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Despite their histological similarity, low-grade astrocytomas vary widely in their clinical behavior. To elucidate this variable behavior, we measured the proliferative potential of 69 primary and 18 recurrent low-grade astrocytomas and correlated the results with the clinical characteristics and outcome. Each patient received an intravenous infusion of bromodeoxyuridine (BUdR); BUdR-labeled nuclei in excised tumor specimens were identified by immunoperoxidase staining. The BUdR labeling index (LI), or S-phase fraction, ranged from <1 to 9.3%; the LI was < 1% in 64 (74%) patients and ≥1% in 23 patients (26%). The LI did not appear to be associated with age, sex, tumor location, or whether the tumor was primary or recurrent. A Cox proportional-hazards analysis of the influence of the LI and other variables (age, sex, tumor location, extent of surgery, primary versus recurrent tumor) on survival showed that the LI and extent of surgery (total resection, subtotal resection, biopsy) were significant in predicting both survival and progression-free survival for all patients and for patients with primary tumors. The LI was also significant in predicting progression-free survival for patients with recurrent tumors. The correlation between the BUdR LI and both survival and time to recurrence suggests that the outcome of low-grade astrocytomas varies according to the proliferative potential. The growth rate of these histologically similar tumors should be assessed individually in order to select specific treatment. [ABSTRACT FROM AUTHOR]

To clarify the biological and clinical behavior and prognosis of mixed gliomas, 47 patients underwent intraoperative bromodeoxyuridine (BrdU) labeling studies. The mean age was 27.8 years at symptom onset and 31.8 years at labeling (median, 36 years). Forty-five tumors were supratentorial, 30 were frontal, and two were cerebellar; 16 were recurrent at labeling. The median labeling index (LI) was 1% (range,<1 to 15.1%). Forty-six tumors had oligodendroglial and astrocytic elements, and one had astrocytic and ependymal elements. The median LI was 4.4% in recurrent tumors and <1% in primary tumors. A higher BrdU LI correlated with an increased risk of recurrence and a shorter time to recurrence. During a median follow-up of 16 months, four patients died; each had a BrdU LI≥4.4%. The median time to recurrence was 4.5 months for tumors with BrdU LI's >5% but was not reached for tumors with LI's <5% (p< 0.003). The histologic grade of the oligodendroglial component correlated with the median time to recurrence (8 months for Smith Grade C tumors, not reached for Smith Grade B tumors; p<0.05); there were too few cases to evaluate the median times to recurrence of Smith Grade A and Grade D tumors. The median time to recurrence was not reached for any astrocytic grade, and there were no significant differences in the Kaplan-Meier survival curves. These findings suggest that the BrdU LI and the grade of the oligodendroglial component of mixed gliomas have prognostic significance. [ABSTRACT FROM AUTHOR]

The study of proliferative characteristics and biochemical aspects seem to be of great importance in order to define brain neoplastic behavior. The purpose of this study is to verify the existence of any possible correlation between Arachidonic Acid (AA) metabolism and proliferative characteristics in 30 meningiomas and 30 neuroepithelial tumors. The most represented metabolite in neuroepithelial tumors is TxB, while 6-Keto-PGF is the lowest represented product. Unimodal DNA distribution was observed in 66% of neuroepithelial tumors and in 87% of meningiomas. Aneuploidy was more frequent in glioblastomas and anaplastic meningiomas as previously reported; AA overall synthesis capacity and profile were similar between unimodal and bimodal cases of neuroepithelial tumors. Total AA metabolite, as well as TxB and PGD, synthesis capacity are significantly higher in cases with S-phase cell percentage ≥ 3% than in cases with S-phase % < 3%. Total production of AA metabolites via the cyclooxygenase pathway is significantly higher in meningiomas with bimodal DNA distribution than in cases with unimodal DNA content; when considering S-phase cell percentage, similarly to what observed in neuroepithelial tumors, meningiomas with S% > 3% shows a significantly higher overall synthesis capacity for AA. AA metabolism capacity well correlates with proliferative patterns in neuroepithelial tumors: the relationship depends preferentially on TxB and PGD synthesis capacity. In cases of meningiomas, the amount of AA metabolites seem to be related to DNA content and proliferative activity when anaplastic features are histologically demonstrated. [ABSTRACT FROM AUTHOR]

Between July 1983 and July 1986, 109 consecutive patients affected by brain tumors and selected for stereotactic biopsy underwent in vitro investigation of cell kinetics. The potential proliferative activity of these different neoplasms, evaluated as in vitro 3H-thymidine labeling index (LI), has been determined in 46 mature astrocytomas, 19 anaplasic astrocytomas, 25 glioblastomas, 5 cystic craniopharyngiomas, 6 metastatic tumors, 4 primary C.N.S. lymphomas, 3 pineal germinomas and one choroid plexus papilloma. The relevance of LI on prognosis has been evaluated in 35 patients affected by glial tumors with adequate follow-up longer than 2 years. This retrospective study allowed us to demonstrate the prognostic value of LI in mature astrocytoma and anaplasic, astrocytoma series. The feasibility of LI determination by in vitro procedure has been demonstrated also in non-neuroectodermal tumors. In craniopharyngioma the LI investigations allowed to demonstrate a peculiar topographic arrangement of cells in S phase. [ABSTRACT FROM AUTHOR]

One hundred forty-three patients with gliomas of astrocytic origin (61 with glioblastomas multiforme (GM) and 82 with astrocytomas) received an intravenous infusion of bromodeoxyuridine (BUdR), 150-200 mg/m at the time of surgery, to label tumor cells undergoing DNA synthesis. BUdR-labeled cells were identified by the indirect immunoperoxidase method using anti-BUdR monoclonal antibodies. The percentage of BUdR-labeled cells, or BUdR labeling index (LI), was calculated by microscopic examination of selected viable areas of the tissue sections. The GMs had a median LI of 7.5%, and three quarters of these tumors had LIs greater than 5%. Highly anaplastic astrocytomas (HAAs) and moderately anaplastic astrocytomas (MoAAs) had median Lls of 2.3% and less than 1%, respectively. Among the HAAs, the Ll was 1% to 5% in 56% of tumors, greater than 5% in 26%, and less than 1% in 18%. More than 60% of MoAAs had LIs less than 1%, which agrees with the slow clinical progression of this type of tumor, and the remainder had LIs of 1.4% to 9.3%. These results show that histopathologically similar tumors may have different proliferative potentials. Measuring the proliferative potential of individual gliomas is therefore crucial for predicting the prognosis more accurately and for devising more tumor-specific treatment regimens for individual patients. [ABSTRACT FROM AUTHOR]

The cytokinetic response of three murine (AC) and human (GB-1 and GB-2) glioma cell lines to cis-dichlorodiammineplatinum (II) (CDDP) was investigated by flow cytometry. Using the 5-bromodeoxyuridine (BrdU)-Hoechst technique, percentages of cultured glioma cells in the various phases of the cell cycle, and relative phase duration were calculated. This technique proved to be a rapid and easily performed method to characterize phase length and transition rate for the complete cell cycle. In the presence of CDDP IC (a concentration in which 10% inhibition of cell growth be induced as compared to controls), perturbations of the cell cycle in AC and GB-1 cells included G delay or block, decreased transit velocity from G to S phase, and prolongation of G phase. The mean cell cycle time increased 1.4 times in AC and 1.6 times in GB-1 as compared to controls. In CDDP IC-treated GB-2 cells, the mean cell cycle time was prolonged three times longer than control: however, duration of each phase could not be calculated because of significant perturbation of cell cycle. These results suggest that CDDP influences glioma cells at the G/S boundary and in the G phase, resulting in prolongation of the G phase and, to a minor degree, in block of the G phase. [ABSTRACT FROM AUTHOR]

