Alex M. Spence

Fifty-one adult patients with recurrent malignant gliomas were treated in a Phase II trial of multidrug chemotherapy (6-thioguanine, dibromodulcitol, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 5-fluorouracil, and hydroxyurea). Thirty-one patients underwent radical tumor debulking, before the administration of chemotherapy. Fifty-seven percent of all patients had either an objective radiographic response or stabilization of disease after the institution of therapy. The overall median survival time (MST) was 40 weeks; it was 79 and 33 weeks for anaplastic astrocytoma and glioblastoma patients, respectively. The overall median time to tumor progression (MTP) was 19 weeks--32 weeks for anaplastic astrocytoma patients and 13 weeks for glioblastoma patients. Serious chemotoxicity occurred in 35% of patients without permanent morbidity or mortality. The factors that affected response (including disease stabilization), MTP, and MST were identified through a multivariate statistical analysis. A longer MTP was associated with higher Karnofsky scores, lower grade initial histology, lack of prior chemotherapy, greater degree of myelotoxicity, smaller postoperative tumor volumes, greater extent of surgical resection, and a local versus diffuse recurrence pattern. A longer MST was associated with higher Karnofsky scores, lower grade histology at the time of recurrence, greater degree of myelotoxicity, and lobar versus deep tumor location. Response (including disease stabilization) correlated with higher Karnofsky scores, lower grade histology (initial and current), prior lower grade histology, smaller preoperative tumor volume, longer intervals from the time of initial diagnosis, and absence of prior chemotherapy. These results suggest that, in addition to established prognostic factors such as Karnofsky scores, other factors including prior chemotherapy administration, patterns of tumor recurrence, and tumor location may be important variables to consider in future Phase II-III clinical trials. Of the treatment variables analyzed, greater surgical debulking and smaller postoperative tumor volumes were associated with prolonged MTP but not MST, and greater myelotoxicity had a positive association with all outcomes. The significance of this latter relationship and its relevance to chemotherapy dosing will require further study. Standardization in the design and reporting of clinical trials and the use of computer-assisted tumor volume calculations to assess the extent of surgical resection and the response to therapy are advocated.

Normal values for blood flow velocity in some terminal vascular units of the cochlea (stria vascularis and spiral ligament) and for carotid blood pressure are presented along with the percentage changes produced by administration of epinephrine, norepinephrine, vasopressin and serotonin. Increases in flow velocity in these cochlear vessels can be produced. These are closely related to the measured increases in mean carotid blood pressure. Cochlear function as measured by the microphonic response to a moderate acoustic stimulus is not altered by this increase in cochlear blood flow. Some general relations between flow velocity, oxygen utilization and cell function are discussed.

Radiolabelled misonidazole, a radiosensitizing drug that binds to viable hypoxic tumor cells, may be useful in identifying hypoxic cells in cerebrovascular disease. Its potential was investigated in the gerbil stroke model. Biodistribution of [3H]misonidazole was measured in normal gerbils and animals that had been subjected to right common carotid artery ligation to produce cerebral ischemia. The uptake of [3H]misonidazole in the right cerebral hemisphere and right/left hemispheral uptake ratios correlated positively with the severity of the stroke when measured 6-9 hours after carotid ligation. Histologic studies in symptomatic ligated animals showed ipsilateral widespread but patchy acute ischemic changes as well as areas that showed no morphological changes. Microscopic autoradiography in these animals showed diffuse heavy labelling only in the ipsilateral hemisphere. This was over areas that had histological damage as well as in adjacent areas that appeared intact. Studies comparing blood flow measured with [14C]iodoantipyrine and [3H]misonidazole retention in gerbils with carotid artery ligations indicated that flow is not a major determinant of retention of this hypoxia tracer. We conclude that a misonidazole congener labelled with a gamma- or positron-emitting isotope may be useful in nuclear imaging of the degree and regional distribution of hypoxic tissue in cerebrovascular disease.

3-Amino-2-hydroxypropyl phosphorothioate (WR77913), a less toxic phosphorothioate radioprotector than WR2721, has been labeled with 35S. The biodistribution of a radioprotective dose of 800 mg/kg was determined in C3H mice bearing RIF-1 tumors as a function of time after intraperitoneal injection and was expressed as percentage injected dose/gram (% ID/g). Levels of 35S in the blood peaked 10 min after injection, and radioactivity in most tissues was highest at 15 min. Label in most tissues declined markedly between 15 and 60 min, but in gut, salivary glands, tumor, and brain, the levels of radioactivity remained quite stable over 1 hr. At 30 min after injection the highest levels of labeled drug were found in submandibular salivary glands, gut, and kidney, with the lowest level in brain. Tumors had approximately the same amount of label as blood, muscle, skin, and esophagus. Two principal differences between the distribution of label from WR77913 and WR2721 were defined. Although blood levels of 35S-WR2721 also peaked 10 min after injection, the 10-min blood levels achieved for WR77913 were more than fourfold greater than those attained by WR2721. Maximum levels of WR2721 occurred in most tissues 30 to 60 min after administration of the drug, compared to 15 min for WR77913. The basis for these differences remains to be determined, but these results suggest that the optimum interval between administration of WR77913 and irradiation may be shorter than for WR2721.