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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.

Eighteen patients underwent CT guided stereotactic biopsies using either a Riechert-Mundinger stereotactic frame modified for use in the CT scanner or the CT-based intracranial landmark technique of Gildenberg and a Todd-Wells frame. In seven patients undergoing biopsy with the modified frame technique, representative tissue samples were obtained in all cases. Eleven patients had biopsies using the Gildenberg technique and representative tissue samples were obtained in 10 of the 11. No major postoperative complications occurred in either group. Both techniques allowed samples of intracranial tissue to be obtained safely and efficiently. The modified frame technique provided a higher degree of accuracy while the Gildenberg technique required significantly less CT time and provided a satisfactory degree of accuracy. In seven patients with ring enhancing lesions, biopsies of the enhancing rim provided diagnostic tissue while biopsy of the central low density center of the lesion in three patients provided necrotic material which was useful in histologically grading the tumour.

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.

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.

Traditional cerebrospinal fluid (CSF) analysis has been of limited value in the diagnosis of central nervous system (CNS) cancer.92 Abnormalities of biochemical and cellular composition have, with certain exceptions, been nonspecific and of limited diagnostic, prognostic, and therapeutic significance. The development of more sophisticated methods of CSF analysis offers the hope that more useful information can be gained by judicious application of these methods to the CSF of patients with brain cancer.

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.

Malignant melanomas arise from neural crest-derived melanocytes, which are found in the skin, mucous membranes, uveal tract and in the piaarachnoid of the central nervous system (CNS). Theoretically, primary malignant melanomas can arise in any of these sites. However, the vast majority of melanomas arise in the skin, so that tumors found in other locations are generally the result of metastasis. This chapter will review involvement of the CNS by metastatic melanoma and will describe briefly the melanomas which originate in the brain and spinal cord.

A preliminary study utilizing viable HLA mismatched cultured glioma cells as adjuvant therapy for patients with malignant gliomas

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.

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.

We have utilized intraoperative stimulation to establish the functional nature of tissue to be biopsied in 20 patients undergoing CT-guided stereotactic biopsies. We have performed from 1–4 stimulations at 2–100 Hz using a monopolar and/or bipolar electrode at the intended target sites. Thresholds for motor and sensory response have been obtained. Stimulation results have ranged from sensory changes to tonic/clonic motor activity of the contralateral body and face.

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.

✓ Methods for transiently disrupting the blood-brain barrier (BBB) which are consistent with survival are described for immature Fischer 344 rats weighing 40 to 99 gm. A catheter was retrogradely inserted into the external carotid artery to the level of the bifurcation. Perfusion of 1.4 M mannitol or 1.6 M arabinose, at a rate of 0.01 to 0.1 ml/sec for 30 seconds, resulted in transient BBB disruption as measured by Evans blue dye (EBD) staining. Higher flow rates or perfusion with 10% to 30% dimethyl sulfoxide were associated with a mortality rate ranging from 0% to 44%. Perfusion with 0.9% sodium chloride or intrafemoral artery perfusion with 1.4 M mannitol did not disrupt the BBB. Optimum BBB disruption as measured by EBD staining was achieved with 1.6 M arabinose at 0.026 ml/sec for 30 seconds, at which time all of the 42 experimental animals had BBB disruption; all of the animals so treated survived 2 weeks following perfusion. This technique will allow the efficacy of delivering chemotherapeutic agents following BBB disruption to be tested in several of the more commonly used small-animal models for brain-tumor research.

Central nervous system (CNS) malignancies represent one ofthe most devastating forms of cancer. Malignant gliomas, the most commonly occurring primary tumor of the CNS, have a particularly bleak prognosis despite surgery and combined radiation and chemotherapy (1, 2). Immunological approaches to diagnosis and treatment have seemed attractive, but in the past have been frustrated by technological limitations (3, 4). Monoclonal antibody methodology offers major advantages over conventional methods of antiserum production: a practically unlimited source of homogeneous, highly specific reagent which may be prepared using impure or complex antigens. This has led to a new age in neuroimmunology and neuro-oncology, with the potential for better understanding of the basic cell biology of CNS neoplasia, and for improvement in diagnosis, imaging, and therapy.

