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

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

German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma.

The prospective multicenter NOA-03 trial, conducted by the Neuro-Oncology Working Group (NOA) of the German Cancer Society, was initiated to define the feasibility and efficacy of single-agent high-dose methotrexate therapy without concomitant radiotherapy in immunocompetent patients with primary central nervous system lymphoma. Thirty-seven patients (median age, 60 years) received 179 biweekly courses of 8 g/m2 methotrexate. Response was assessed after 3 and 6 courses. We had planned to enter 105 patients into the trial. Since fewer than the projected 18 of 37 patients achieved a complete response after an intermediate analysis, the trial was closed. In intention-to-treat analysis, 11 of 37 patients (29.7%) achieved complete response, whereas 14 of 37 patients (37.8%) were found to have progressive disease. The median relapse-free survival among complete response patients was 13.7 months. Multivariate logistic regression analysis revealed that corticosteroid application during the first methotrexate course was associated with complete response. The regimen was well tolerated, but, unlike previously reported results, the activity of high-dose methotrexate was only moderate

Postoperative Strahlen- und Chemotherapie mit BCNU und VM 26 bei malignen supratentoriellen Gliomen des Erwachsenenalters Abschlussbericht

Tumour diagnosis by biopsy alone was found to have a poorer result than partial or total tumour resection. Relieving the brain mass from the tumour tissue was confirmed again to be essential although a particularly aggressive approach was not found to be advantageous if followed by post-operative irradiation (+ chemotherapy). The newly introduced method of total brain irradiation (40 gray) + local tumour irradiation (20 gray) was compared with the previous method of mere local tumour irradiation and was found to have no advantage over the latter. Althought the addition of VM 26 to BCNU in the combination therapy group resulted in side-effects to have a higher rate of nausea and vomiting and, hence, precluded the full exploitation of the range potentially offered by combination therapy, the segment of patients with a longer survival period within the overall group showed the combination treatment groups to have a small but statistically insignificant advantage. There were just weak indications of therapy interaction with the otherwise most important prognostic factor, i.e. patient age. The conclusions drawn suggested a more aggressive treatment of patients with a Karnofsky value of 70 and higher whereas patients with a poor general condition should undergo but mild or, possibly, no chemotherapy at all. The study was also aimed at examining the correlations between therapy and side-effects more accurately. Special emphasis was placed on the determination of pulmonary function because of the well-known pulmonary toxicity of BCNU. (orig./Uhe)Es ergab sich, dass lediglich die rein bioptische Tumordiagnosesicherung schlechter abschneidet als eine partielle oder totale Resektion des Tumors. Es zeigt sich erneut, dass die Entlastung des Gehirns von Tumorgewebe wesentlich ist, aber andererseits ein besonders radikales Vorgehen nicht von Vorteil ist, sofern eine Nachbestrahlung (+ Chemotherapie) erfolgt. Die neu eingefuehrte Ganzhirnbestrahlung mir 40 Gray + 20 Gray Tumor-Lokalbestrahlung wurde verglichen mit der zuvor ueblichen rein lokalen Tumorbestrahlung, wobei sich kein Vorteil der Ganzhirnbestrahlung ergab. Obwohl das Hinzufuegen von VM 26 zu BCNU in der Kombinationsgruppe bei den Nebenwirkungen nur zu einer vermehrten Rate von Uebelkeit und Erbrechen fuehrte und somit der moegliche Rahmen einer Kombinationstherapie mit Sicherheit nicht ausgeschoepft ist, liess sich fuer die Gesamtgruppe im Bereich der laenger ueberlebenden Patienten ein kleiner, statistisch nicht signifikanter Vorteil fuer die Kombinationsgruppe beobachten. Eine Therapieinteraktion mit dem ansonsten wichtigsten prognostischen Faktor, dem Lebensalter der Patienten, fand sich nur angedeutet. Als Schlussfolgerung ergibt sich daraus, dass Patienten mit einem Karnofskywert von 70% und mehr aggressiver behandelt werden sollten, waehrend Patienten mit schlechtem Allgemeinzustand einer milden oder moeglicherweise auch gar keiner Chemotherapie zugefuehrt werden sollten. Erklaertes Ziel der Studie war es auch, den Zusammenhaengen von Therapie und Nebenwirkungen exakter nachzugehen. Wegen der bekannten Lungentoxizitaet des BCNU wurde besonderes Augenmerk auf die Erfassung der Lungenfunktion gelegt. (orig./Uhe)SIGLEAvailable from TIB Hannover: F93B939+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials

Background Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis. Methods We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (on) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis. Findings Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min. Interpretation Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit