Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Angiosarcomas--clinical profile,pathology and management

Files of 8 patients with primary angiosarcomas treated in the Department of Radiation Oncology at the University of the Witwatersrand from 1982 to 1995 were identified. None of these patients had received prior radiotherapy or chemotherapy which would have predisposed them to the formation of an angiosarcoma. Slides of 6 patients were reviewed. Five of the 6 were confirmed as having angiosarcomas, while 1 patient was found to have a peripheral neuro-epithelial tumour. Four patients had angiosarcomas of the breast, while there was 1 patient each with angiosarcoma of the skin, intestine and brain. Complete excision was the primary modality of management whenever possible. Postoperative radiotherapy was given in cases of incomplete excision, patient refusal of radical surgery or gross tumour. Four patients died within 4 months of diagnosis. Three patients are alive (2 with no evidence of disease) 22-96 months after diagnosis. In 1 patient follow-up details were not available as he did not return for treatment. Angiosarcomas are aggressive malignant tumours arising from the endothelial cells. Complete surgical excision is the treatment of choice in the management of this aggressive disease, which has a poor prognosis.     

Safety of vaginal birth after cesarean delivery.

OBJECTIVE: To compare the outcomes of labor induction in women with a history of 1 cesarean section (CS) who undergo trial of labor. METHODS: A prospective observational study of 702 pregnant women who had 1 previous CS was conducted at Women's Hospital, Hamad Medical Corporation, Doha, Qatar, between April 2003 and April 2004. Those with no history of vaginal delivery were assigned to one group and those with a history of vaginal delivery were assigned to another group, and the latter group was then divided into 2 subgroups according to the results of trial of labor. RESULTS: Of these 702 women with a history of 1 CS, 62.4% also had a history of vaginal delivery. After trial of labor, vaginal delivery occurred more often among women with no history of vaginal delivery (64.8%). Moreover, trial of labor resulted in a vaginal delivery more often in women who were delivered only once and by CS (87.7%) than in women who also had a history of vaginal delivery (79.2%). CONCLUSION: These findings indicate that women who have had a CS should strongly consider natural delivery for subsequent pregnancies.     

A placebo controlled, double-blind study of mecamylamine treatment for cocaine dependence in patients enrolled in an opiate replacement program.

A placebo controlled, double-blind trial of mecamylamine treatment of cocaine dependence was performed in methadone or LAAM maintained subjects who met DSM-IV criteria for cocaine dependence. After an eight-week placebo run-in screening period, 35 subjects were randomly assigned to receive either mecamylamine (6 mg/day) or placebo transdermal patches for a 16-week treatment period. Outcome measures included quantitative urine benzoylecognine (BE) levels, self-report of cocaine use, cocaine craving, global impression scores, mood, retention, and safety. Mecamylamine was well tolerated, and study retention did not differ by treatment group. Evidence for cocaine use, based on urine BE levels and cocaine abstinence rates, did not differ by treatment group. Self reported cocaine use, cocaine craving, and global impression scores showed moderate improvement in both groups, with a significantly greater reduction in cocaine craving (p < 0.05) and self-rated severity of cocaine dependence (p < 0.05) in the placebo group. This pilot study does not support the effectiveness of mecamylamine for the treatment of cocaine dependence in methadone or LAAM maintained patients.     

Synthesis and Structure-Activity Relationships of Vasicine Analogues as Bronchodilatory Agents

The series of vasicine (1) analogues, an alkaloid from Adhatoda vasica Nees., were synthesized with changes in A, B or C rings. Compounds 13-19 were evaluated for in vitro bronchodilatory activity using isolated guinea pig tracheal chain. Compounds 3-8 were also synthesized in good yields using microwave-mediated synthesis under solvent free conditions. Compounds 5 and 8 with seven-member C ring were more active than etofylline and caused 100% relaxation of both the histamine and acetycholine pre-contracted guinea pig tracheal chain. The structure-activity relationship studies showed that the quinazoline and oxo functionalities were essential for activity. The compounds without C ring and instead having aliphatic and phenyl substitutions in B ring showed relaxation against histamine pre-contracted tracheal chain only, 2-methyl substituted analogues, 12 and 13, being most active with 100% relaxation effect.