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Prediction of tumor doubling time in recurrent meningiomas

Cell kinetics studies with bromodeoxyuridine labeling

Kyung G. Cho, Takao Hoshino, Tadashi Nagashima, Judith A. Murovic, and Charles B. Wilson

✓ Eight patients with recurrent meningiomas (four malignant, two hemangiopericytic, and two nonmalignant) were given intravenous bromodeoxyuridine (BUdR), 200 mg/sq m, at the time of surgery to label cells in the deoxyribonucleic acid (DNA) synthesis phase; labeled cells were detected in excised tumor specimens by immunoperoxidase staining using anti-BUdR monoclonal antibody. These tumors showed a wide range of BUdR labeling indices (LI's), calculated as the percentage of BUdR-labeled cells divided by the total number of cells scored, from 0.3% to 5.4%. The tumor doubling times (Td's), estimated from serial computerized tomography scans, ranged from 8 to 440 days and showed a close inverse correlation with the BUdR LI's. A semilogarithmic linear regression analysis of these values yielded a correlation coefficient of 0.99. Tumor doubling time (Td) can be estimated using the formula: Td = 500 × Exp (−0.73 × LI), where Exp signifies the natural log base. By predicting the growth rate of meningiomas, the BUdR LI may supplement histopathological diagnosis and improve both the determination of prognosis and the design of treatment modalities in individual patients.

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Tadashi Nagashima, Judith A. Murovic, Takao Hoshino, Charles B. Wilson, and Stephen J. DeArmond

✓ At the start of transsphenoidal microsurgery for removal of various types of pituitary adenomas, 21 patients received a 1-hour intravenous infusion of 5-bromodeoxyuridine (BUdR, 200 mg/sq m) to label tumor cells in the deoxyribonucleic acid (DNA) synthesis phase (S-phase). Excised tumor specimens were fixed in 70% ethanol and stained by the indirect peroxidase method using anti-BUdR monoclonal antibody as the first antibody. The percentage of BUdR-labeled cells, or S-phase fraction, was calculated for each specimen. The S-phase fraction was less than 0.1% in nine cases, 0.1% to 0.5% in seven, and greater than 0.5% in five. Except in two cases of Nelson's syndrome, in which it was greater than 1%, the S-phase fraction did not correlate with any other variable, including patient age, tumor size, or the duration of signs and symptoms.

The small S-phase fraction of most of the pituitary adenomas correlates well with the clinical behavior of these tumors, which grow much more slowly than other kinds of brain tumors such as gliomas. However, the S-phase fractions varied by as much as one order of magnitude. The higher S-phase fractions may reflect aggressive and invasive growth. These results indicate that immunohistochemical studies of cell kinetics using BUdR and anti-BUdR monoclonal antibodies may provide information about the biological characteristics of pituitary adenomas which could lead to the design of appropriate treatment regimens (including surgery, radiation therapy, and chemotherapy) for individual patients.

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Takao Hoshino, Tadashi Nagashima, Judith A. Murovic, Charles B. Wilson, Michael S. B. Edwards, Philip H. Gutin, Richard L. Davis, and Stephen J. DeArmond

✓ Thirty-eight patients undergoing surgical removal of neuroectodermal tumors of the central nervous system were given a 1-hour intravenous infusion of bromodeoxyuridine (BUdR), 150 to 200 mg/sq m, to label tumor cells in the deoxyribonucleic acid (DNA) synthesis phase (S-phase). The excised tumor specimens were divided into two portions: one was fixed with 70% ethanol and embedded in paraffin and the other was digested with an enzyme cocktail to make a single-cell suspension. The paraffin-embedded tissues were stained by an indirect peroxidase method using anti-BUdR monoclonal antibody (MA) as the first antibody. Single-cell suspensions were reacted with fluorescein isothiocyanate (FITC)-conjugated anti-BUdR MA's for flow cytometric analysis. S-phase cells that had incorporated BUdR into their DNA were well stained by both methods. The percentage of BUdR-labeled cells, or S-phase fraction, was calculated in tissue sections by microscopic examination and in single-cell suspensions by flow cytometric analysis. The biological malignancy of the tumors was reflected in the S-phase fractions, which were 5% to 20% for glioblastoma multiforme, medulloblastoma, and highly anaplastic astrocytoma, but less than 1% in most moderately anaplastic astrocytomas, ependymomas, and mixed gliomas. Two juvenile pilocytic astrocytomas and two low-grade astrocytomas from children had high S-phase fractions despite the fairly benign and slow-growing nature of these tumors. These results indicate that the S-phase fraction obtained immunocytochemically with anti-BUdR MA's may provide useful information in estimating the biological malignancy of human central nervous system tumors in situ.