Showing papers by "Dennis E. Bullard published in 1988"
Journal Article•
TL;DR: This demonstration of specific chromosomal abnormalities in near-diploid gliomas provides the basis for the investigation of genes which may be quantitatively or qualitatively altered in these neoplasms.
Abstract: Karyotypic analysis of 54 malignant human gliomas (5 anaplastic astrocytomas, 43 glioblastoma multiformes, 3 gliosarcomas, 2 giant cell glioblastomas, 1 anaplastic mixed glioma) has demonstrated that 12 tumors contained normal stemlines or only lacked one sex chromosome. The 42 tumors with abnormal karyotypes included 38 tumors which could be completely analyzed. Six of these 38 cases had near-triploid or near-tetraploid stemlines and 32 had near-diploid stemlines. Statistically significant numerical deviations in the near-diploid group were gains of chromosome 7 (26 of 32; P less than 0.001), and losses of chromosome 10 (19 of 32; P less than 0.001). Double minutes occurred in 18 of 32 near diploid tumors. The distribution of structural abnormalities was analyzed statistically by comparing the incidence of breakpoint in each chromosomal arm to the expected value based on chromosomal arm length. This analysis demonstrated that structural abnormalities of 9p and 19q were significant statistically (P less than 0.005 and P = 0.02, respectively). Although chromosome 1, 6p, the centromeric region of chromosome 11, 13q, and 15q were also frequently involved in structural abnormalities, the incidence of these breaks did not reach statistical significance. This demonstration of specific chromosomal abnormalities in near-diploid gliomas provides the basis for the investigation of genes which may be quantitatively or qualitatively altered in these neoplasms.
337 citations
TL;DR: This issue is selected because of its major implications for any treatment that is directed at a specific portion of the brain rather than the whole brain: BBB disruption, intracarotid drug administration, and brain brachytherapy.
Abstract: Supratentorial glioblastoma multiforme (GBM) is a lethal malignancy. Subtotal surgical resection and post operative external beam radiotherapy palliate symptoms and prolong survival, but very few patients survive more than 3 years following diagnosis.‘,3,20*32,43,46,48*5’*58,66 Whereas the probability of survival of supratentorial anaplastic astrocytoma (AA) is slightly better, most patients will still succumb to the tumor.58-60*66 The resistance of these neoplasms to conventional therapies has prompted many physicians to undertake new clinical and laboratory investigations. These have included the use of chemotherapy,44 immunotherapy,40 multiple-fraction-perday radiotherapy,2’,34,49 radiotherapy with chemical radiosensitizers,6’ and neutron radiotherapy.45 As interest in the biology and treatment of malignant gliomas has increased, many conceptual verities have been proposed to guide therapeutic investigations, These include the significance of the cellular heterogeneity of AA and GBM,‘2,24 the presence of the blood-brain-barrier (BBB) as a functional obstruction to chemotherapy, and the local nature of these tumors. In this editorial, we focus on the last of these premises. We have selected this issue because of its major implications for any treatment that is directed at a specific portion of the brain rather than the whole brain: BBB disruption, intracarotid drug administration, and brain brachytherapy. Interstitial brachytherapy is used for primary and recurrent GBM and AA. The technique consists of the stereotactic computed tomography (CT) or magnetic resonance imaging (MRI) guided placement of coaxial catheters within and around the tumor. Radioactive sources are after-loaded into the catheters to deliver continuous low-dose rate irradiation. After a specified dose is delivered, the system is removed.22~27~28~39~45 Interstitial hyperthermia generated by implanted microwave antennae may be administered in conjunction with the radiation.52 One of the justifications invoked for brachytherapy is the concept of malignant gliomas as localizedlesions. Allusions to this concept abound in the literature. “Most malignant gliomas are localized to a single area of the brain, central nervous system (CNS) metastases from these tumors are uncommon and systemic metastases are rare.“29 “Since an astrocytoma is almost invariably a nonmetastatizing single mass, ideally it should lend itself best to regional treatment.“** “Because a primary brain tumor is most often a localized disease, hyperthermia, intratumoral chemotherapy, and interstitial irradiation, the stereotactic placement of radioactive sources directly into brain tumors, have been suggested as possible local treatments for brain tumors.“*’
127 citations
TL;DR: In patients with supratentorial tumor sites, cranial nerve palsies, microcystic changes, and mitotic figures were important, while in patients with infratentorial tumors, widened sutures, increased head circumference, age, epithelial features, and subependymal features significantly affected survival.