We examined the growth potential of 17 medulloblastomas by single and double immunohistochemical staining with bromodeoxyuridine (BUdR) and MIB 1, a monoclonal antibody for Ki-67 protein, in serial sections of ethanol-fixed, paraffin-embedded tissues; we also assessed the heterogeneity of the immunoreactivity in the tumors. In the most active areas, the BUdR labeling index (LI) was 6.8 to 26.9% (HCl hydrolysis) and 7.5 to 28.8% (microwave heating), and the MIB 1 proliferating cell index (PQ was 14.9 to 56.5%). Linear regression analysis showed that the BUdR LI correlated with the MIB 1 PCI (p < 0.001). The ratio of MIB 1-positive to BUdR-positive cells was 2.2 ± 0.4 by both single and double staining. BUdR-positive nuclei were heterogeneously distributed in all cases, especially in areas with scattered foci of necrosis. Three tumors had areas with many MIB 1-positive but few BUdR-positive nuclei; these areas were associated with recent tumor necrosis. However, in most of the tumors, the densities of BUdR-positive and MIB 1-positive cells changed concomitantly from area to area. These changes were clearly shown by double immunostaining. Thus, transcapillary passage of BUdR does not appear to be impeded in most medulloblastomas. This study suggests that MIB 1 immunostaining provides essentially the same data as BUdR labeling for assessing the proliferative potential of medulloblastomas. [ABSTRACT FROM AUTHOR]

Effects of hyperthermia on the cell kinetics of glioblastoma cells were investigated using flow cytometry. Pulse-labeling with 5-bromodeoxyuridine (BUdR) and chasing of the labeled cells revealed temporary accumulation of the labeled cells in GM phase and a reduction of DNA synthesis. The level of cyclin B rises rapidly in G phase and falls at the end of mitosis in normal cycling cells. Cyclin B binds to p34, resulting in histone kinase activity which is necessary for the initiation of mitosis. The amount of p34 remains constant throughout the cell cycle. The level of cyclin B was measured using an anti-cyclin B antibody and flow cytometry in order to investigate the cause of the G accumulation induced by hyperthermia. A low level of cyclin B, in comparison with that of normal cycling cells, persisted for more than 3 h after hyperthermia. These results indicate that the temporary accumulation of cells in GM phase after hyperthermia may be caused, at least in part, by an insufficient level of cyclin B. [ABSTRACT FROM AUTHOR]

In an effort to optimize immunocytochemical methods to evaluate cell kinetics in brain tumors, we studied two newly-developed antibodies which react with formalin resistant epitopes of Proliferating Cellular Nuclear Antigen (PCNA) and Ki-67. These results were compared with standard flow cytometric cell cycle data from the same tumor specimens to determine if these methods correlate with each other, and whether retrospective analysis using these antibodies is feasible for cell kinetic analysis of brain tumors. Thirty-one specimens of glial tumors submitted for flow cytometry during 1992 were also reacted with antibodies to PCNA (PC-10) and Ki-67 (MIB-1). Flow cytometry scores for S-phase Fraction were compared with immunocytochemical scores for both antibodies, using an arbitrary rating of 1 (low, < 4%), 2 (intermediate, 4-6%), 3 (high, > 6%), and 1 (< 25% positive), 2 (26-75% positive), 3 (> 75% positive), respectively. MIB-1 results were found to correlate significantly with the S-phase fraction as determined by flow cytometry. The MIB-1 data showed a trend toward underestimating, i.e., lower scores, the proliferative index compared with flow cytometry. There was less of a correlation between PC-10 antibody scores and flow cytometry S-phase fraction, as PC-10 immunostaining typically overestimated the proliferative rate of brain tumors when compared with flow cytometry. There was an exact correlation between PC-10 and MIB-1 in only 4 cases, whereas in the remaining specimens, PC-10 results were always higher than MIB-1. These new immunostaining methods, which react with formalin fixed deparaffinized tissue and require microwave pre-treatment to optimize the results, have demonstrated their usefulness in retrospectively analyzing tumor cell kinetics. For one antibody, namely MIB-1, excellent correlation with standard flow cytometric analysis was achieved. Further studies comparing patient outcome with immunoreactivity to both Ki-67 and PCNA proteins is now possible and may be done on large numbers of achived specimens. [ABSTRACT FROM AUTHOR]