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Esref Tel, Takao Hoshino, Marvin Barker, and Charles B. Wilson

✓ In Fischer 344 rats, 9L tumors were implanted in the left cerebral hemisphere. Compared with control animals not operated on, rats treated with an LD10 dose of BCNU 1 hour before or 1 or 12 hours after surgery on Day 16 postimplant had an increased life span of over 200% (greater than a 6 log cell kill). Minimal effect on survival was found when BCNU was administered during surgery. On the other hand, BCNU administered 12 hours before or 24 or 72 hours after surgery did not show any additive effect of surgery on BCNU treatment. These results suggest that in a clinical setting, a bolus of BCNU administered to tumor patients within 12 hours of surgery might increase substantially the total tumor cell kill compared with surgical resection alone.

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Takao Hoshino, Charles B. Wilson, Mark L. Rosenblum, and Marvin Barker

✓Four patients received 3H-thymidine 4 to 7 days and vinblastine 4 to 6 hours prior to operation for recurrent malignant gliomas (three glioblastomas and one anaplastic astrocytoma). Tumor biopsies obtained at operation were fixed for routine histological studies and radioautography. The tumors' growth fractions averaged 0.28 with a range of 0.14 to 0.39. The tumor cell cycle time calculated in three patients had a mean duration of 57 hours with a standard deviation of 6 hours. The authors concluded that: 1) single short-term courses of cell-cycle specific chemotherapeutic agents alone will probably fail to achieve either significant reduction in tumor mass or dramatic clinical improvement; 2) cell-cycle phase-specific drugs should be administered to maintain effective blood levels over 2 to 3 days for maximal tumor cell kill. Tumor growth rate appears to correlate with the fraction of proliferating cells rather than the length of the tumor cell cycle. The scientific basis for combination drug and multimodality therapy is discussed.

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Takao Hoshino, Marvin Barker, Charles B. Wilson, Edwin B. Boldrey, and Derek Fewer

✓ Eleven selected patients with brain tumor were given 3H-thymidine intravenously at the time of operation. Parts of the excised tumor were fixed for routine histological studies as well as for simple radioautography. Other parts were minced immediately after excision and incubated at 37°C with 14C-thymidine, and were thus doubly labeled. Simple radioautography of the tumor specimen showed fairly even distribution of labeled cells in the astrocytoma group and uneven labeling of tumor cells in malignant gliomas, including glioblastomas. In most glioblastomas, the labeling index (percentage of cells labeled with 3H-thymidine) varied from near 0% in the necrotic areas to approximately 20% in the most viable parts of the same tumor; the labeling index of viable parts of the tumor ranged from 5% to 10% with the exception of astrocytomas in which the index was 1% or less. The duration of DNA synthesis ranged from 7 to 10 hours in the majority of tumors regardless of the nature or grade of malignancy.

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Graded cryohypophysectomy in the rhesus monkey

Histopathology and endocrine function

Suleyman Saglam, Clifford L. Kragt, Charles B. Wilson, Selna L. Kaplan, and Marvin Barker

✓ Histopathology and endocrine function of the pituitary gland of rhesus monkeys subjected to graded cryohypophysectomy were compared with the histopathology and endocrine function in hypophysectomized and sham-operated monkeys. Freezing at −50°, −100°, and −150°C destroyed 72.3%, 78.3%, and 93.1% of the pituitary respectively. The posterior lobe was more resistant to the damaging effects of cold. A nearly complete (96.3%) histological hypophysectomy was accomplished at −190°C; nearly all remaining viable tissue was in the posterior lobe. Freezing at −150°C appears to result in a complete functional hypophysectomy. Of the adenohypophyseal cells, the gonadotropin-secreting cells were the most susceptible to cold, with the growth-hormone-producing cells next in susceptibility. Adrenocorticotropin-secreting cells were more resistant. Cells producing thyroid-stimulating hormones were not susceptible, and the pituitary stalk was quite resistant to the damaging effects of freezing at these temperatures. Thus, a predictable partial hypophysectomy by means of cryosurgery seems feasible, and, with a predetermined time, it is evident that the degree of cold is critical in achieving a complete cryohypophysectomy.