Gamma knife radiosurgery in the management of arteriovenous malformations of the Basal Ganglia region of the brain.

OBJECTIVES: The authors report the results of gamma knife (GK) radiosurgery on a clinical series of selected patients with basal ganglia arteriovenous malformations (BGAVMs) in the brain. Clinical, epidemiological, anatomical and functional characteristics of BGAVMs and of supratentorial cortical AVMs are comparatively analyzed, and their influence on radiosurgical outcome is discussed. METHODS: At our Department, 33 BGAVMs (21 with FU > 2 years) and 209 cortical AVMs (110 with FU > 2 years) with a radiosurgical volume

Prognostic factors in low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76 surgically treated adult patients.

A retrospective uni-multivariate statistical analysis was performed on 32 prognostic factors to investigate their importance in predicting survival in a series of 76 adult patients with low-grade supratentorial astrocytomas treated over a 13-year period. The end point used for this study was the length of survival. The median survival time was 40 months. Overall actuarial survival at 2, 5, and 10 years was 69%, 38%, and 22%, respectively. Radical resection of the neoformation, a higher preoperative Karnofsky performance status (KPS) score, and an age younger than 50 years are strongly correlated with survival; postoperative radiotherapy appears to be associated with increased survival only in patients under 50 years of age.

A euristic approach to the volume reconstruction of arteriovenous malformations from biplane angiography.

Three-dimensional (3D) volume reconstruction is easily feasible with axial, coronal or sagittal CT and MRI scans. On the other hand, radiosurgical treatment of arteriovenous malformations (AVMs) is exclusively based on two orthogonal stereotactic projections, obtained with angiographic procedures. Most commonly AVM volumes have been calculated by assimilating the nidus volume to a prolate ellipsoid. We present an algorithm dedicated to 3D volume reconstruction starting from two stereotactic orthogonal projections. This has been achieved using a euristic approach which has been widely adopted in the artificial intelligence domain. Tests on phantoms of different complexity have shown excellent results. The importance of the algorithm is considerable. Firstly, it allows calculations of complex structures far removed from a regular ellipsoid. Secondly, it permits shape recovery. Thirdly, it provides AVM visualization on axial planes.

Quality assessment of magnetic resonance stereotactic localization for Gamma Knife radiosurgery.

Artifacts in magnetic resonance imaging (MRI) may lead to anatomical distortion and inaccurate stereotactic coordinates. A special phantom for MRI and computed tomography (CT) was built to test the quality and precision of the two neuroradiological procedures. The phantom is fixed with the Leksell frame, and it has 15 orthogonal markers visible by CT and MRI techniques. The coordinates of the markers were calculated first on the CT scans and then on MR images. Two groups of different distortions were analysed: artifacts depending on the frame and its components and artifacts depending on the MR unit and image characteristics. A good target-coordinate correlation was found between CT and MRI in the axial plane, while in the coronal plane there was always a small error. This error is not constant, but changes from test to test, consequently it is hard to reform the image.

Gamma Knife radiosurgery in AIDS-related primary central nervous system lymphoma.

The frequency of AIDS-associated primary central nervous system (PCNS) lymphoma is rapidly increasing in adults and children. In AIDS-related PCNS lymphoma, different authors have reported an overall poorer response rate to conventional radiation compared with immunocompetent patients. This poorer response consists of a significantly positive, although transient effect on survival following radiotherapy (XRT), with a poor toleration for prolonged whole-brain RT (WBR) and with radiation-induced changes within the normal CNS tissue on autopsy examinations after a course of XRT. These observations led us to consider highly focused single-session radiosurgical treatments as a potentially useful therapeutic modality for AIDS-associated PCNS lymphomas. A multi-institutional diagnostic and therapeutic protocol for the evaluation and treatment of AIDS patients with high-risk intracerebral space-occupying lesions has been developed at the University Hospital of Verona. Therapy is based on tumor biopsy. Tumors < or = 3.5 cm in diameter are subjected to Gamma Knife radiosurgery, whereas tumors < or = 4.5 cm are treated with stereotactic brachytherapy. At the Department of Neurosurgery, Verona, Italy, Gamma Knife treatment was performed in 2 cases of deep-seated histologically verified malignant non-Hodgkin's lymphoma. A short-term cliniconeuroradiological follow-up (2 months later) showed neurologic improvement and virtually complete disappearance of the tumor in both patients. The excellent local control and the well-tolerated single-session treatment and absence of brain toxicity signs on CT scan indicate a putative role for Gamma Knife radiosurgery in the treatment of these patients.

