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.     

Pak-1 expression increases with progression of colorectal carcinomas to metastasis.

PURPOSE: The p21-activated kinase-1 (Pak-1) promotes cell motility and invasiveness. Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3'-kinase/AKT pathway activation. Because Pak-1 plays a central role in regulating cell motility and invasiveness, we sought to determine whether Pak-1 may be involved in the malignant progression of colorectal carcinoma. EXPERIMENTAL DESIGN: Pak-1 expression was examined by immunohistochemistry in archived tissues from normal human colons, tubular and tubulovillous adenomas, invasive adenocarcinomas (stages I-III/IV), and lymph node metastases (184 total specimens from 38 patients). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore (stain intensity x percentage of epithelium stained). RESULTS: Pak-1 expression was increased significantly with colorectal cancer progression from normal tissue to lymph node metastases (P < 0.0001). Furthermore, Pak-1 expression was increased significantly in adenomas, invasive carcinomas, and lymph node metastases compared with normal colon (P < 0.0001). Strikingly, Pak-1 expression was significantly higher in lymph node metastases than in invasive cancers, adenomas, or normal colon (P < 0.0001). Moreover, in patients with multiple lesions representing different stages of disease, Pak-1 expression was increased specifically in the most advanced lesions. CONCLUSIONS: This study demonstrates that Pak-1 expression is increased significantly with malignant progression of human colorectal carcinoma. These data, along with numerous functional studies demonstrating a central role for Pak-1 activity in tumor invasiveness and motility, implicate Pak-1 as an exciting target for therapy of colorectal carcinoma.     

Molecular Genetics in the Diagnosis and Prognosis of Solid Pediatric Tumors

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management. Received November 20, 1997; accepted April 20, 1998.     

The validity of continuous automated fluid monitoring during endometrial surgery: luxury or necessity?

Thirty-four consecutive women undergoing endometrial laser ablation, as a treatment of menorrhagia, were recruited to assess the validity of fluid absorption monitoring by a new continuous automated system (AquaSens). The same group of women also had monitoring of fluid absorption carried out by our standard technique of weighing. The intra-class correlation coefficient for the fluid deficit estimated by AquaSens compared to our standard technique of manually weighing the irrigation bags was 0.98 (95% CI 0.96–0.99). Aquasens therefore provides a valid and non-invasive method of continuously monitoring fluid deficit amongst patients undergoing operative hysteroscopy procedures, thereby reducing the risk of unexpected fluid absorption and its potentially fatal sequelae.     

Serial Transvaginal Ultrasonography Following McDonald Cerclage and Repeat Suture Insertion

Summary: The aim of this study was to explore the hypothesis that serial transvaginal ultrasonography identifies early evidence of suture failure and that repeat cerclage delays delivery. We undertook a review of our policy of transvaginal ultrasonographic cervical surveillance after McDonald cerclage and of repeat suture insertion if persistent cervical effacement developed. Data from 26 pregnancies in 26 women are analyzed. The women had had a total of 57 mid-trimester miscarriages with a median of 2 (1–6) mid-trimester losses per woman. Twelve (46%) of the 26 women developed cervical changes at scan and underwent repeat cerclage. All 14 women who had a single suture inserted progressed to live births but 1 of the 13 women who had repeat cerclage had a mid-trimester miscarriage (p>0.05). The median gestation at delivery for the women who had repeat cerclage was 35 (22–39) weeks compared with 38 (36–40) weeks for those who had a single suture (p>0.05). The median interval from the detection of cervical changes at scan to delivery was 13 (4–19) weeks. Serial transvaginal ultrasonography after cervical cerclage identifies a group of women who are more likely to deliver preterm, and provides an opportunity for intervention (repeat cerclage) which appears to delay delivery by an average of 7 weeks.