Institute from 1972 to 1978 were found to have brain metastases. Seventy-three percent of the patients had multiple brain metastases. Male to female ratio was 1.9:l. The median survival of the untreated group of patients was 3 weeks as compared with that of 6 weeks for the patients maintained on steroids only, 9 weeks for those who received radiotherapy, 11 weeks for the patients treated with intraarterial chemotherapy, and 26 weeks for the patients who underwent successful surgical excision of a solitary lesion.Cancer 53:2550-2552, 1984.ALIGNANT MELANOMA, in its advanced Stages, is a M devastating disease capable of metastasizing to ev-From the Departments of Neurosurgery and Soft Tissue Melanoma,

Acute regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in monkeys (Macaca mulatta) by selective embolization of the internal carotid (ICA) bifurcation with minimum surgical intervention in the neck under sedated conditions. Two of five hours after embolization, brain water (measurement of dry weight) and tissue concentration of sodium and potassium were determined in the tissues of the sylvian cortex, putamen and subcortical white matter in the affected MCA territory. As early as three hours, initial increase in brain water was detected in the samples of the putament without noticeable change in tissue electrolytes in two of three animals. Gross ischemic swelling of the gray matter, in both the sylvian cortex and putamen, became obvious in six of eight animals after four to five hours. This swollen gray matter showed marked increase in brain water (up to 36% swelling), increase in tissue sodium (up to 100% of the control value), and decrease in tissue potassium (down to 55%). On the other hand, edema in the white matter, if present at all, was minimal without detectable change in tissue electrolytes and was always accompanied by much greater ( greater than two to seven times) edema in the gray matter. Thus, the gray matter edema, in both the deep subcortical structures and the cortex, appeared to play the major role in the development of hemispheric swelling of the brain which may begin within hours of the onset of the MCA stroke in monkeys. Microscopically, the swollen gray matter which showed more than 10% swelling with a definite shift of tissue sodium and potassium content appeared to be dead tissue. However, early edema in the gray matter which showed less than 10% swelling without detectable change in electrolytes might be caused by simple diffusion of water through the dysfunctional capillary wall or cell membrane with or without a permeability gradient between the intravascular cerebrospinal fluid and cerebral tissue compartment and might possibly be reversible.

Five 1-beta-D-arabinofuranosylcytosine conjugates and two cytidine conjugates of thioether lipids (1-S-alkylthioglycerols) linked by a pyrophosphate diester bond have been prepared and their antitumor activity against an ara-C2 sensitive (L1210/0) and two ara-C resistant L1210 lymphoid leukemia sublines in mice were evaluated. These prodrugs of ara-C include ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (8a), ara-CDP-rac-1-S-octadecyl-2-O-palmitoylthioglycerol (8b), and ara-CDP-rac-1-S-octadecyl-2-O-methyl(or -ethyl, -hexadecyl)thioglycerols (8c-e). The cytidine conjugates include CDP-rac-1-S-octadecyl-2-O-palmitoyl(or -methyl)- 1-thioglycerols (9a and 9b). Sonicated solutions of the conjugates existed in the form of micellar disks (size 0.01-0.04 microns). Single doses (200-400 mg/kg) of 8a and 8b produced significant increase in life span (257-371%) in mice bearing ip implanted L1210/0 leukemia. In contrast, conjugates 8c-e were less effective (ILS 19-75%) and cytidine conjugates (9a and 9b) were ineffective. Even though 8a and 8b were found to be curative in a high percentage of mice bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C(I)], they were completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C(II)]. However, the present results, together with the previous, demonstrate that 8a and 8b are promising new prodrugs of ara-C with improved efficacy.

Twenty-five adults who harbored malignant gliomas received 72 courses of intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 mg/m2) and 67 courses of systemic vincristine (1.0 mg/m2) and procarbazine (100 mg/m2) as induction therapy (BVP) followed by 106 courses of systemic 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU) (130 mg/m2), vincristine, and procarbazine as maintenance therapy (MVP). With a 6-week interval between each treatment, the median and range for the number of courses of BVP were 3 and 1 to 4 and those for MVP were 3 and 0 to 14, respectively. Fifteen patients (60%) responded to both BVP and MVP, and 10 (40%) did not. The overall median survival time was 12.7 months (range, 1.8 to 48.5+ months). Two of 3 patients who had recurrent gliomas responded and survived for 37+ to 45+ months. Seven of 10 who had nonirradiated glioblastomas responded and survived for 9 to 22 months. Four who had nonirradiated anaplastic astrocytomas all responded and survived for 38+ to 48.5+ months. Two who also received radiotherapy (1 glioblastoma and 1 primitive neuroectodermal tumor) benefited and survived for 16.9 and 28.5+ months. All who did not respond favorably died within 8 months. During the infusion of BCNU, complications included transient orbital and head pain, periorbital and scleral erythema in all patients, and a focal seizure in 1 (4%). During the 6-month induction periods, leukopenia and thrombocytopenia occurred in 1 (4%), deep vein thrombosis occurred in 9 (36%), pulmonary emboli occurred in 8 (32%), upper respiratory infections occurred in 6 (24%), pneumonia occurred in 9 (36%), and herpes zoster occurred in 1 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY Selective embolization of the internal carotid artery bifurcation (ICA bifurcation) was performed in monkeys (Macaca mulatto) to study acute regional cerebral ischemia in the middle cerebral artery (MCA) territory with minimum surgical intervention in the neck under sedated conditions.The anthropomorphic similarity in angio-anatomy of the carotid system of monkeys and the use of silastic spheres, as artificial emboli, of the critical diameter of 1.2 to 1.4 mm resulted in the overall success rate of 87% in localizing the site of embolization to the ICA bifurcation, producing ischemia in the whole middle cerebral artery territory.All the animals with ICA-bifurcation embolization had contralateral deep motor weakness and conjugate eye deviation with nystagmus toward the site of embolization. Simultaneous EEC recording showed flattening of the basic background activities over the affected MCA area and cerebral arteriograms showed definite retrograde filling of the proximally occluded MCA. Clinical recovery was observed in a few animals within two to five hours of embolization. Gross ischemic swelling in the affected MCA territory, particularly in the gray matter, became obvious in six of eight animals which were exposed to four to five hours of ischemia.The angio-anatomical study of the carotid system of this experimental animal as a background for this MCA stroke model confirmed the previous observations of other investigators that the extremely abundant leptomeningeal anastomoses would be one of the major factors leading to the variability in the clinicopathological pictures seen in the models of proximal MCA occlusion. In addition, the prc-parenchy mal anastomoses in the base of brain between the medial striate arteries from the proximal anterior cerebral (ACA) and lateral lenticulostriate arteries from the MCA were observed and described as a possible functional collateral to the basal ganglia in case of proximal MCA occlusion.