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Biomedical subjects

Weichung J Shih

Publications and source records attributed to Weichung J Shih.

12 recordsLinked to original sources
PubMed2005

Strong correlation between meiotic crossovers and haplotype structure in a 2.5-Mb region on the long arm of chromosome 21.

Although the haplotype structure of the human genome has been studied in great detail, very little is known about the mechanisms underlying its formation. To investigate the role of meiotic recombination on haplotype block formation, single nucleotide polymorphisms were selected at a high density from a 2.5-Mb region of human chromosome 21. Direct analysis of meiotic recombination by high-throughput multiplex genotyping of 662 single sperm identifies 41 recombinants. The crossovers were nonrandomly distributed within 16 small areas. All, except one, of these crossovers fall in areas where the haplotype structure exhibits breakdown, displaying a strong statistically positive association between crossovers and haplotype block breaks. The data also indicate a particular clustered distribution of recombination hotspots within the region. This finding supports the hypothesis that meiotic recombination makes a primary contribution to haplotype block formation in the human genome.

Chromosome Mapping↗
PubMed2005

The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer.

Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of morbidity and mortality from cancer. For more than two decades, these two important but not clearly related aspects in the biology of cancer have been extensively studied. Specifically, P-glycoprotein and CD44 have been characterized and are known to be determinants of multidrug resistance (MDR) and metastases. Despite this body of knowledge, few reports have linked the two phenotypes and only recently have there been reasons to suspect a direct connection. In this report, we show that a novel physical and genetic interaction between CD44s and P-glycoprotein is in part responsible for the correlation between MDR and invasive potential in cancer cells. P-glycoprotein-specific substrates that interfere with its function reduced in vitro invasion, migration, and the physical colocalization of CD44s and P-glycoprotein. CD44 expression in sensitive cells promoted the expression of P-glycoprotein and the MDR phenotype. RNA interference of MDR1 inhibited the rate of cell migration. These data indicate that there is a close interaction between CD44 and P-glycoprotein that results in the concurrent expression and modulation of two malignant phenotypes, invasion and MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.

PURPOSE: To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. PATIENTS AND METHODS: Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. RESULTS: Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by > or = 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). CONCLUSION: This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.

Adenocarcinoma↗
PubMed2005

A phase II trial of imatinib mesylate in patients with prostate specific antigen progression after local therapy for prostate cancer.

PURPOSE: To test the hypothesis that progression of androgen sensitive prostate cancer is dependent on growth factors, such as platelet derived growth factor (PDGF), and inhibition of PDGF receptor (PDGF-R) with imatinib will induce anti-tumor activity. PATIENTS AND METHODS: This phase II study evaluated imatinib in patients with androgen sensitive prostate cancer and prostate specific antigen (PSA) progression after local therapy. Patients received 400 mg of imatinib orally twice a day for 24 weeks (six cycles). Patients were monitored every 4 weeks for an effect on PSA and toxicity. Immunohistochemistry (IHC) for PDGF-R was performed in available tumor specimens. RESULTS: Twenty-one patients were enrolled on this trial with a median age of 64 years. A total of 72 cycles of therapy were administered. Sixteen patients were evaluable for a response. Nine of the 16 patients demonstrated a stable PSA. Seven patients demonstrated PSA progression. Grade 3 and 4 toxicity included rash (4.1%), hematuria (1.4%), diarrhea (1.4%), and neutropenia (2.7%). Testosterone levels did not change during therapy. Four patients with available tumor demonstrated PDGF-R alpha and beta by IHC. CONCLUSIONS: This first study evaluated the efficacy and safety of imatinib in patients with early androgen sensitive prostate cancer following local therapy. As a single agent at this dosing, imatinib had limited biochemical activity.

Aged↗
PubMed2005

Two-stage adaptive design for clinical trials with survival data.

