Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma.

Aberrant hepatocyte growth factor (HGF)/MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in hepatocellular carcinoma. We sought to investigate the in vitro and in vivo antitumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of hepatocellular carcinoma. The antiproliferative activity of AMG 337 was evaluated across a panel of hepatocellular carcinoma cell lines in a viability assay.

Clinical trials in "emerging markets": regulatory considerations and other factors.

Clinical studies are being placed in emerging markets as part of global drug development programs to access large pool of eligible patients and to benefit from a cost effective structure. However, over the last few years, the definition of "emerging markets" is being revisited, especially from a regulatory perspective. For purposes of this article, countries outside US, EU and the traditional "western countries" are discussed.

Relationship between epoetin alfa dose and mortality: findings from a marginal structural model.

Background And Objectives: Observational studies relating epoetin alfa (EPO) dose and mortality frequently use analytic methods that do not control time-dependent confounding by indication (CBI). The relationship between EPO dose and 1-year mortality, adjusting for the effects of time-dependent CBI, was examined using a marginal structural model.

Design, Setting, Participants, & Measurements: This retrospective cohort study included 27,791 hemodialysis patients between July 2000 and June 2002.

Comparison of several imputation methods for missing baseline data in propensity scores analysis of binary outcome.

We performed a simulation study comparing the statistical properties of the estimated log odds ratio from propensity scores analyses of a binary response variable, in which missing baseline data had been imputed using a simple imputation scheme (Treatment Mean Imputation), compared with three ways of performing multiple imputation (MI) and with a Complete Case analysis. MI that included treatment (treated/untreated) and outcome (for our analyses, outcome was adverse event [yes/no]) in the imputer's model had the best statistical properties of the imputation schemes we studied. MI is feasible to use in situations where one has just a few outcomes to analyze.

Evolving statistical methods to facilitate evaluation of the causal association between erythropoiesis-stimulating agent dose and mortality in nonexperimental research: strengths and limitations.

Findings from randomized controlled trials examining the efficacy of therapy with erythropoiesis-stimulating agents (ESAs) to normalize hemoglobin levels in patients with chronic kidney disease or kidney failure have raised questions regarding the safety of this class of drugs. However, no trial to date has specifically assessed the safety of ESA-dosing algorithms used to achieve the lower hemoglobin targets typically using in clinical practice. Although a wealth of nonexperimental data is available for dialysis patients, analyses based on these data are more susceptible to confounding bias than randomized controlled trials.

Exploring relative mortality and epoetin alfa dose among hemodialysis patients.

Background: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results.

Gatekeeping procedures in dose-response clinical trials based on the Dunnett test.

This paper discusses multiple testing procedures in dose-response clinical trials with primary and secondary endpoints. A general gatekeeping framework for constructing multiple tests is proposed, which extends the Dunnett test [Journal of the American Statistical Association 1955; 50: 1096-1121] and Bonferroni-based gatekeeping tests developed by Dmitrienko et al. [Statistics in Medicine 2003; 22:2387-2400].

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Unlabelled: Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume.

Introduction: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data.

The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis.

In a recent study of women with postmenopausal osteoporosis, treatment with teriparatide for a median of 19 months increased bone mineral density and decreased the risk of vertebral and nonvertebral fractures. Using the same cohort, the current study evaluated the relationship between these therapeutic effects and the patient's baseline age, vertebral bone mineral density, and prevalent vertebral fractures. In women over 65 years of age, treatment resulted in a greater increase in vertebral bone mineral density than in younger women (treatment-by-age interaction, p = 0.