Pulsed electromagnetic field stimulation may improve fusion rates in cervical arthrodesis in high-risk populations.

OBJECTIVES: Pulsed electromagnetic field (PEMF) stimulation was evaluated after anterior cervical discectomy and fusion (ACDF) procedures in a randomized, controlled clinical study performed for United States Food and Drug Administration (FDA) approval. PEMF significantly increased fusion rates at six months, but 12-month fusion outcomes for subjects at elevated risk for pseudoarthrosis were not thoroughly reported. The objective of the current study was to evaluate the effect of PEMF treatment on subjects at increased risk for pseudoarthrosis after ACDF procedures. METHODS: Two evaluations were performed that compared fusion rates between PEMF stimulation and a historical control (160 subjects) from the FDA investigational device exemption (IDE) study: a post hoc (PH) analysis of high-risk subjects from the FDA study (PH PEMF); and a multicentre, open-label (OL) study consisting of 274 subjects treated with PEMF (OL PEMF). Fisher's exact test and multivariate logistic regression was used to compare fusion rates between PEMF-treated subjects and historical controls. RESULTS: In separate comparisons of PH PEMF and OL PEMF groups to the historical control group, PEMF treatment significantly (p < 0.05, Fisher's exact test) increased the fusion rate at six and 12 months for certain high-risk subjects who had at least one clinical risk factor of being elderly, a nicotine user, osteoporotic, or diabetic; and for those with at least one clinical risk factor and who received at least a two- or three-level arthrodesis. CONCLUSION: Adjunctive PEMF treatment can be recommended for patients who are at high risk for pseudoarthrosis.Cite this article: D. Coric, D. E. Bullard, V. V. Patel, J. T. Ryaby, B. L. Atkinson, D. He, R. D. Guyer. Pulsed electromagnetic field stimulation may improve fusion rates in cervical arthrodesis in high-risk populations. Bone Joint Res 2018;7:124-130. DOI: 10.1302/2046-3758.72.BJR-2017-0221.R1.

Comparison of intravenous versus intracarotid therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea in a rat brain tumor model.

Currently numerous clinical trials are in progress utilizing intracarotid (i.c.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of malignant gliomas based upon the proposed focal nature of these tumors and the assumption that the i.c. route delivers higher levels of drug to the tumor. To date, however, increased efficacy in an animal model has not been clearly demonstrated for the i.c. delivery of BCNU. We have evaluated the dose-response curve for the i.v. and i.c. administration of BCNU in a commonly utilized experimental brain tumor model, the 9L rat gliosarcoma. An initial toxicity trial utilizing the i.p. 10% lethal dose (LD10) of BCNU by the i.v. and i.c. routes failed to demonstrate any significance in toxicity between the two routes. Tumor-bearing animals were then treated on Day 15-16 after tumor inoculations with 1, 10, 25, 50, 75, and 100% of the LD10 dose by either the i.v. or the i.c. route. Both i.v. and i.c. BCNU gave maximum survival increases at 75-100% LD10 doses, and there was no therapeutic advantage seen from i.c. delivery. However, at 50% of the LD10 dose (6.65 mg/kg), triplicate experiments demonstrated that the i.c. but not the i.v. dose maintained maximum efficacy equivalent to 100% of the LD10 given either i.v. or i.c. When the dose was reduced to 25% of the LD10 dose (3.33 mg/kg), two of three experiments showed efficacy of the i.c. delivery of this lower drug dosage to be equivalent to 100% of the LD10 given i.v. or i.c. The i.v. dosage resulted in a significant reduction in survival in all three trials. At 10% of the LD10 dose (1.30 mg/kg), neither the i.v. nor the i.c. administration retained equivalent efficacy to 100% of the LD10. However, in one of two trials, the i.c. groups had statistically better survival than controls, while in neither experiment was any advantage over controls seen in the i.v. treated groups. At 1% of the LD10 dose, neither the i.v. nor the i.c. route demonstrated any therapeutic efficacy. From our data, the advantage of the i.c. delivery of BCNU in the intracranial 9L rat gliosarcoma appears to be in the fact that significantly lower dosages than those given i.v. may be utilized to achieve equivalent survival with potentially less systemic toxicity.

Production and characterization of two human glioma xenograft-localizing monoclonal antibodies.

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.

Comparison of monoclonal antibody delivery to intracranial glioma xenografts by intravenous and intracarotid administration.

Monoclonal antibody 81C6, which is directed against a human gliomamesenchymal extracellular matrix antigen, was used to evaluate the potential advantage of intracarotid (i.c.) administration versus i.v. delivery to D-54 MG human glioma intracranial xenografts in immunosuppressed rats. Two approaches were taken. In paired-label analysis, 125I-labeled 81C6 and 131I-labeled isotype control antibody were given to separate groups of animals by either the i.v. or i.c. route. Biodistribution measurements as a function of time were analyzed in terms of the percentage of injected dose/g of tissue and localization indices. No significant difference (P greater than 0.19 to P greater than 0.56) was demonstrated between the i.v. and i.c. routes. To control for the large localization variation inherent in the animal model used, an alternative experimental design, paired-injection analysis, was performed in which 125I- and 131I-labeled 81C6 were simultaneously administered by the i.c. and i.v. routes to the same animal. Significantly higher levels of percentage of dose/g of tissue and localization ratios (P less than 0.05 to P less than 0.005) were shown from Day 1 to Day 3 for 81C6 given i.c. Approximately 20% more antibody was delivered to the D-54 MG intracranial tumor by the i.c. route during the experimental period of 5 days. No difference in the levels of normal tissue exposure between the two routes of administration was seen. These data suggest an advantage exists for whole monoclonal antibody given i.c. and that, theoretically, a greater advantage may be present for smaller molecules such as Fab and F(ab')2 fragments.

Specific chromosomal abnormalities in malignant human gliomas.

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.

Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model.

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 micrograms. The doses given by injection per animal for labeled 81C6 were 50, 250, 500, and 1000 mu Ci and 500 and 1000 mu Ci 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 mu Ci 81C6 (P less than 0.001) and 2 of 3 for 1000 mu Ci 81C6 (P = 0.001 and less than 0.001). At 5000 mm3, statistically significant growth delays were seen with radiolabeled 81C6 in 2 of 2 experiments at 250 mu Ci (P = 0.01 and 0.02), 4 of 4 at 500 mu Ci (P = 0.03-less than 0.001), and 2 of 2 at 1000 mu Ci (P = less than or equal to 0.001) and with radiolabeled 45.6 in 1 of 1 at 1000 mu Ci (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 mu Ci. For radiolabeled 81C6, there were 0 of 6 regressors at 50 mu Ci, 1 of 16 (6%) at 250 mu Ci, 7 of 38 (18%) at 500, and 15 of 28 (54%) at 1000 mu Ci. Statistically significant tumor regression was seen only at doses of 500 and 1000 mu Ci of 131I-81C6.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of intracranial human glioma xenografts with 131I-labeled anti-tenascin monoclonal antibody 81C6.

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 less than or equal to 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 less than or equal to 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 less than or equal to 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 less than 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.

Phase II diaziquone-based chemotherapy trials in patients with anaplastic supratentorial astrocytic neoplasms.

We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.

The morphologic response of cell lines derived from human gliomas to dibutyryl adenosine 3':5'-cyclic monophosphate.

