Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.     

Diagnostic considerations in virilization: iodomethyl-norcholesterol scanning in the localization of androgen secreting tumors

Accurate localization of the source of androgen hypersecretion is critical to the appropriate surgical or medical management of women with virilization. Seven patients with virilization and hyperandrogenism of various causes were evaluated with the use of sequential studies: testosterone stimulation and suppression tests; computerized tomography (CT); selective venous catheterization; and 131I-iodomethyl-norcholesterol (NP-59) scintigraphy. Comparison of the diagnostic accuracies of these localization studies with the ultimate diagnoses in this group of virilized women showed that: endocrinologic suppression/stimulation studies are of limited value in tumor localization and helpful only in patients with steroidogenic enzyme deficiencies; both selective catheterization and CT scanning may provide spurious localization data; and NP-59 scintigraphy, by depicting both the anatomic localization and functional androgen hypersecretion, may provide the most significant localization data in the evaluation of patients with virilizing syndromes.     

Comparison of amniotic fluid disaturated phosphatidylcholine and the lecithin-sphingomyelin ratio in the prediction of fetal lung maturity

Although use of the lecithin-sphingomyelin (L/S) ratio has contributed to a reduction in the frequency of respiratory distress syndrome (RDS), its accuracy in pregnancies complicated by fetomaternal disease has been questioned. Disaturated phosphatidylcholine is the major active component of surfactant and has been advocated as being a more specific indicator of fetal lung maturity. A study of 105 pregnancies in which a L/S ratio and disaturated phosphatidylcholine assay were performed on amniotic fluid was carried out to ascertain if amniotic fluid disaturated phosphatidylcholine is indeed a more accurate predictor of RDS. The results of this investigation reveal no significant difference in the reliability of these two tests in predicting neonatal RDS. Five infants developed RDS with a mature L/S ratio ranging from 2.0 to 3.36, suggesting that the disaturated phosphatidylcholine assay may be a helpful adjunctive test in instances in which the L/S ratio is less than 3.5.     

Surgical incision for cesarean section

Ninety-seven women undergoing cesarean section were delivered through a muscle-cutting Maylard or a Pfannenstiel abdominal incision. In these two similar groups of women, the mean Maylard incision length was significantly greater (18.3 +/- 4.5 cm) than that of the Pfannenstiel incision (14.0 +/- 2.1 cm), with no difference in operative morbidity. Difficulty with infant delivery was significantly less frequent with both the Maylard and Pfannenstiel when the incision was at least 15 cm in length. These results suggest that cesarean delivery is performed optimally with an adequate surgical incision, and that the Maylard incision is a safe option which should be strongly considered when risk factors (eg, macrosomia, twins) demand maximal surgical exposure for nontraumatic abdominal delivery.     

Novel dental anomalies associated with congenital contractural arachnodactyly: a case report

Congenital contractural arachnodactyly (CCA) is an inherited disorder of connective tissue similar to Marfan's syndrome. The craniofacial and oral features of a young girl with CCA are described. The patient has the typical features of CCA as well as some additional dental anomalies which have not previously been reported with this syndrome. These include banded pitted enamel hypoplasia and hypomineralization, long, spindly tapered roots, and pulp canal obliteration with multiple pulp stones. Dentists must be aware of the clinical features of a patient's syndrome to determine whether there are implications for dental treatment such as a need for antibiotic prophylaxis. It is important to exclude Marfan's syndrome as a differential diagnosis for CCA because the former has more associated complications and a less favorable prognosis.     

Surgical repair of intercostal pulmonary hernia secondary to cough induced rib fracture

Intercostal pulmonary hernia, a protrusion of lung parenchyma with overlying pleural membranes through an abnormal defect in the thoracic cage, is an uncommon phenomenon. Rib fractures caused by coughing similarly represent an infrequently occurring clinical presentation. Pulmonary herniation through an intercostal defect caused by cough fractures has been described twice in the literature to our knowledge. We present a case of pulmonary herniation secondary to cough fracture in a chronic bronchitic, successfully treated by thoracotomy with application of the basic principles of hernia repair, and a discussion of the mechanisms of injury.