Gamma Knife radiosurgery of primary and metastatic malignant brain tumors, a preliminary report.

Between February 1993 and March 1994, 75 metastases, 16 gliomas and 2 AIDS-related malignant lymphomas were treated with Gamma Knife radiosurgery. Metastatic brain tumors (54% lung cancer, 14% breast cancer, 13.5% melanoma) were the most frequent and clinically rewarding cases. So-called local control was achieved in almost all patients, the vast majority showing neurological improvement associated with radiological disappearance or dramatic shrinkage of the tumor within 9-12 weeks from treatment. According to our modified 'Pittsburgh' protocol, we have treated up to four distinct intracranial lesions, up to a total maximum volume of 20 cm3, with an average surface dose of 25 Gy, with or without additional whole brain radiotherapy (WBR). Preliminary follow-up data seem to confirm increased quality of life and survival rates. The results were particularly striking whenever primary tumors were under control, and were poorly influenced by associated WBR. Gamma Knife treatment was also performed in a selected group of patients with small-to-medium-sized, well-defined, histologically proven, cerebral gliomas. The main indications for radiosurgery were high-risk surgery, multifocal disease, ventricular seeding and unresected or recurrent tumor. The prescription doses ranged from 18 to 30 Gy, with a mean of 27 Gy. Low-grade astrocytomas (9/16 cases) showed the better clinical and radiological response to treatment, with neurological recovery and significant reduction in tumor volume within 3-5 months in 5 of the 9 patients. In 4 of 7 high-grade gliomas, there was little or no response. However, an impressive radiological regression with full clinical recovery was observed in 2 high-grade cases with small tumor volumes: a recurrent, anaplastic 'mixed glioma' of the pineal region and a double ventricular seeding of a previously operated anaplastic astrocytoma.

Gamma Knife stereotactic radiosurgery of ocular metastases: a case report.

A case of a choroidal metastasis treated with Gamma Knife stereotactic radiosurgery is reported. A 48-year-old Caucasian man afflicted with lung cancer (adenocarcinoma) was referred to the University Hospital of Verona, Italy, for loss of vision in his left eye due to a choroidal mass with exudative retinal detachment. Clinical investigation was conclusive of a well-defined, bilobed choroidal metastasis located in the temporal and inferior portion of the posterior pole of the eye. The lesion was characterized by a maximum thickness of 5.2 mm and a maximum lateral extension of 14 mm. The staging was negative for other metastatic localizations. Using the Gamma Knife technique, a surface dose of 25 Gy was administered at the 50% isodose line using the 8-mm collimator (5 shots) with equally weighted fields. After a 3-month follow-up period, a marked reduction in the lesion size as well as in the exudative retinal detachment was observed. This improvement was unchanged 6 months after the treatment, and the lesion appeared completely controlled. To the best of our knowledge, this is the first case report of an ocular metastasis treated with stereotactic Gamma Knife radiosurgery.

Stereotactic radiosurgery of uveal melanomas: preliminary results with Gamma Knife treatment.

Twelve cases of uveal melanoma (T3N0M0:11 patients, T4N0M0:1 patient) treated with Gamma Knife stereotactic radiosurgery are reported. Our protocol includes preoperative ocular and systemic assessments with complete ocular examination, ophthalmoscopy, fundus photography, fluorangiography, standardized echography, CT and MRI, chest X-rays, liver echography and blood tests. The follow-up program is mainly based on echographic evaluation of tumor thickness and size. The procedures include fixation of the eye, application of the stereotactic Leksell frame G, CT/MRI localization of the melanoma, dose planning and treatment with the Gamma Knife (B type). A mean surface dose of 55 +/- 10 Gy was administered at the 60-90% isodose curve using 4- to 14-mm collimators and a number of shots ranging from 1 to 6. A significant reduction (10-41%) in echographic thickness of the tumor was shown in 6 cases with a follow-up of 3-12 months. In 4 patients, the tumor size was still unchanged after 1-10 months. The single high-dose radiation delivered to the target and the high spatial accuracy are the main advantages of stereotactic radiosurgery for the treatment of posterior uveal melanomas. A longer followup is needed to further validate this new application of Gamma Knife radiosurgery.

