Faculty Bibliography

The primitive neuroectodermal tumor of the central nervous system is one of a number of tumors in which deletions on chromosome 17p have been identified. The tumor suppressor gene, p53, is located in the region of the deletion. To determine if the p53 gene is involved in the development of primitive neuroectodermal tumors, deoxyribonucleic acid (DNA) blot analysis, ribonucleic acid blot analysis, and p53 complementary DNA sequencing were performed on 34 primitive neuroectodermal tumors removed from children. No rearrangement in the gene was detected in 21 tumors. The p53 messenger ribonucleic acid was of the expected size in all 18 tumors for which ribonucleic acid was available. Sequencing of p53 Exons 5 through 9 revealed a mutation in the cell line DAOY and in only 1 of 14 tumors examined. A DNA rearrangement was detected in the DNA from one tumor with a probe mapping to the distal portion of 17p. Taken together, these data suggest that the p53 gene is not involved in the development of most primitive neuroectodermal tumors. In addition, a gene of interest may be present on distal 17p.

The records of 58 patients with gangliogliomas surgically treated between January 1, 1980, and June 30, 1990, were retrospectively reviewed in order to determine long-term survival, event-free survival, and functional outcome resulting after radical resection and to assess the impact of histological grading on outcome. Tumors were located in the cerebral hemisphere in 19 cases, the spinal cord in 30, and the brain stem in nine. Forty-four patients had gross total resection and 14 had radical subtotal resection. Only six patients underwent postoperative irradiation or chemotherapy and, therefore, the outcome was generally related to surgery alone. Of the 58 gangliogliomas, 40 were classified as histological grade I, 16 were grade II, and two were grade III. The median follow-up period was 56 months. There were no operative deaths, and the operative morbidity rate was 5%, 37%, and 33% for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas, respectively. The 5-year actuarial survival rates for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas were 93%, 84%, and 73%, respectively (p = 0.7). The event-free survival rate at 5 years was 95% for cerebral hemisphere gangliogliomas and 36% for spinal cord gangliogliomas (p < 0.05); for brain-stem gangliogliomas the event-free survival rate at 3 years was 53% (p < 0.05). Neurological function at recent follow-up evaluation was stable or improved in 81% of patients. Multivariate analysis (Cox linear regression) revealed tumor location to be the only variable predictive of outcome, with spinal cord and brain-stem gangliogliomas having a 3.5- and 5-fold increased relative risk of recurrence, respectively, compared to cerebral hemisphere gangliogliomas. Histological grade was not predictive of outcome, although in each location there was a trend for higher-grade tumors to have a shorter time to recurrence. It is concluded that radical surgery leads to long-term survival of patients with gangliogliomas, regardless of location, and adjuvant therapy can probably be reserved for special cases

Background. Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent