History and lower extremity physical examination of the pediatric patient

The pediatric foot and ankle examination is a specialized yet important skill for the modern podiatric medical practitioner. An organized and sequential history and physical examination yields a thorough database of information for which to establish a successful treatment regimen.     

Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation

SummaryPurpose Because raised matrix metalloprotease (MMP) levels are associated with glioma invasion and angiogenesis, we tested the efficacy of marimastat (MT) an orally active drug that can reduce MMP levels, in patients with gliomas.Patients and Methods A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter, double-blind, placebo-controlled, parallel group study conducted at 20 institutions. Seventy-nine patients (57 male, 22 female, median age 58 years) were randomized to receive placebo (PB), and 83 patients (51 male, 32 female, median age 57 years) were randomized to receive MT, 10 mg orally twice daily, until tumor progression.Results This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival (P=0.38, log rank test). The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group, with a hazard ratio of 1.16 (95% CI 0.83 to 1.60). There were no statistically significant differences in quality of life between the PB and MT groups, as assessed by the FACT-BR questionnaire. Musculoskeletal toxicities led to dose modification or withdrawal in 20% of MT-treated and 1.2% of PB-treated patients.Conclusion MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy. Therefore, single-agent MT appears unwarranted; however, MT in combination with cytotoxic chemotherapy may be warranted, as suggested by observations in our study and other studies. ^★This work was presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, on May 13, 2001, and supported by British Biotech Pharmaceuticals, Watlington Road, Oxford, OX4 6LY, UK. No author currently has a financial interest in Marimastat. Mark Baillet is currently with Origin Pharmaceutical Services Ltd.*Participating institutions are listed in Table 1. Clinician authorship required ≥10 patient accrual from participating institution.     

Isolation ofepi-oleanolic acid from korean mistletoe and its apoptosis-lnducing activity in tumor cells

A triterpene was isolated as a cytotoxic principle from the dichloromethane extract of Korean mistletoe (KM; Viscum album coloratum) by repeated silica gel chromatography and recrystallization. In in vitro analysis of cytotoxic activity using various human and murine tumor cell lines, the dichloromethane extract of KM was highly cytotoxic against these cells. We isolated the most active compound, referred to VD-3, from the dichloromethane extract of KM. The VD-3 was shown to be less cytotoxic to normal cells (murine splenocytes). From the identification of the chemical structure of VD-3 by spectral data and chemical synthesis, the compound was proven to be epi-oleanolic acid. Tumor cells treated with VD-3 showed a typical pattern of apoptotic cell death, such as apparent morphological changes and DNA fragmentation. These results indicate that epi-oleanolic acid is an important compound responsible for antitumor activity of KM.     

Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]-naphthyridinium salts from aaptamine

The marine sponge constituent aaptamine (1) has been converted to the cancer cell growth inhibitor and antibiotic designated hystatin 2 (8a). Herein, we also report results of an initial SAR evaluation of new benzyl derivatives of aaptamine (1). Single benzylation was found to occur at nitrogen N-4 and led to the formation of the 4-benzylaaptamine derivatives 7a-c, whereas double benzylation gave the quaternary 1H-benzo[de][1,6]-naphthyridinium salts 8a-c. The anticancer and antimicrobial properties of these aaptamine derivatives are described. The quaternary ammonium salts 8a (hystatin 2) and 8b exhibited significant inhibitory activity against the murine P388 lymphocytic leukemia and a minipanel of human cancer cell lines. Salts 8a and 8b also had broad spectrum antimicrobial activities and were most potent against Mycobacterium tuberculosis, Neisseria gonorrhoeae, and Micrococcus luteus. Naphthyridinium chloride 8a was selected for further development, and results of an initial cell cycle analysis and a cDNA microarray study showed effects consistent with inhibition of the S-phase of cell growth.     

Wikyungtang inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing cyclooxygenase-2 activity

Wikyungtang, an oriental herbal formulation, has been known to exert anti-inflammatory and anti-tumoral activity. However, its molecular mechanism of action is not understood. The purpose of the present study was to examine the effect of the water extract of Wikyungtang (WKT) on the growth of A549 human lung cancer cells. Treatment with WKT resulted in a dose-dependent growth inhibition coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of WKT induced caspase-3 and caspase-9 activation accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase and phospholipase C-gamma1. In addition, WKT-induced apoptosis in A549 cells was associated with a decreased expression of the anti-apototic Bcl-XL expression. WKT treatment also inhibited the expression of cyclooxygenase (COX)-2 and the accumulation of prostaglandin E2 without significant changes in the levels of COX-1. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of WKT.