EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force.

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3-3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.

Accelerated radiotherapy with concomitant ACNU/Ara-C for the treatment of malignant glioma.

PURPOSE: To evaluate activity and toxicity of simultaneous ACNU and Ara-C with concurrent accelerated hyperfractionated radiotherapy in the treatment of high-grade glioma. PATIENTS AND METHODS: Thirty patients aged 23-71 years (median 47.5), 16 patients with glioblastoma multiforme (GBM) and 14 patients with grade-III glioma, received 93 courses of ACNU/Ara-C (median 4 courses) at following dose levels (ACNU/Ara-C in mg/m2/day): 70/90 (11 courses), 75/100 (36 courses) and 90/120 (46 courses). ACNU was administered IV on day 1 of each cycle, Ara-C as a 2 h-intravenous infusion on days 1-3. Patients received concomitant radiation therapy with 2 daily fractions of 1.75 Gy up to 57 Gy (median). RESULTS: Median survival of all patients was 13 months, 11 months for GBM and > 28 months for grade-III glioma; 31% (9 patients) survived longer than 24 months. The percentage of grade IV hematological toxicity was dose-dependent: 33% at the 70/90 dose level, 40% at 75/100 and 58% at 90/120. Six patients required platelet transfusion, 1 patient red blood cells; no febrile neutropenia occurred. Among 18 patients evaluable for response, 3 (17%) showed PR, 8 (44%) NC and 7 (39%) PD at completion of chemoradiation. No acute or late neurological toxicity occurred in this study. Younger age (p = 0.0001) and grade-III histology (p = 0.0009) were important prognostic factors for prolonged survival. CONCLUSION: This chemoradiation regimen is active in malignant gliomas and can be safely recommended at a dose level using 70 mg/m2 ACNU together with 90 mg/m2 Ara-C.

Primary central nervous system lymphoma: from clinical presentation to diagnosis.

Immunocompetent patients with primary central nervous system lymphoma (PCNSL) present with a median age of 55 years, immunosuppressed patients with a median age of 40 years. They show a broad range of signs and symptoms. Symptoms of increased intracranial pressure and personality change are most frequent, followed in frequency by ataxia and hemiparesis. The median time from onset of symptoms to diagnosis is 3-5 months in immunocompetent patients and 2 months in immunodeficient patients. The time to diagnosis can be considerably longer in patients with slowly developing personality change or fluctuating symptoms due to spontaneous or steroid-induced remission of so-called sentinel lesions. Native CT scans show iso- or hyperdense lesions with homogenous contrast enhancement. T1-weighted MRI scans show hypointense and T2-weighted scans hyperintense lesions. The definitive diagnosis of PCNSL requires biopsy. In some cases, however, the definitive diagnosis may exclusively be made by the demonstration of malignant B-lymphocytes in the cerebrospinal fluid.

SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa.

The SELEDO (from selegiline plus levodopa) study was carried out as a randomized, prospective, placebo-controlled, double- blind, multicenter long-term, 5-year trial to evaluate the possible advantages of combining selegiline and levodopa in the early treatment of Parkinson's disease. One-hundred-and-sixteen patients were randomized either to selegiline or placebo. Before starting the study medication, the levodopa dose was titrated to the individual requirements of each patient. The primary study end point (time when levodopa had to be increased by >50% of the titrated dose) was reached in 23 of 59 patients in the selegiline group and 26 of 48 patients in the placebo group. At the end of the 5 years' treatment period the rates derived from a life-table analysis were 50.4% in the selegiline group and 74.1% in the placebo group (P = 0.027, log-rank test). The median time to reach the primary end point was 4.9 years in the selegiline group and 2.6 years in the placebo group. In patients treated with selegiline, the mean levodopa dose changed only slightly over the 5 years of treatment compared to the initially titrated dose, but rose markedly in the placebo group, where the dose of levodopa had to be adjusted earlier than in the selegiline group. At the same time, the lower levodopa dosage in the selegiline group was accompanied by at least equal therapeutic efficacy (which is necessary for an unambiguous interpretation). Subgroup analyses showed greater benefit for selegiline treated) patients in the earlier stages. Long-term side effects appeared later in the selegiline group, although the difference was not significant. The early combination of selegiline and levodopa proved to be clearly superior to levodopa monotherapy.

Tolerance and cerebrospinal fluid pharmacokinetics of intrathecally administered human natural interleukin-2: a phase I trial.

Recombinant interleukin-2 (rIL-2) is at present widely applied in the immunotherapy of various advanced cancers. As a number of side effects following the administration of rIL-2, either alone or in combination with lymphokine-activated killer (LAK-) cells, have been reported, a preparation of human leukocyte-derived and fully glycosylated interleukin-2 was used in the present study. We have recently demonstrated in cats that this natural IL-2 (nIL-2) is well tolerated and that the distribution and elimination half-lifes following intrathecal (i.th.) application are considerably longer than those after intravenous (i.v.) injection. To determine whether these long half-lifes and the good tolerance of i.th. given nIL-2 are also found in man, four patients with meningeosis neoplastica received repeated injections of human nIL-2 i.th.. Cerebrospinal fluid samples were drawn at different time intervals from either the lateral ventricle or lumbar subarachnoid space. The doses of nIL-2 ranged from 2 x 10(4) to 4 x 10(5) IU per injection. Only minor side effects were noted in one patient. The half-lifes for distribution and elimination of i.th. given nIL-2 ranged between 0.5-1.7 hours and 4.9-14.4 hours respectively. A linear relationship exists between the i.th. dose of nIL-2 and the area under the cerebrospinal fluid activity time profile curve.

