Biomedical subjects

Kouros Owzar

Publications and source records attributed to Kouros Owzar.

4 recordsLinked to original sources

PubMed2006

P-value calculation for multistage phase II cancer clinical trials.

Due to ethical and practical issues, clinical trials are conducted in multiple stages, but the reported p-values often fail to reflect the design aspect of the trials. We investigate some approaches to p-value calculation in analyzing multi-stage Phase II clinical trials that have a binary variable, such as response, as the primary endpoint. The sample space consists of the paired outcomes of the stopping stage and the number of responses, which jointly define a complete and sufficient statistic for the true binomial proportion. Calculating a p-value requires an ordering of the paired outcomes so that outcomes more extreme than the observed can be identified. We consider the orderings based on the maximum likelihood estimator and the uniformly minimum variance unbiased estimator. We will compare, using some examples, the p-values based on these alternative orderings and the one ignoring the multistage design aspect of phase II trials.

Algorithms↗

PubMed2005

Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis.

Hedgehog (Hh) pathway activation promotes tumors in several endodermally derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hh signaling, activation of the Hh pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hh signaling. This pathway is activated when Hh ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hh pathway components and activated Hh transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hh signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hh signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.

Animals↗

PubMed2005

A multiple testing procedure to associate gene expression levels with survival.

In many microarray studies the primary objective is to identify, from a large panel of genes, those which are prognostic markers of a censored survival endpoint such as time to disease recurrence or death. Often, these genes are considered prognostic in that their respective expressions are associated with the survival endpoint of interest. To assess this association requires specifying an appropriate measure of association, a suitable test statistic and, as the number of genes is large, proper handling of multiplicity issues. In this paper, we will address these issues by utilizing a general correlation measure, a non-parametric test statistic, and control of the family-wise error rate by employing permutation resampling. Comprehensive simulation studies are conducted to investigate the statistical properties of the proposed procedure. The proposed method is applied to a recently published data set on patients with lung cancer.

Adenocarcinoma↗

PubMed2005

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.

BACKGROUND: Medullary thyroid carcinoma is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN-2A) or type 2B or familial medullary thyroid carcinoma. We sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with MEN-2A who had a mutated allele of the RET proto-oncogene could prevent or cure medullary thyroid carcinoma. METHODS: A total of 50 patients 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutation characteristic of MEN-2A underwent total thyroidectomy. Five to 10 years after the surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents. RESULTS: In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay (proportion, 0.88; 95 percent confidence interval, 0.76 to 0.95). Two patients had basal and stimulated plasma calcitonin levels above the normal range. Stimulated plasma calcitonin levels had increased but remained within the normal range in four patients. The data suggest that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before eight years of age and in children in whom there were no metastases to cervical lymph nodes. CONCLUSIONS: In this study, young patients identified by direct DNA analysis as carriers of a RET mutation characteristic of MEN-2A had no evidence of persistent or recurrent medullary thyroid carcinoma five or more years after total thyroidectomy. A longer period of evaluation will be necessary to confirm that they are cured.

Adolescent↗