127 citations
Journal Article•
TL;DR: Tumor response was measured by growth delay in reaching 1000 or 5000 mm3 tumor volumes using the Wilcoxon rank sum test, and by comparing the proportion of tumors that had regression in volume after treatment using the Fisher exact test.
Abstract: The development of Mabs, particularly those reactive with primary brain tumors but not with normal brain, provides a potential means of delivering therapeutic agents selectively to human malignant gliomas. Mab 81C6, an IgG2b immunoglobulin, which defines an epitope of the glioma-associated extracellular matrix protein tenascin, has been shown to bind to human glioma cell lines, glioma xenografts in nude mice, and primary human gliomas, but not to normal adult or fetal brain. To test the therapeutic potential of this Mab for targeted delivery of isotopes, nude mice bearing progressively growing s.c. xenografts of D-54 MG, a human glioma cell line, were given injections via the tail vein of either buffer, unlabeled 81C6, 131I-labeled 81C6, or 131I-labeled 45.6, a nonspecific control Mab of the same isotype. Specific activities of the Mab range from 6.0 to 15.5 mCi/mg with protein doses from 7.6 to 167 µg. The doses given by injection per animal for labeled 81C6 were 50, 250, 500, and 1000 µCi and 500 and 1000 µCi for 45.6. Tumor response was measured by growth delay in reaching 1000 or 5000 mm3 tumor volumes using the Wilcoxon rank sum test, and by comparing the proportion of tumors that had regression in volume after treatment using the Fisher exact test. Statistically significant growth delays at 1000 mm3 were noted in 1 of 3 experiments with 500 µCi 81C6 ( P < 0.001) and 2 of 3 for 1000 µCi 81C6 ( P = 0.001 and <0.001). At 5000 mm3, statistically significant growth delays were seen with radiolabeled 81C6 in 2 of 2 experiments at 250 µCi ( P = 0.01 and 0.02), 4 of 4 at 500 µCi ( P = 0.03-<0.001), and 2 of 2 at 1000 µCi ( P = ≤ 0.001) and with radiolabeled 45.6 in 1 of 1 at 1000 µCi ( P = 0.01). The percentage of animals with tumor regression progressively increased with increasing doses of isotope. For radiolabeled 45.6, there were 0 of 10 regressors at 500 and 1 of 10 at 1000 µCi. For radiolabeled 81C6, there were 0 of 6 regressors at 50 µCi, 1 of 16 (6%) at 250 µCi, 7 of 38 (18%) at 500, and 15 of 28 (54%) at 1000 µCi. Statistically significant tumor regression was seen only at doses of 500 and 1000 µCi of 131I-81C6. The initial tumor size for those regressing was significantly smaller than those not regressing ( P = 0.01 for 500 µCi and 0.0009 for 1000 µCi). The estimated dose to tumor was 9719 cGy for 1000 µCi 81C6 and 2346 cGy for 1000 µCi 45.6. Doses to other organs for 81C6 and 45.6 were equivalent ranging from 135 cGy for brain to 2415 cGy for lung. Whole body dose determined by total body measurement with dose calibrator and direct individual tissue counting with a gamma counter were equivalent. Comparative dosimetry calculations were made based upon data extrapolated from prior trace-labeled localization studies (5 µCi/5 µg/animal). The estimated radiation dose to tumor from these studies in which no therapeutic tumor response was seen underestimated the dose observed in a directly measured therapeutic trial by 35–52%. In this xenograft model, a radiolabeled antiglioma Mab against the extracellular matrix protein tenascin demonstrated therapeutic efficacy. The promising results obtained in this animal model suggest a potential value for this form of therapy against human malignant gliomas.
105 citations
Journal Article•
TL;DR: Intacranial human glioma xenografts were treated successfully with 131I-labeled 81C6 but not control Mab, and normocellularity was observed in most marrow tissue examined microscopically.