Interleukin-2 and blood brain barrier in cats: pharmacokinetics and tolerance following intrathecal and intravenous administration.

Single bolus doses of glycosylated human interleukin-2 (n IL-2) in the range of 2.8 x 10(3) to 2.0 x 10(6) IU/kg were administered to anesthesized cats via the cephalic vein (n = 10) or using suboccipital puncture (n = 8). CSF (cerebrospinal fluid) and blood samples were collected by repeated puncture. The n IL-2 concentration in four cats was determined on the basis of its biologic activity using 3H-thymidine incorporation into human ConA-blasts and by radioimmunoassay. In additional experiments radioactivity was determined in cerebrospinal fluid and serum after intravenous and intrathecal (i.th.) application of 5.8 x 10(3) - 3.2 x 10(3) IU/kg of 14C-acetyl-n IL-2 in regular time intervals. CSF and serum concentration time-profiles show a biexponential decline in the plasma elimination phase with half-lives of 4 min (alpha-phase) and 90 min (beta-phase) after intravenous and 20-120 min (alpha-phase) and 2-16 hours (beta-phase) after intrathecal application. There is a trend towards longer terminal elimination half-lives with increasing doses. Interleukin-2 is able to penetrate the blood brain barrier from the circulation into the cerebrospinal fluid and vice versa. Due to a slow rate of penetration and rapid elimination from blood only traces of n IL-2 (2-8 IU/ml) are detected in CSF after i.v. injection of 2 x 10(6) IU/kg, whereas concentrations between 400 and 1600 IU/ml are maintained in CSF for several hours following i.th. administration of 2-10 x 10(5) IU/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis--results of the German multicenter study.

In a double-blind controlled trial of 194 patients with clinically definite active multiple sclerosis, 98 were randomized to treatment with cyclosporine (CyA, 5 mg/kg/day), and 96 to treatment with azathioprine (Aza, 2.5 mg/kg/day). Eighty-five patients in the CyA group and 82 in the Aza group completed a treatment period of 24 to 32 months in accordance with the study protocol. No significant differences could be detected between the two treatment groups at the end of the trial. Assessment was done by serial quantitative neurological examinations and Kurtzke's Expanded Disability Status Scale. Frequency of relapse and patient self-evaluation also failed to show significant differences. Overall deterioration observed in both groups during the trial was only minor. The incidence of side effects in the CyA group was more than two times that in the Aza group. We conclude that CyA as a single agent cannot be the drug of final choice in long-term immunosuppressive treatment of relapsing-remitting and relapsing-progressive multiple sclerosis.

Interferon-beta in patients with low-grade astrocytomas--a phase I study.

In 3 patients with low-grade astrocytomas clinical pharmacology of interferon-beta (10(7) U/mg protein) was investigated. Interferon-beta with escalating dosage (2.3, 6.9, 23, 69 X 10(6) U/patient) was given to each patient in 4 infusions at weekly time intervals. In these patients dose-dependent plasma-levels of interferon-beta of up to 5800 IU/ml were achieved. Plasma concentrations showed a biphasic decline (T1 1/2:0.095-0.49 hrs and T2 1/2: 5-14.5 hrs). Side effects were: mild fatigue, myalgia, tachycardia, hypertension, and fever; the latter was well controlled by pretreatment application of paracetamol. Hematological changes included lymphopenia (2-6 hrs after infusion) and granulocytosis (3-6 hrs after infusion). Natural Killer cell activity was also monitored: 6 hours after infusion a drop of activity - not clearly dose dependent - was observed to a minimum of 1% pretreatment activity; 24 hrs after infusion activity increased up to a maximum of 400%. In this phase I study high biological activity of interferon-beta could be detected in plasma of astrocytoma patients - clinical tolerance was good and only mild toxicity was observed.

[Cortical blindness, clinical, psychologic, and localizatory findings (author's transl)]. / Rindenblindheit. Klinische, testpsychologische und hirnlokalisatorische Befunde.

Description and evaluation of a case in which both occipital lobes of the brain and adjacent temporal and parietal areas were heavily damaged by malignant meningiomas. Loss of simple and complex visual functions resulted. During a 5-year period the clinical, neurologic, ophthalmologic, and psychologic findings could be completed by self-observation by the highly intelligent patient and compared with findings from three operations. Postmortal neuropathologic analysis showed loss of both left and right areas 17 and 18 and of right area 19. The localizations of elementary and complex visual functions in the brain are discussed.