The addition of exogenous cyclic nucleotides to cultured neoplastic cells has been reported by others to cause changes in growth properties and cellular morphology. We have studied the in vitro morphologic response to exogeneous dibutyryl adenosine 3':5'-cyclic monophosphate (DBcAMP) of twelve permanent cell lines derived from human gliomas, thirteen sublines and clonal lines derived from human gliomas, and nine cell lines derived from neoplastic and non-neoplastic human tissue from sources other than gliomas. Replicate samples from each cell line were evaluated during log phase growth by counting cells with cytoplasmic extensions greater than two times the diameter of the cell body and at saturation density for the percentage of cells morphologically responding to DBcAMP. The mean percentage of glioma-derived cells responding ranged from 5.0 to 97.3 percent during log phase growth and from 0 to 100 percent at saturation density; from 0 to 95.0 percent of non-glioma derived cells responded. The percentages of responding cells from gliomas and controls for any given line was reproducible within and between triplicate observations. Further evaluation of the twelve permanent human glioma-derived cell lines during log phase growth and at confluence delineated two clearly separate groups of cell lines. During log phase growth, eight of twelve lines had between 19.7 and 88.0 percent responding cells. At confluence, these same cell lines had between 25 and 100 percent responding cells. The other four cell lines had, respectively, 5.7 to 7.7 percent and 0 to 10 percent responding cells. The spectrum of percentage of responding cells and the variable nature of the response elicited provide evidence for the heterogeneity of the cell populations present within human glioma-derived cultured cell lines. The in vitro morphologic response to DBcAMP was reproducible and could be quantitated, but the nature and mechanism of the response to DBcAMP, whether "toxic," "differentiating," or otherwise, could not be determined from these studies.

Growth and chemotherapeutic response in athymic mice of tumors arising from human glioma-derived cell lines.

Fifteen permanent cell lines derived from human gliomas were subcutaneously transplanted into athymic nude mice (nu/nu genotype, NIH Swiss and BALB/c backgrounds). Four were tumorigenic. Three of the four (D-54 MG, U-118 MG, and U-251 MG) produced progressively growing, solid, noncystic tumors. Subcutaneous volume measurement of these tumors, which correlated directly with tumor weight, was a reliable method for monitoring growth. All three cell lines which produced progressively growing subcutaneous tumors were also tumorigenic when cells were inoculated intracerebrally. These grew as well-circumscribed, intraparenchymal brain tumors. After initial implantation, each of the progressively growing, solid, subcutaneous tumors was histologically similar to the permanent cell lines from which it was derived. Tumors could be reliably passed, and stabilization of latency periods and growth rates developed. Tumors became morphologically less distinct in later passages, though some individual features remained. Mice bearing subcutaneous tumors from each of these cell lines were treated with a single ip dose of 25 mg/kg BCNU and compared to controls receiving only drug vehicle. A significant, but different, amount of reduction in tumor mass occurred among each of the three tumor lines. This model allows cell lines derived from human gliomas to be grown in animal hosts, thereby providing a potential means for evaluating growth parameters and chemotherapeutic responsiveness of tumors derived from individual human gliomas or cell lines.

Relationship of in vitro morphologic and growth characteristics of established human glioma-derived cell lines to their tumorigenicity in athymic nude mice.

Fifteen permanent cell lines derived from human gliomas which are individually distinct by immunologic and biochemical criteria were evaluated to determine if morphologic or cell biologic parameters distinguished the 4 lines which were tumorigenic in athymic nude mice. By subjective morphologic appraisal, the 4 tumorigenic lines were considered "malignant" or "borderline," but 4 of the non-tumorigenic lines were also classified in this way. By objective criteria, these 15 lines varied markedly in percentage of piled-up cells, chromatin pattern, pleomorphism, nuclear to cytoplasmic ratio, number of bizarre multinucleate giant cells, presence of abnormal mitotic figures, percentage of colony formation in soft agar, saturation density, population doubling time, and absolute plating efficiency. Among these criteria, percentage of colony formation in soft agar had the highest correlation coefficiency with tumorigenicity, and when this parameter was held constant the only additional characteristic which correlated significantly (p less than .05) was the number of bizarre multinucleate giant cells. When the 11 non-tumorigenic lines were ranked by these 2 criteria, 1 non-tumorigenic line (U-251 MGsp) had greater than .95 predicted probability of tumorigenicity. Although further tumorigenicity testing may increase the number of tumorigenic lines, the lines with few "malignant" characteristics may correspond to the population resembling cells of low grade astrocytomas seen within glioblastomas. The histologic pleomorphism of human gliomas is reflected in their morphologic and cell biologic diversity in culture.

