Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series.

BACKGROUND: Grade IV malignancies of the brain, such as glioblastoma multiforme (GBM), are associated with a dismal prognosis. Autocrine and paracrine loops of platelet-derived growth factor (PDGF) signaling, as well as other signal transduction pathways, have been postulated to play a role in glioblastoma transformation, and molecules involved in these pathways can potentially serve as targets for therapeutic inhibitory agents. Imatinib, an inhibitor of PDGF receptors alpha and beta, as well as other selected tyrosine kinases, is indicated for treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Unfortunately, imatinib, as with many conventional chemotherapeutic agents, has limited efficacy as monotherapy in GBM. In preclinical studies, the chemotherapeutic agent hydroxyurea is demonstrated to have cytotoxic effects additive with imatinib. PATIENTS AND METHODS: We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time. RESULTS: Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively. CONCLUSION: The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.

[Long-term results of endoscopic sphincterotomy in patients with gallbladder in situ]. / Langzeitergebnisse nach endoskopischer Sphinkterotomie bei Patienten mit Gallenblase in situ.

The place of endoscopic sphincterotomy (EST) as primary and sole invasive treatment was retrospectively analysed in 185 patients who had the procedure performed because of choledocholithiasis and/or stenosis of the papilla. EST was successful in 99.5%, with an early complication rate of 3.8%, an early mortality rate of 0.5% and an emergency operation rate of 0.5%. Freedom from stone in the choledochal duct or adequate bile flow was achieved in 94.1%. Late complications, on average 36.5 (6-75) months after the procedure, was 16.9%, late mortality 2.8% and operation rate for complications 5.6%. Even without stones in it the gallbladder was the cause of late complications in over 60% of cases. Comparison of results between operative treatment and EST indicated advantages of the former up to the age of 60 years, combined cholecystectomy and EST up to 70 years, while EST alone seems justified in older patients.