Showing papers by "Dennis E. Bullard published in 1986"
TL;DR: It is shown that in addition to double minutes, certain other gross structural abnormalities also are clearly associated with the early evolution of this type of tumor.
141 citations
TL;DR: Toxicity was limited to neutropenia without any episodes of infection and therapeutic results compare favorably with other reports of therapy for recurrent medulloblastoma and support the inclusion of vincristine and cyclophosphamide in randomized adjuvant therapy trials of patients with medullOBlastoma.
Abstract: We conducted a Phase II study of combination therapy with vincristine and cyclophosphamide in the treatment of patients with recurrent or metastatic medulloblastoma. Fourteen patients were treated with vincristine 2 mg/m2 (2.0-mg maximal dose) by intravenous bolus on Day 1 and cyclophosphamide 1 g/m2 by intravenous infusion on Days 1 and 2, with cycles repeated every 4 weeks. All 4 patients with extraneural disease (biopsy-proven bony metastases) responded (duration of responses 2+, 6+, 8, and 16+ months) and 4 of 8 evaluable patients with neuraxis disease responded (duration of response 2, 2+, 2+, and 21+ months). Toxicity was limited to neutropenia without any episodes of infection. These therapeutic results compare favorably with other reports of therapy for recurrent medulloblastoma and support the inclusion of vincristine and cyclophosphamide in randomized adjuvant therapy trials of patients with medulloblastoma.
78 citations
TL;DR: Radiolabeled 81C6, a specific antiglioma MA, proved to be significantly better for imaging small and intermediate-sized tumors than the control MA's, suggesting that specific MA's have a role to play in both the diagnosis and treatment of primary intracranial human tumors.
Abstract: ✓ Current diagnostic and therapeutic modalities for malignant human gliomas are largely nonspecific. The development of monoclonal antibodies (MA's) with their high degree of specificity may allow precise tumor imaging and selective administration of therapeutic agents. However, the ability of these antibodies to specifically localize tumor tissue in vivo remains speculative. This study compares the localization and imaging properties of two MA's: a specific human glioma-associated extracellular matrix glycoprotein MA, 81C6, and a nonspecific control MA, 45.6, against a human glioma cell line, D-54 MG, intracranially inoculated into athymic rats. Forty-one animals received MA's labeled with iodine-131 (131I) or 125I and underwent imaging with a gamma camera. The images were independently evaluated and compared to tissue radioactivity levels. Radiolabeled antiglioma MA 81C6 specifically localized in intracranial xenografts. The percent of injected dose per gram of tissue for tumor was 1.707 ± 0.405/gm for ...
47 citations
Journal Article•
TL;DR: Two Mabs, C12 and D12, which localized specifically to tumors in athymic mouse-human glioma xenograft paired label localization assays, are IgG3 antibodies; both bind readily to staphylococcal protein A in column purification and radioimmunoprecipitation procedures.
Abstract: Multiple fusions following immunization of athymic mice with the extensively characterized human glioma cell line D-54 MG resulted in the selection of several antibodies (Mabs) highly reactive with tumors of neuroectodermal origin and unreactive with normal nervous system tissue. Two Mabs, C12 and D12, which localized specifically to tumors in athymic mouse-human glioma xenograft paired label localization assays, are IgG3 antibodies; both bind readily to staphylococcal protein A in column purification and radioimmunoprecipitation procedures. Both iodinate via the chloramine-T method yielding 125I-immunoreactive product by direct cell surface radioimmunoassay and absorption assay. By indirect cell surface radioimmunoassay, a cultured cell line panel consisting of 17 gliomas, 3 medulloblastomas, 2 neuroblastomas, 2 melanomas, and 2 fetal and 2 adult brain-derived cell lines was examined; the two Mabs were highly similar but distinct in their reactivity profiles. Each was positive with greater than 47% of the gliomas tested (C12, 9 of 17; D12, 8 of 17); and with 1 of 3 medulloblastomas, 1 of 2 melanomas, and cell lines derived from 12- and 16-week-gestation human fetal brain. No reactivity was observed with neuroblastoma or adult brain-derived cell lines or with neutral glycolipids and gangliosides extracted from D-54 MG xenografts or human glioma cell lines. Notable extraneuroectodermal reactivity included that of Mab D12 for splenic trabeculae and the spermatids and Sertoli cells in the testes. Following immunoprecipitation of [3H]leucine labeled cell membrane preparations, Mabs C12 and D12 have consistently yielded unique bands in the Mr 180,000 and Mr 88,000 regions respectively. When used in paired label localization experiments in s.c. D-54 MG xenograft-bearing athymic mice, Mabs C12 and D12 demonstrate similar localization patterns, attaining peak localization indices at day 3 (D12) or 4 (C12); the maximum percentage of injected Mab bound to tumor ranged from 5% (D12) to 8% (C12). The peak tumor/normal brain localization ratios (167-181) attained by these Mabs at days 1-2 followed by their rapid clearance suggest that these Mabs are potentially useful imaging and therapeutic agents for further investigation.
27 citations
TL;DR: Initial experience using the Gildenberg technique for computed tomography-guided stereotactic biopsies is reviewed, finding that homogeneous lesions could be biospied with target selection based upon a primary regard for safety rather than imaging characteristics.
Abstract: Initial experience using the Gildenberg technique for computed tomography-guided stereotactic biopsies is reviewed. Of 50 patients, adequate tissue was obtained in 49. In one patient, the stereotactic frame was unable to reach the selected biopsy site. In 32 of 49 patients, the diagnosis was obtained with one biopsy; in the remainder, two to five samples were required. In 4 cases, a subsequent craniotomy was performed; these provided similar histopathological tissue and in no case was the diagnosis altered. The lesions were categorized by CT as ring-enhancing lesions (REL), enhancing lesions with surrounding low density (ELLD), and low density lesions with and without peripheral areas of enhancement. Of the REL, 21 of 23 were primary tumors. Of the ELLD, 5 of 13 were primary tumors; the remainder had a wide spectrum of disease. Of the low density lesions without enhancement, 6 were primary tumors and 1 was an inflammatory process. Three patients had low density lesions with peripheral areas of enhancement and proved to have malignant primary tumors. The remaining patients had multiple lesions with both primary and metastatic disease. Twelve RELs were biopsied in multiple sites. An accurate diagnosis was best obtained by performing the first biopsy in the enhancing rim with additional biopsies as needed in the low density center. Homogeneous lesions could be biospied with target selection based upon a primary regard for safety rather than imaging characteristics. Three patients had transiently increased hemiparesis and one had a transient decrease in level of consciousness after biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)
17 citations
TL;DR: The animal models used provide a sensitive method of evaluating MAbs in pre-human trials and indicate that operationally specific MAbs and MAb Fab can specifically localize and be used to image human tumors transplanted into immunocompromised animals.
Abstract: At the present time, specific imaging and treatment of central nervous system malignancies is not possible. The development of monoclonal hybridoma technology may provide the solution to this problem. We have utilized human glioma-derived cell lines (HGCL) transplanted subcutaneously and intra-cranially into athymic mice and rats to evaluate the imaging and localizing properties of a panel of MAbs. MAbs 81C6, C12, and D12 and 81C6 Fab have shown significant in vivo localization against HGCL D-54 MG and 81C6 against U-251 MG when compared to equivalent non-specific MAbs. In subcutaneous D-54 MG-induced xenografts, maximal localization indices (LI) of up to 15.0 for 81C6, 6.8 for 81C6 Fab, 6.48 for C12, and 4.47 for D12 have been seen. The tumor-tissue ratios for normal brain have ranged from 235 for 81C6 to 167 for D12. The total percent injected dose for 81C6 was nearly 5% in U-251 MG tumors and 10% of the initial dose in D-54 tumors, while the percent injected dose for control MAb were 1.9% and 2.8%, respectively. Four subcutaneously growing U-251 MG tumors were clearly imaged using 131I-81C6. With intracranial growing D-54 MG,131I-81C6 provided external imaging of intracranial tumors at sizes as small as 20 mg while 131I-45.6, a non-specific MAb, provided imaging only when tumors achieved sizes greater than 300 mg. These data indicate that operationally specific MAbs and MAb Fab can specifically localize and be used to image human tumors transplanted into immunocompromised animals. The animal models described in this paper provide a sensitive method of evaluating MAbs in pre-human trials.
9 citations
01 Jan 1986
TL;DR: The observa-tion that near-diploid human gliomas double their chromosome complements as they establish in culture and as transplantable lines in nude mice suggests that the near-tetraploid tumors in Group II are at a later stage of karyotypic progression than the near -diploids tumors in Groups I and III.
Abstract: We karyotyped 27 malignant human gliomas including 3 anaplastic astrocytomas (AA), 23 glioblastoma multiformes (GBM), and 1 gliosarcoma (GS) in direct preparation, short term culture, or both, and found that they could be grouped according to their karyotypic patterns. Six of these tumors (3 GBM) had normal stemlines or only lacked one sex chromosome (Group la). Two tumors (Group lb) lacked one sex chromosome but showed, in addition, numerical and structural deviations. Three tumors were near-tetraploid (Group II) and contained double minutes (DMs). The remaining 16 tumors (I AA, 14 GBM, 1 GS) had near-diploid stemlines (Group III), often with gains of No. 7, loss of No. 10, structural abnormalities of No. 9 and DMs. These different patterns could be reflecting activation and/or amplification of different oncogenes. Alternatively they could be reflecting induction by different agents. But quite apart from their theoretical significance these karyotypic patterns could prove useful as prognostic indicators. The observa-tion that near-diploid human gliomas double their chromosome complements as they establish in culture and as transplantable lines in nude mice suggests that the near-tetraploid tumors in Group II are at a later stage of karyotypic progression than the near-diploid tumors in Groups I and III. There is also a spectrum of stage of karyotypic progression within Groups I and III ranging from tumors with only simple numerical deviations to those with complex numerical and structural abberations. The present series is too small and therapeutic regimens of individual patients are too diverse to determine if stage of karyotypic progression is a useful prognostic indicator. Long term studies of a large group of patients will be necessary to define these relationships.
1 citations