15 patients had intracranial CT-guided stereotactic biopsies. Biopsies were performed either with a Riechert-Mundinger stereotactic frame modified for use in the CT or by using the CT scan to establish the relationship of the intracranial lesion to identifiable bony landmarks, and subsequently performing the biopsy in a Standard stereotactic frame. Both systems provided safe and accurate methods for obtaining intracranial tissue.

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. There were no patients with long-term morbidity in this series. From our experience, we believe this technique offers a safe, accurate, and relatively inexpensive alternative for performing-CT-guided intracranial biopsies.

Sixteen of 17 anaplastic human gliomas (AHGs) transplanted into athymic mice produced progressively growing subcutaneous nodules at the site of implantation. Thirty-four of 68 animals (50%) receiving transplanted tissue developed 500 m3 tumors in 24 to 364 days. Fourteen AHG were passed to a second animal generation, and 11 showed continued growth. Eight of these were serially passed, with one reaching a sixth animal generation, four reaching a fifth, and a three third. Once growth occurred in a second animal generation, no AHGs were lost in subsequent passages because of failure to grow. Of 234 animals receiving tumors beyond the first animal generation, 189 (80.8%) developed tumors. Average doubling times of the exponentially growing tumors in serial passage ranged from 3.0 to 19.1 days. This growth rate tended to increase and stabilize in early animal passages. The tumors growing in animals contained cell types which were present in the original human tumors, including fibrillary and protoplasmic astrocytes, small anaplastic cells, gemistocytes, anaplastic spindle cells, and multinucleate giant cells. Glial fibrillary acidic protein (GFAP) was detected in 15 of 17 biopsy specimens and in 12 of 14 AHGs in animals. These data illustrate the value of the athymic mouse system for the investigation of human brain tumors by demonstrating a high rate of successful transplantation, quantitative growth data on serially passed tumors, and morphological and immunochemical resemblance of the tumors in mice to the original human tumors.

✓ Stereotaxic ventrolateral thalamotomies have been successful in treating a wide spectrum of involuntary movement disorders, but very little has been reported concerning their use in posttraumatic movement disorders (MD's). This procedure has been used to treat 11 patients who developed persistent MD following severe closed head injuries. Among these, seven had action tremors, nine hemiballismic movements, two choreoathetoid movements, and two truncal ataxia. In two patients the MD was significant bilaterally, and in eight patients more than one type of MD was present. Standard thermal lesions based on the middle anterior commissure-posterior commissure line, 10 to 15 mm lateral to the midline, were performed following stimulation. Within the immediate postoperative period, all 11 patients had some degree of improvement in their MD; five showed marked improvement, four moderate improvement, and two minor improvement. One patient had recurrence of the MD 24 hours postoperatively requiring a second procedure, with marked improvement subsequently. In five of the six patients who underwent a left-sided procedure, a transient increase in preoperative dysarthria was noted. Nine patients had follow-up examinations 2 months to 3 years following surgery. Some persistent improvement in the MD was noted in all. Of three patients whose dysarthria was worse at 3 to 4 months, subsequent improvement was noted at 9 to 12 months in two. Stereotaxic thalamotomy appears to be an effective form of treatment for persistent posttraumatic MD. The major limitation is increased postoperative dysarthria. Further studies to evaluate risk factors associated with dysarthria and further refinement to prevent its occurrence are needed.

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.

We report a patient with a colloid cyst of the 3rd ventricle. The computed tomographic scan demonstrated a ringenhancing lesion rather than the classically described homogeneous hyperdense lesion. A brief review of the literature and theoretical explanations for this case are presented.

Thirty-five patients with an unremarkable or a negative water-soluble contrast myelogram and a diagnosis of foraminal neural entrapment made or more firmly established by computed tomography (CT) were detected in evaluating 950 patients presenting for myelography. The CT criterion of forminal neural entrapment was the presence of a mass displacing epidural fat and encroaching on the neural intervertebral foramen or lateral recess so as to compromise an emerging nerve root. The entrapment (confirmed operatively) was due to a laterally prolapsed disc (16 cases), superior articular hypertrophy (4 cases), lateral recess stenosis (3 cases), posterolateral vertebral bone lipping (2 cases), tumors (6 cases), postoperative scarring (2 cases), spondylolisthesis (1 case), and synovial cysts that encroached on the neural foramina (1 case). CT is an important additional investigation in patients with a painful radiculopathy and a negative or equivocal water-soluble contrast myelogram.