Long-term beneficial effects of adrenal medullary autografts supported by nerve growth factor in Parkinson's disease.

Parkinson's disease has been the object of several therapeutic strategies based upon replacement of the degenerating dopaminergic neurons. Adrenal medullary transplants were tried initially, because of the biochemical relationship between chromaffin cells of the medulla and dopaminergic neurons of the substantia nigra. Compared to transplant of fetal neurons, autologous grafts of adrenal medullary tissue has the advantage of using a readily available source of tissue without the problems of immunosuppression. However, these cells have not proven to be as effective as fetal neurons, probably because they do not fully differentiate into neurons. In animal models, brief treatment with nerve growth factor can facilitate such differentiation. This study is a clinical evaluation of the efficacy of adrenal medullary cell transplantation, combined with nerve growth factor infusion. Two patients were selected who were moderately to severely affected (Hoehn-Yahr stage 2 in on-phase and stage 4 in off-phase). After adrenalectomy, small pieces of medulla were prepared and implanted stereotactically into the dorsal putamen on one side of the brain. A catheter filled with mouse beta-nerve growth factor (NGF) was placed close to the grafts. Infusion of NGF was continued for one month. Despite a progressively deteriorating course prior to surgery, both patients showed improvement on the rating scales postoperatively. There was also significant improvement in timed motor tests. Motor readiness evoked potentials showed increased voltage over the operated hemisphere. The study points to methods and feasibility of supplying nerve growth factor intraparenchymally to the human brain. Possible implications with respect to other growth factors, particularly Glial cell-line Derived Neurotrophic factor (GDNF) are discussed.

Leptomeningeal tissue: a barrier against brain tumor cell invasion.

BACKGROUND: Primary brain tumors are characterized by an extensive infiltrative growth into the surrounding brain tissue. This process is confined to the central nervous system, and tumor cell metastasis to other organs is rare. However, other tumors of non-neural origin may frequently metastasize to the central nervous system. PURPOSE: The purpose of the present study was to examine the invasive behavior of different glioma cells into tissues of neural (brain aggregates) as well as non-neural origin (leptomeningeal tissue). Using the same target tissues, the invasive characteristics of two neural metastatic tumors (one malignant melanoma and one small-cell lung carcinoma) were also studied. This direct comparison of the invasive behavior between tumors of neural and non-neural origin provides valuable information regarding the mechanisms of glioma cell dissemination in the central nervous system. METHODS: The in vitro invasive behavior of human tumors of the central nervous system into human leptomeningeal tissue as well as into normal rat brain tissue was studied. For this purpose, a co-culture system consisting of tumor biopsy specimens, human leptomeningeal cell aggregates, and brain cell aggregates was established. Three glioblastomas, one oligodendroglioma, one meningioma, one small-cell lung carcinoma, and one malignant melanoma were studied. RESULTS: In co-cultures of gliomas and leptomeningeal cell aggregates, a well-defined border between the two tissues was observed. The brain cell aggregates, in contrast, were consistently invaded by the glioma cells. The brain metastases showed a different invasion pattern. The metastatic cells invaded and progressively destroyed leptomeningeal cell aggregates, whereas they did not invade the brain cell aggregates. Upon confrontation of the leptomeningeal tissue with the meningioma, a fusion of the two tissues was observed. Immunostaining of the leptomeningeal tissue showed a strong expression of the basement membrane components fibronectin, collagen type IV, and laminin with no expression of glial fibrillary acidic protein, neuron-specific enolase, or S-100 protein. CONCLUSIONS: The present study indicates that there may be important biologic differences between the invasive behavior of gliomas and non-neuroepithelial tumors. Our co-culture experiments suggest that leptomeningeal cells and associated acellular components may constitute a barrier against glioma cell invasion. However, this barrier may not be functional for metastatic tumors to the brain. The presence of glioma cells within the leptomeninges should not necessarily be taken as evidence of aggressive growth or as an indicator of malignancy.

Treatment of craniopharyngiomas: the multimodality approach.

A Multimodality Protocol for the treatment of craniopharyngiomas, where stereotactic methods are used preferentially, give long-term results not inferior to those reported when microsurgical removal has been the first therapeutic choice. Case material, treated in accordance with this protocol, is presented in a long-term perspective. The features of the protocol are discussed.

The results of Gamma Knife surgery of meningiomas, related to size of tumor and dose.

In Bergen, 20 patients with meningiomas have been treated with a follow-up period in excess of 1 year. While this is too short a period to allow more than tentative conclusions to be drawn, some trends can be determined nonetheless. There has been some variation in the reporting of the results of treatment of meningiomas, with one group producing a reduction in size in 7% of patients and another in 34%. In the current material, 10 patients received 10 Gy or less to the edge of the tumor. In 4 of these 12 patients there was increase in the volume of the tumor within 1 year of treatment. Ten of the patients received 12 Gy or more to the edge of the tumor. Of these 10 patients, 4 had tumors which showed a reduction in volume. It is suggested that the difference in the reported rate of tumor volume reduction is related to differences in dose, which is discussed in relation to other treatment parameters.

The effects of Gamma Knife surgery of pituitary adenomas on tumor growth and endocrinopathies.

Fifteen patients were treated in the Gamma Knife Unit and followed for 18 months or longer. Four patients had Cushing's disease, 4 had acromegaly, 3 had Nelson's syndrome and 3 had prolactinomas. One patient had no endocrinopathy. One of the patients with acromegaly and 2 of those with prolactinomas had been operated prior to Gamma Knife treatment. Radiological tumor localization was not an insuperable problem in this series. The effect of Gamma Knife treatment on the anterior pituitary neoplasia, as such, was consistently successful. All the tumors which received 10 Gy or more to the edge showed either a reduction in volume or at least cessation of growth. On the other hand, the effect of the treatment was less consistent in respect to the endocrinopathies. These results are discussed in respect of dose and tumor size. It is suggested that the role of the Gamma Knife in the treatment of pituitary adenomas requires further clarification, based on prospective studies.

Effects of high and low single dose irradiation on glioma spheroid invasion into normal rat brain tissue in vitro.

The effects of radiation on direction on directional migration in monolayer cultures and brain tissue invasion by two glioblastoma cell lines (D-54 MG, D-247 MG) were investigated. The Leksell Gamma Unit was the radiation source and invasion was registered in an in vitro invasion assay developed in our laboratory. As tumor spheroids and brain tissue aggregates were treated simultaneously in cocultures; the effects of radiation on the interaction between the two tissues could be investigated. Tumor spheroids from both cell lines retained their ability to invade and destroy normal brain tissue, even after irradiation with 47.6 Gy. However, while the D-54 MG tumor spheroids showed a dose-dependent reduction of invasion, tumor spheroids from the D-247 MG cell line did not. In addition, radiation produced a dose dependent inhibition of directional migration of cells from D-54 MG spheroids. A similar significant inhibition of directional migration was found in D-247 MG, but it was not dose-dependent. Transmission electron microscopy revealed a loosening of the neuropil in the brain tissue of irradiated cocultures. However, this structural change did not seem to affect the invasiveness of the tumor. In this preliminary study, irradiation could not prevent invasion of two different glioblastoma cell lines into fetal rat brain tissue. Further studies using the same technique may help to understand the influence of ionizing radiation upon the invasion process in gliomas.

[Radiosurgery. A different kind of neurosurgery]. / Strålekirurgi. Et annerledes prinsipp i neurokirurgi.

A Leksell Gamma Knife has been used at Haukeland Hospital, Bergen, since October 1988. This is a powerful instrument in the treatment of some intracranial lesions. The article briefly describes the principles of treatment and the uses and limitations of the Gamma Knife.

Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease. One-year follow-up of first clinical trial.

Experimental studies in rodents show that beta-nerve growth factor can increase the survival, neurite outgrowth, and functional effect of grafts of adrenal chromaffin cells to the basal ganglia. We, therefore, have begun to investigate whether treatment with nerve growth factor might also increase the functional effect of autografts of adrenal medullary tissue in patients with Parkinson's disease. Previous studies have shown that stereotactic implantation of adrenal tissue pieces produces a transient functional improvement that lasts for a few months. This report describes a trial of grafting of adrenal chromaffin tissue into the putamen, supported by infusion of nerve growth factor. The patient is a 63-year-old woman with a 19-year history of Parkinson's disease, now complicated by on-off phenomena and drug-induced hyperkinesia, despite optimized medical management. The left adrenal gland was removed, and the medulla was dissected into 1- to 2-mm3 pieces in a solution containing nerve growth factor purified from mouse submandibular gland. Pieces were implanted in six tracts 3 to 4 mm from a previously placed cannula in the left putamen. Through the cannula, nerve growth factor was infused for 23 days for a total dose of 3.3 mg. Clinical assessment consisted of global ratings for rigidity and/or hypokinesia and for drug-induced hyperkinesia. Measures of gait and fine-motor control were also made. The motor readiness potential and auditory evoked potentials were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Multicellular tumor spheroids from human gliomas maintained in organ culture.

Tumor tissue from seven human gliomas was maintained in long-term agar overlay culture as multicellular organotypic spheroids. Light microscopic and ultrastructural observation of the spheroids displayed morphological features similar to those of the original tumor tissue in vivo; in this respect they were different from spheroids obtained from permanent cell lines. The spheroids contained preserved vessels, connective tissue, and macrophages, revealing a close resemblance to the conditions in the original tumor. Flow cytometric deoxyribonucleic acid measurements of cells from the tumor spheroids and from biopsy material obtained directly from the operation revealed the same ploidy and the same amount of proliferating cells in the spheroids as in the original tumor. Fluorescence microscopy using bromodeoxyuridine (BUdR) incorporation and anti-BUdR monoclonal antibody confirmed the proliferative potential of tumor cells in the spheroids. Diameter measurements showed that the size of the spheroids from two of the tumors increased over time while in three other cases it decreased. Spheroids from the remaining two tumors showed no change in size, even after 80 days in culture. These growth data and the relatively high number of proliferating cells, as measured by flow cytometry, indicate that the degree of cell proliferation and cell loss from the spheroids are closely linked, as is the case for tumors in vivo. The culture system presented provides a valuable alternative to propagation of human tumors in animals.

Interaction between human brain tumour biopsies and fetal rat brain tissue in vitro.

The invasiveness of human intracranial tumours was studied in an organ culture system. Biopsies from six glioblastomas, four astrocytomas, two mixed gliomas, one ependymoma, four meningiomas and two carcinoma metastases were cut into fragments of 0.5 mm diameter, and placed in agar overlay tissue culture. The tumour specimens formed spheroids which were co-cultured with cell aggregates or fragments from fetal rat brain for up to 10 days in vitro. The invasiveness of the glioblastoma spheroids was characterised by a gradual destruction of normal brain tissue by tumour cells, followed by replacement of normal tissue by these cells. Co-cultures from two glioblastomas showed lesions in the normal brain tissue in areas removed from the tumour cells. Tumour spheroids from four glioblastomas totally destroyed the normal brain tissue without any change in the original tumour spheroid configuration. The low-grade gliomas were less invasive than the glioblastomas. The meningiomas and the metastases were non-invasive. This organ culture assay appeared to reflect the in situ invasive behaviour of the brain tumours examined. It is suggested that it may be used for evaluating the aggressiveness of individual brain tumours with the specific aim of correlating clinical data with the biological character of the tumour.

Treatment of craniopharyngiomas--the stereotactic approach in a ten to twenty-three years' perspective. I. Surgical, radiological and ophthalmological aspects.

A multi-modality treatment programme, where stereotactic methods were used preferentially, gave results in a consecutive series of craniopharyngiomas, not inferior to those reported after microsurgical removal. Fourty-two patients with a follow-up range of 10-23 years are reported.

Treatment of craniopharyngiomas--the stereotactic approach in a ten to twenty-three years' perspective. II. Psychosocial situation and pituitary function.

Fourty-two consecutive patients with craniopharyngioma were treated by "stereotactic approach", i.e. preferentially stereotactic puncture and installation of colloid isotope into cystic tumours and external stereotactic single dose irradiation to solid tumour parts. In a minority of cases, such treatment was less suitable, and surgical removal and/or radiotherapy was used. There was no peroperative mortality. A long-term follow up (observation time 10-23 years) of the 31 patients alive indicated that they were socially well adapted with a high rate of fulltime work and a low rate of intercurrent disease. In spite of substitution therapy for pituitary insufficiency in most cases, the patients were subjectively seldom disturbed by their disease. Our results support a change in the choice of therapy for craniopharyngioma patients, from open neurosurgery to the less invasive stereotactic techniques.

Stereotactic biopsies as a model for studying the interaction between gliomas and normal brain tissue in vitro.

In order to study tumor invasiveness, the authors used a model system which allows the direct interaction between glioma cells and normal brain tissue to be studied. The spiral needle biopsy technique provides a tissue core with a completely preserved architecture from brain tumors. These biopsies, once cultured, produce three-dimensional multicellular tumor spheroids; they display morphological features similar to those of the original tumor in vivo. As a target fetal rat brain cell aggregates were used, in order to study the invasive process in the microscope. Not surprisingly, different tumors show different patterns of invasion; this variability is not yet clearly correlated with the clinical course of the patient.

Radiosurgery in intracranial tumors and vascular malformations.

In 1951 Leksell first coined the term "radiosurgery" indicating a new tool for the neurosurgeon by means of ionizing radiations. The technique consists of cross-firing a stereotactic target with several well-collimated "shots" of radiation. This produces well-defined lesions in the brain without opening the skull. After several significant improvements of this technique, now assisted by a computer, today it is possible to "tailormake" composite radiation fields for any single lesion. Some interesting clinical applications are Cushing's disease, acoustic tumors, pineal region tumors and arteriovenous malformations.

Colloidal radioisotopes as part of a multi-modality treatment of craniopharyngiomas.

The therapy of craniopharyngiomas has always been a challenge for the neurosurgeon. These tumors often display a cystic or polycystic portion usually bigger than the solid portion. This paper reports therapeutic results in a series of 42 cases; the follow-up range is 10 to 23 yrs. The results are particularly rewarding in the group treated by stereotactic methods exclusively. In any case the optimal management of a craniopharyngioma should include a careful study of the anatomy of the tumor and the intracystic treatment as the first choice if more than 50% of the total tumor bulk is cystic and the number of cysts reasonable.