A hyperthermic syndrome in two subjects with acute hydrocephalus.

Although intracranial hypertension may cause autonomic disturbances, as well as alterations in the regulation of body temperature, an acute hyperthermic syndrome with autonomic disturbance as a consequence of hydrocephalus has not been described previously. Two subjects presented with such a syndrome, with each of several episodes of acute shunt failure and hydrocephalus. With correction of the hydrocephalus, the autonomic disturbances and fever immediately cleared. Observations from human and experimental studies suggest some potential mechanisms for the development of the syndrome. One of the subjects of this report was being treated with neuroleptics at the time of hospitalization; in him, and potentially in other similar patients, the syndrome could easily be confused with the neuroleptic malignant syndrome. The need for prompt appreciation of the correct diagnosis was emphasized by the rapid clearing of all neurological signs after correction of the shunt malfunction in both of these patients.

Comparative localization of glioma-reactive monoclonal antibodies in vivo in an athymic mouse human glioma xenograft model.

Radioiodinated murine monoclonal antibodies (Mabs) 81C6, Me 1-14, C12, D12, and E9, made against or reactive with human gliomas but not normal brain, and Mab UJ13A, a pan-neuroectodermal Mab reactive with normal human glial and neural cells, were evaluated in paired label studies in the D-54 MG subcutaneous human glioma xenograft model system in nude mice. Following intravenous injection in the tail vein of mice bearing 200-400 mm3 tumors, specific localization of Mabs to tumor over time (6 h-9 days) was evaluated by tissue counting; each Mab demonstrated a unique localization profile. The comparison of localization indices (LI), determined as a ratio of tissue level of Mab to control immunoglobulin with simultaneous correction for blood levels of each, showed Mabs 81C6 and Me 1-14 to steadily accumulate in glioma xenografts, maintaining LI from 5-20 at 7-9 days after Mab injection. Mab UJ13A peaked at day 1, maintaining this level through day 2, and declining thereafter. Mabs D12 and C12 peaked at days 3 and 4, respectively, and E9 maintained an LI of greater than 3 from days 3-9. Percent injected dose localized/g of tumor varied from a peak high of 16% (81C6) to a low of 5% (Me 1-14 and UJ13A). Immunoperoxidase histochemistry, performed with each Mab on a battery of primary human brain neoplasms, revealed that Mabs 81C6 and E9, which demonstrated the highest levels of percent injected dose localized/g of tumor over time, reacted with antigens expressed in the extracellular matrix. This finding suggests that extracellular matrix localization of antigen represents a biologically significant factor affecting localization and/or binding in the xenograft model used. The demonstration of significant localization, varied kinetics and patterns of localization of this localizing Mab panel warrants their continued investigation as potential imaging and therapeutic agents for human trials.

Chromosomal evolution in malignant human gliomas starts with specific and usually numerical deviations.

Our previous karyotypic studies of malignant human gliomas have demonstrated that their most consistent early or primary gross changes include gains of #7, losses of #10, #22, and the gonosomes, and the presence of double minutes. Karyotypes of 15 additional malignant human gliomas reported here have confirmed these observations and, by enlarging our series, we can now show that in addition to double minutes, certain other gross structural abnormalities also are clearly associated with the early evolution of this type of tumor. The most prevalent deviations are deletions and translocations involving 9p. Other chromosomes commonly involved in rearrangements are #1, #6, and #13, and less frequently #7, #11, and #16.

Heterotransplantation of human craniopharyngiomas in athymic "nude" mice.