Characterization of BK virus variants rescued from human tumours and tumour cell lines.

Episomal BK virus (BKV) DNA was detected in primary human brain tumours, in Kaposi's sarcoma and in cell lines from brain tumours. Ewing sarcoma and osteogenic sarcoma. Infectious BKV was rescued from several tumours and tumour cell lines by transfection of total cellular DNA into human embryonic fibroblasts. Restriction endonuclease and nucleotide sequence analysis showed that all the rescued viruses are similar to BKV-IR, a BK variant previously isolated from a human tumour of pancreatic islets, indicating that a specific BKV strain may be associated with certain types of human tumours. All the variants contain a putative transposable elements in the regulatory region of the viral genome. This region has mutagenic properties and enhancing activity in transformation, suggesting a possible role of these variants in tumour induction or progression.

Overexpression of N-ras oncogene and epidermal growth factor receptor gene in human glioblastomas.

Five human glioblastoma cell lines were analyzed for oncogene activation with a panel of probes. Abnormal expression of the epidermal growth factor receptor (EGFr) gene was detected in four of five lines; N-ras oncogene overexpression was found in all five cell lines. These results were subsequently confirmed with fresh brain tumor and nonneoplastic brain tissue biopsy samples; increased expression of the N-ras proto-oncogene was observed in five of five glioblastomas, all of which also showed EGFr gene overexpression, but not in well-differentiated gliomas or in nonneoplastic brain tissue specimens. No significant differences in Ha-ras and Ki-ras expression were observed. Preliminary histochemical observations showed that intracellular levels of transforming growth factor alpha, a putative biochemical link between these two oncogenes, were significantly higher in glioblastoma cells than in controls.

Sensitivity of human glioma cells to cytotoxic heteroconjugates.

Several anti-human glioma cytotoxic conjugates were studied in vitro. Monoclonal antibodies (MAbs) to the GE2 glioma-associated antigen (anti-GE 2) and MAbs to HLA-DR antigens (D1/12) or human diferric transferrin (Tfn) were linked to the potent cytotoxin ricin (anti-GE 2-ricin) or to its A subunit (anti-GE 2-RTA, D1/12-RTA, Tfn-RTA). Anti-GE 2-RTA had low cytotoxic activity in both the absence and the presence of lysosomotropic substances inhibiting intracellular degradation. Anti-GE 2-ricin was about 1,000 times more toxic than RTA alone, but showed only 14-fold target specificity. D1/12-RTA was about 20 times more toxic than RTA and its cytotoxic effect increased about 6- to 7-fold when cell-surface HLA-DR antigen expression was enhanced by IFN-gamma treatment. Human diferric Tfn linked to RTA demonstrated the highest cytotoxic activity, being about 5,000 times more toxic than RTA alone for glioma cells and about 6,000 times more toxic for Jurkat cells in the presence of the carboxylic ionofore monensin. Ricin toxin was only about 5 times more toxic for Jurkat and glioma cells than Tfn-RTA-monensin. Tfn-RTA was over 100,000 times more potent than the chemotherapeutic agent BCNU in reducing glioma cell survival in vitro. Addition of 80% human pooled cerebrospinal fluid (CSF) reduced Tfn-RTA toxicity about 10-fold. Kinetics of Tfn-RTA cytotoxicity at non-saturating concentrations indicated that over 80% of target cells could be killed within 8-10 hr in the absence and within 10-12 hr in the presence of human pooled CSF.

Increased number of chromosome 7 is related to overexpression of EGF receptor gene in human glioblastomas.

Karyotype and nucleic acid analyses have been performed on glioblastoma-derived primary cell lines at early passages. Four out of five cell lines displayed a significant increase in copy number of epidermal growth factor (EGF) receptor gene, which was related to polisomy of chromosome 7, where the gene is the been localized. Since EGF is a potent growth factor for human glial cells, and EGF receptor gene is the cellular homologue of the v-erb-B oncogene, we analyzed its expression in the tumor cell lines. Our results show that numerical alteration of chromosome 7 was constantly associated with overexpression of EGF receptor gene. Moreover, the high level of EGF receptor specific transcripts detected in two cell lines suggests that deregulation of the transcriptional activity of EGF receptor gene also occurred in these tumor cells.

