Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Characterization of bortezomib-adapted I-45 mesothelioma cells

Background  

Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.     

Management of acute suppurative appendicitis in the small rural hospital: A report of one hundred consecutive cases

The history of appendicitis has been briefly reviewed and a plea made for a renewed interest in this disease on the part of all physicians.A series of one hundred consecutive cases of acute suppurative appendicitis, with two deaths, has been presented. In twenty-five of these the appendix had perforated with one death—a mortality rate of 4.0 per cent. In the seventy-five cases without perforation there was one death—a mortality rate of 1.33 per cent. The mortality rate for the entire series was 2.0 per cent.These attacks occurred for the most part in young and middle aged patients, 70 per cent being less than thirty years old and 80 per cent less than forty.The symptoms as seen in this series have been presented as follows: pain, tenderness, rigidity, vomiting, rapid pulse, fever, leucocytosis, diarrhea and constipation. The constant presence of pain, although not usually severe, and the overwhelming frequency of tenderness and rigidity have been pointed out. Nausea and vomiting in association with abdominal pain have been emphasized as of major significance.The importance of early diagnosis and operation and their relationship to mortality and morbidity has been stressed.The danger of laxatives has been reiterated.Treatment has been discussed with a plea for early operation.The advantages of certain points in technic have been mentioned.A frank statement of the need for more and earlier consultations in suspected appendicitis and a discussion of the responsibilities of both physician and surgeon have been presented.