Surgical biopsies from 2 human craniopharyngiomas were transplanted subcutaneously into 6 athymic "nude" mice. Morphologically characteristic craniopharyngiomas grew in 5 of these animals. In 4 animals growth was sufficient to allow transplantation into a second generation of animals. In all, 11 craniopharyngiomas were present at autopsy in the 14 animals into which the tumors had been transplanted. The tumors that grew in the animals had the same adamantinomatous architecture, epithelial nests, and keratinized nodules that were present in the original surgical sample and that are characteristic of human craniopharyngiomas. It may be possible to study growth characteristics and therapeutic sensitivities of human craniopharygniomas growing in "nude" mice.

Foreign body reaction to rubber Torkildsen catheters: a report of two cases.

Two patients came to clinical attention because of foreign body reactions to rubber catheters. In one patient, the reaction presented as multiple levels of aseptic meningitis and, in the second patient, the reaction caused an intracranial mass with localized neurological dysfunction.

Further experience utilizing the Gildenberg technique for computed tomography-guided stereotactic biopsies.

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)

Carotid artery injections in 40- to 99-g Fischer rats: technical note and evaluation of blood flow by various injection techniques.

Despite extensive clinical use of brain tumor chemotherapy via the internal carotid artery (ICA), demonstration of efficacy and toxicity screening of ICA chemotherapy in brain tumor models has been limited. A method for performing ICA injections in 40- to 99-g Fischer rats is described, with documentation of its effect upon cerebral blood flow. A 33 gauge cannula was secured into a PE-10 catheter and, after ligation of the external carotid (ECA) and the pterygopalatine arteries, injections were made into the common carotid artery (CCA). The reliability of this method compared to CCA injection with and without ligation of the ECA was evaluated utilizing 15-micrometers 103Ru microspheres. With this technique, 68.3 +/- 11.19% of the microspheres lodged in the brain, compared to 28.9 +/- 21.3% to 32.7 +/- 19.8% for the other techniques (P less than 0.01). With this technique, regional perfusion of brain tumors can be done in the avian sarcoma virus rat glioma model, the D-54 MG human glioma-immunosuppressed rat transplantation model, and any of the large rat brain tumor models. The relevance of this method of experimental regional perfusion for the preclinical assessment of the efficacy and of the toxicity of chemotherapy and immunotherapy via the ICA is discussed.

Central nervous system metastases in malignant melanoma.

In a series of 1341 patients with histologically proven malignant melanoma seen at Duke University Medical Center from 1968 to 1978, 107 patients developed central nervous system (CNS) metastases. These patients were evaluated on the basis of which factors were associated with the development of CNS metastases. Male patients, patients with invasive primary lesions as measured by Clark's system, and patients with primary lesions of the head/neck or oral mucosa had higher incidences of CNS metastasis. Age and race were not significant factors. Clinically, single CNS metastases were seen in 48.8% of the patients; multiple cerebral lesions were seen in 37.2% of the patients. In 22% of the patients there was CNS metastasis alone, in 41% a second organ was involved, and in 20% three organs were involved.

A case of Ollier's disease associated with two intracranial gliomas.

Ollier's disease or multiple enchondromatosis is a deforming dysplastic disease of cartilage involving primarily the metaphyses and diaphyses of long bones. It is only rarely associated with sarcomatous degeneration of the enchondromas or other generalized neoplasms. A related disease, Maffucci's syndrome, is, however, associated with generalized tumors. We present the case of a 29-year-old, albino, black man with Ollier's disease who, as a child, underwent a number of orthopedic procedures for multiple limb deformities and fractures. At age 25, he developed hydrocephalus, progressive cranial nerve palsies, and a large enchondroma of the skull base. He subsequently underwent multiple shunt procedures and two suboccipital craniectomies. Eighteen months later, a brain computed tomographic (CT) scan revealed an intracerebellar mass, which was found to be an anaplastic astrocytoma. Two years later, he developed a right hemiparesis and sensory dysfunction with a diffuse supratentorial mass on CT scan. A stereotactic biopsy showed this to be a similar anaplastic astrocytoma. The literature concerning Ollier's disease is reviewed, and the intracerebral lesions associated with both Ollier's disease and Maffucci's syndrome are examined.