between concentration ratios after slow IA and fast IA infusion are significant (p < 0.01); those between fast IA and IV infusion are not significant.

Intra-arterial drug administration at infusion rates analogous to those currently used clinically results in drug streaming with markedly heterogeneous drug deposition in the perfused hemisphere. This may cause suboptimal drug levels in the tumor, and toxic levels at sites within the perfused hemisphere. This effect can be abrogated by techniques that eliminate drug streaming.

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Robert J. Lutz, Robert L. Dedrick, John W. Boretos, Edward H. Oldfield, J. Bob Blacklock and John L. Doppman

✓ Sporadic instances of retinal damage and of focal brain toxicity have been observed following intracarotid artery infusions of chemotherapeutic agents (such as BCNU and cis-platinum) for the treatment of glioblastomas. The episodic nature of these toxicities is consistent with the possibility that the drug solutions were streaming from the catheter tip and, therefore, were not well mixed or not uniformly distributed in all branches distal to the catheter tip location. To test this hypothesis, an in vitro system was fabricated which included a transparent model of the human carotid artery and its major branches. These were furnished with pulsatile flow of a blood simulant. Dye solutions infused at several infusion rates through various types of catheters in both supraophthalmic and infraophthalmic positions were monitored and recorded on videotape and photographic film. The effluent streams from distal branches of the model were collected, and the relative concentrations of dye in each branch were determined spectrophotometrically. The results indicate that infusate streaming occurs at low infusion rates. In some cases, the concentration in a given branch can be at least five times the expected concentration. Similar occurrences of streaming in vivo could cause focal toxicity. Methods to improve mixing should be used during intra-arterial administration of drugs; these include increasing the infusion rates and improving catheter tip design.