Abstract: Lack of tumor specificity renders current modalities for treating malignant glioma ineffective. The administration of 131I-labeled monoclonal antibody (Mab) 81C6, which reacts with the glioma-associated extracellular matrix antigen, tenascin, to nude mice carrying s.c. human glioma xenografts has resulted in significant tumor growth delay and tumor regression. In this study, we evaluated the therapeutic efficacy of 131I-labeled 81C6 in athymic rats bearing intracranial human glioma xenografts, a more appropriate model for human gliomas. Mab 81C6, an IgG2b immunoglobulin, and an isotype-matched control Mab, 45.6, were labeled at 12.5–23.6 mCi/mg with chloramine-T. The Mabs were given i.v. at 1.25 and 2.5 mCi/animal for 131I-labeled 81C6, and 1.25 mCi for 131I-labeled 45.6 control. Therapeutic response was evaluated by survival prolongation using Wilcoxon rank sum analysis. Three experiments were done. No significant survival prolongation was found in the trial in which the average tumor size at the time of Mab administration was 60 ± 14 mm3, two-thirds the size which causes animal death. In experiment 2, Mab was given at 16 ± 14 mm3 average intracranial tumor volume. Statistically significant ( P ≤ 0.005) survival prolongation was found for animals treated with 2.5 mCi 131I-labeled 81C6. In that experiment, male animals with intracranial xenografts had significantly shorter survival than females ( P ≤ 0.005). When only female animals were used in the analysis, the 1.25-mCi 81C6 group also was found to have longer survival benefit ( P ≤ 0.01). In the third experiment, only female animals were used and the tumor size at the initiation of treatment was 20 ± 9 mm3. Highly significant survival prolongation again was found in both 1.25 ( P = 0.001) and 2.5 mCi ( P < 0.001) 131I-labeled 81C6 groups. The estimated dose to intracranial tumors from 1.25 mCi of 131I-labeled Mab was 1585 rads for 81C6 and 168 rads for 45.6. Dose to other organs from 81C6 and 45.6 was similar, ranging between 31 rads to the brain and 734 rads to the bone marrow. However, normocellularity was observed in most marrow tissue examined microscopically. Three animals receiving the low dose (1.25 mCi 81C6) survived for more than 71 days with apparent cures. In conclusion, intracranial human glioma xenografts were treated successfully with 131I-labeled 81C6 but not control Mab.
78 citations
TL;DR: The responses to morphine and bromocriptine suggest that the opiate and dopaminergic pathways play roles in the entity and the clinical similarity of the two diverse etiologic groups suggests the common theme is a release of the brain stem from higher control.
Abstract: Nine patients with autonomic dysfunction syndrome (ADS) characterised by sympathetic discharge and extensor posturing are presented. Morphine was given to three patients and in all cases consistently stopped the episodes. Dantrolene was given to one patient and reduced the severity of the extensor posturing without affecting the other components of the ADS. Bromocriptine was given to three patients and appeared to have both short- and long-term effects. Acutely, the drug partially corrected the hyperthermia and diaphoresis associated with these episodes. Two patients were given bromocriptine long-term. In one patient, the ADS was completely controlled and in the other, the frequency of the episodes decreased. The autonomic dysfunction syndrome appears to be related to both severe closed head injury and acute hydrocephalus. The clinical similarity of the two diverse etiologic groups and the absence of precipitating increased ICP in the former suggests the common theme is a release of the brain stem from higher control. The responses to morphine and bromocriptine suggest that the opiate and dopaminergic pathways play roles in the entity.
72 citations
TL;DR: The authors report the first case of limbic encephalitis associated with testicular carcinoma and the first histologically confirmed encephalopathy which responded to antineoplastic therapy of the associated neoplasm.
Abstract: Limbic encephalitis (encephalopathy) is a rare paraneoplastic syndrome which rarely responds to antineoplastic therapy. The authors report the first case of limbic encephalopathy associated with testicular carcinoma and the first histologically confirmed encephalopathy which responded to antineoplastic therapy of the associated neoplasm. The clinical and pathologic characteristics of paraneoplastic encephalopathies are discussed along with the potential for reversal of the neurologic process with effective antitumor therapy.
66 citations
TL;DR: The normal immune response is reviewed, followed by a discussion of the factors responsible for graft rejection, and the modification of these factors to allow successful CNS transplantation is discussed.
