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.     

Exercise training for claudication.

Exercise advice is a well established component of the conservative management of intermittent claudication. Supervised programmes of exercise remain relatively uncommon and are provided mainly in secondary care. This review outlines the evidence for the effectiveness of different exercise regimens and the relative benefits of exercise therapy, where comparisons have been made with medical therapy, angioplasty and surgery.     

Tailoring Management Strategies for the Patient With Menstrual Migraine: Focus on Prevention and Treatment

Many women report an increased frequency of headaches around the time of menses. For some women, these headaches are more severe, of longer duration, and lead to greater disability than those occurring at other times in the menstrual cycle. A headache diary is critical to properly diagnose menstrual migraine (MM) by prospectively documenting headache days, severity of headache, and the headaches' relationship to menses. In women with diagnosed MM, acute treatment has been proven to be effective in randomized clinical trials. For those women who have predictable periods and may require preventive therapy, short-term prevention is a reasonable approach due to the predictability of MM. Although several agents (eg, naproxen sodium, magnesium, triptans) have been evaluated for prevention of MM, all but triptans have been assessed in small trials of between 20 and 35 women. Naratriptan, frovatriptan, and, most recently, zolmitriptan have been proven effective in preventing MM. Triptans are generally well tolerated, and the long-term safety of these agents is currently being evaluated. The flexibility of using acute and preventive therapy allows physicians to tailor treatment of MM and meet the needs of individual patients.     

Toxocariasis: a serological survey of blood donors in the Australian Capital Territory together with observations on the risks of infection

The sera from 660 healthy blood donors from Canberra were tested for antibodies to Toxocara canis by the ELISA test. The results were compared with those from patients with suspected or confirmed visceral larva migrans or ocular toxocariasis. Over 7% of Canberra sera showed elevated levels of antibody reacting with T. canis antigen. Sera from patients resident in Australia with other helminth parasites did not cross-react with T. canis antigen in our tests. However, studies of sera collected in several tropical countries with other parasitic infection, show that cross-reactions with other parasites are possible. The use of purified glycoprotein antigen does not alter the possibility of cross-reaction. Observations and experiments show that people in Canberra may be exposed to the infective eggs of T. canis.     

Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.     

Effects of tumor necrosis factor alpha on parathyroid hormone-induced increases in osteoblastic cell cyclic AMP

Summary Tumor necrosis factor α (10⁻¹⁰–10⁻⁸M) had no effects on cyclic AMP production by the osteoblastic osteosarcomal cells, Saos-2 and G292, or normal rat calvarial cells. The cytokine did, however, inhibit the parathyroid hormone (PTH)-induced effect on cyclic AMP in the Saos-2 and normal rat osteoblastic cells. This inhibitory effect did not occur on prostaglandin E₂-induced cyclic AMP increases in the osteoblastic cells. Interleukin-1 (10 U/ml −100 U/ml) did not produce any effect on basal levels or PTH-induced cyclic AMP increases in these cells.