In vitro analysis of BCNU-sensitivity in human malignant gliomas. II. Cross-resistance studies with cisplatinum and nitrosoureas.

With the use of the Human Brain Tumor Stem Cell Assay (HBTSCA) in a cross-resistance study, four early (3-4) culture passages of human malignant gliomas (glioblastoma multiforme) were tested for in vitro chemosensitivity with three of the most effective single agents for brain tumor chemotherapy: BCNU, CCNU and cisplatinum (DDP). The shapes of the dose-response curves indicated complete cross-resistance between BCNU and CCNU, i.e. two chloroethyl-nitrosoureas sharing a common alkylating-carbamoylating activity, with no evident cross-resistance between the two nitrosoureas and the DDP, a DNA binder with a putatively different antitumor action. Probably because of differences in drug delivery kinetics or in the cytotoxic mechanism, DDP might play a role in the treatment of nitrosourea-resistant gliomas.

In vitro analysis of BCNU-sensitivity in human malignant gliomas. I. A model study with alkylating, cross-linking and carbamoylating agents in anaplastic astrocytomas of pediatric age.

Like all chloroethyl-nitrosoureas of major clinical use, 1,3 bis-(2-chloroethyl)-1-nitrosourea (BCNU) - which is one of the most effective chemotherapeutic agents for CNS malignancies - biologically degrades into active alkylating and carbamoylating moieties. Using a human brain tumor stem cell assay, we analyzed a series of anaplastic astrocytomas of pediatric age, characterized by different degrees of BCNU-resistance. Early (2-4) passage cultures from these tumors were treated in vitro with model drugs for alkylation (BCNU, CHLZ (2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose), ENU (N-ethyl-N-nitrosourea), cross-linking (BCNU, CHLZ) and carbamoylation BHCNU (1,3 bis (trans-4-hydrocyclohexyl)-1-nitrosourea): dose-schedules were compatible with clinically achievable levels. Results of chemosensitivity tests confirmed that - as previously reported in malignant gliomas of the adult - cellular resistance to BCNU was closely related to the cross-linking activity of alkylating species. However, in pediatric gliomas the levels of cell kill after treatment with the purely carbamoylating agent BHCNU, even at the highest doses tested, were lower than expected.

Prediction of the relative in vitro sensitivity of 9L rat brain tumor cells to nitrosoureas by the sister chromatid exchange assay.

In an earlier study we showed that there is a good correlation between sister chromatid exchange induction and cell kill in 9L cells treated with certain nitrosoureas. In the study reported here, we treated four 9L cell lines that have different sensitivities to chloroethylnitrosoureas with 1,3-bis (2-chloroethyl)-1-nitrosourea, chlorozotocin, and ethylnitrosourea and determined the number of sister chromatid exchanges induced. Cell lines that were most sensitive to the drugs with respect to cell kill were also most sensitive to induction of sister chromatid exchanges for a given drug, and the assay based on sister chromatid exchange is therefore predictive of the relative sensitivity of these cells to the drugs used.

Spontaneous ("erosive") cerebrospinal rhinorrhea, with pneumococcal meningitis from anterior optic glioma. Case report.

A 6-year-old girl, operated upon for an optic nerve astrocytoma (resection limited to the intraorbital portion of the nerve), developed 3 years later symptoms and signs of chiasmatic invasion. Nine years after surgery (1980), she suffered from pneumococcal meningitis, due to cerebrospinal rhinorrhea that had been present in the last few years. A repeated neuroradiological investigation showed the site of the fistula and cerebral ventricles of normal size. The case is argued for bulb-to-chiasm resection of an optic nerve glioma: a spontaneous cerebrospinal rhinorrhea with its potential dangers of meningitis seems to be one more complication of a limited resection of these tumors. It is felt that this is an unusual instance of spontaneous rhinorrhea from direct tumoral erosion. The diagnostic value of metrizamide cisternography for the assessment of presence and site of the fistulous leak is confirmed.