Abstract: The brain has long been considered an immunologically privileged site. Tissue transplanted to the central nervous system (CNS) is immunologically better tolerated than grafts to other regions of the body. With improved graft survival, tissue transplantation may provide new treatment options for previously incurable CNS disorders. The normal immune response is reviewed, followed by a discussion of the factors responsible for graft rejection. The modification of these factors to allow successful CNS transplantation is discussed.
20 citations
TL;DR: The localisation of the radioiodinated Fab fragment of monoclonal antibody (Mab) 81C6, reactive with a glioma-associated extracellular matrix antigen, was studied in athymic mice bearing subcutaneous and intracranial xenografts of D-54 MGglioma cells to realise the theoretical benefits of fragments as localising agents.
Abstract: The localisation of the radioiodinated Fab fragment of monoclonal antibody (Mab) 81C6, reactive with a glioma-associated extracellular matrix antigen, was studied in athymic mice bearing subcutaneous and intracranial xenografts of D-54 MG glioma cells. In vitro 81C6 Fab showed a marked loss of immunoreactivity and affinity for antigen compared to intact Mab 81C6. In vivo, the plasma half-life of 81C6 Fab was 7.0 hours compared to 2.1 days for 81C6. 81C6 Fab levels in tumours peaked at 2.6-3.8% injected dose/g in 2-6 h; Mab 81C6 reached 33.9% dose/g at 48 h. Localisation indices and tumour:tissue ratios were superior for Mab 81C6. Estimated radiation doses to tumour and normal tissues were lower for 131I-81C6 Fab than 131I-81C6. To realise the theoretical benefits of fragments as localising agents, Fab fragments of higher immunoreactivity and affinity, or bivalent F(ab')2 fragments are required.
20 citations
TL;DR: It appears that patients with more profound neurologic compromise and/or bilateral involvement as evidenced by poor performance on the MLP, tissue loss on CT scanning, or previous thalamic lesion, are most at risk for memory and language dysfunction postoperatively.
19 citations
TL;DR: A case of a brain stem abscess that was successfully treated using CT guided stereotaxy together with antibiotic therapy is presented and the role of stereOTaxy in the treatment of brainstem abscess is discussed.
01 Jan 1988
TL;DR: Reduced speed limits and mandatory seat belt laws are likely to increase further the population of surviving, disabled patients.
Abstract: Death and disability are major problems of closed head injuries. It has been estimated that, in the United States alone, head injury causes approximately 24 deaths/100,000 population [16]. Perhaps more troubling is the morbidity that occurs among those who survive severe head injuries: six months after their accident, 1%–5% of patients remain vegetative and 5%–18% severely disabled [17]. These disabled individuals represent a significant proportion of the population. In the United States, their number is not clearly defined. In Britain, where head injuries are somewhat less common, (9 deaths/100,000 population) the number of individuals with major handicaps persisting after head injury has been estimated at 150/100,000 persons; one in 300 British families has such a member [1, 16]. Reduced speed limits and mandatory seat belt laws are likely to increase further the population of surviving, disabled patients.
TL;DR: The results of the laboratory study done in animals, in the brain and in the spinal cord as well as the clinical experience of the impedance recordings in the DREZ procedure for some chronic pain conditions, correlating the measurements at the time of the operation with normal conditions.
Abstract: The measurement of electrical impedance of normal and pathologic tissue has not been fully utilized in neurosurgery. This is a report of electrical impedance measurement in the central nervous system of both man and animals. We show the results of the laboratory study done in animals, in the brain and in the spinal cord as well. Also we show the clinical experience of the impedance recordings in the DREZ procedure for some chronic pain conditions, correlating the measurements at the time of the operation with normal conditions, with comments about the findings.
TL;DR: The data indicate that postbiopsy hematomas are a relatively common occurrence, that intraoperative electrical stimulation within abnormal lesions can identify functional potential, and that avoidance of biopsies within these functional areas may be associated with reduced morbidity.
Abstract: 44 patients underwent intraoperative stimulation with a monopolar electrode prior to computed tomography (CT)-guided stereotactic biopsy. Stimulation at 2–100 Hz resulted in functional responses in 6/