In long-term clinical trials we often need to monitor the patients' enrollment, compliance, and treatment effect during the study. In this paper we take the conditional power approach and consider a two-stage design based on the ideas of Li et al. (2002) for trials with survival endpoints. We make projections and decisions regarding the future course of the trial from the interim data. The decision includes possible early termination of the trial for convincing evidence of futility or efficacy, and projection includes how many additional patients are needed to enroll and how long the enrollment and follow-up may be when continuing the trial. The flexibility of the adaptive design is demonstrated by an example, the Coumadin Aspirin Reinfarction Study.

Anticoagulants↗
PubMed2004

Two-stage adaptive strategy for superiority and non-inferiority hypotheses in active controlled clinical trials.

In active controlled trials without a placebo arm, there are usually two study objectives: to test a superiority hypothesis that the experimental treatment is more effective than the active control therapy, and to test a non-inferiority hypothesis that the experimental treatment is therapeutically no worse than the active control within a defined margin. For a two-stage adaptive design, it is not necessary to give a fixed sample size calculation at the planning stage of the study when treatment effect information is often insufficient. Instead, decision and estimation of the design specifications can be made more reliably after the first stage when interim results are available. We propose the use of conditional power approach to determine the sample size and critical values for testing the superiority and non-inferiority hypotheses for the second stage based on the observed result of the first stage. The proposed adaptive procedure preserves the overall type I error rate for both superiority and non-inferiority, and has the flexibility of early termination of the study (for futility or efficacy) or extending the study by appropriate sample size.

Controlled Clinical Trials as Topic↗
PubMed2004

Development of a bioanalytical liquid chromatography method for quantitation of 9-nitrocamptothecin in human plasma.

9-Nitrocamptothecin (9-NC) is an orally administered camptothecin (CPT) that is under evaluation in clinical trials. This compound is not fluorescent, which has hampered development of a sensitive high-performance liquid chromatographic (LC) assay for measurement of drug concentrations in clinical trials. We now report development of an assay that involves reduction of 9-NC to the fluorescent compound 9-aminocamptothecin (9-AC). The method is based on enzymatic reduction of 9-NC using bovine liver S-9 fraction. This method is validated to quantitate 9-NC and 9-AC in patient samples, and yields results comparable to those obtained with an LC/MS method.

Animals↗
PubMed2004

Adaptive two-stage designs for single-arm phase IIA cancer clinical trials.

The main purpose of a phase IIA trial of a new anticancer therapy is to determine whether the therapy has sufficient promise against a specific type of tumor to warrant its further development. The therapy will be rejected for further investigation if the true response rate is less than some uninteresting level and the test of hypothesis is powered at a specific target response rate. Two-stage designs are commonly used for this situation. However, in many situations investigators often express concern about uncertainty in targeting the alternative hypothesis to study power at the planning stage. In this article, motivated by a real example, we propose a strategy for adaptive two-stage designs that will use the information at the first stage of the study to either reject the therapy or continue testing with either an optimistic or a skeptic target response rate, while the type I error rate is controlled. We also introduce new optimal criteria to reduce the expected total sample size.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Controlling type I error rate for fast track drug development programmes.

The U.S. Food and Drug Administration (FDA) Modernization Act of 1997 has a Section (No. 112) entitled 'Expediting Study and Approval of Fast Track Drugs' (the Act). In 1998, the FDA issued a 'Guidance for Industry: the Fast Track Drug Development Programs' (the FTDD programmes) to meet the requirement of the Act. The purpose of FTDD programmes is to 'facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs'. Since then many health products have reached patients who suffered from AIDS, cancer, osteoporosis, and many other diseases, sooner by utilizing the Fast Track Act and the FTDD programmes. In the meantime several scientific issues have also surfaced when following the FTDD programmes. In this paper we will discuss the concept of two kinds of type I errors, namely, the 'conditional approval' and the 'final approval' type I errors, and propose statistical methods for controlling them in a new drug submission process.

Clinical Trials, Phase III as Topic↗
PubMed2002

A sample size adjustment procedure for clinical trials based on conditional power.

When designing clinical trials, researchers often encounter the uncertainty in the treatment effect or variability assumptions. Hence the sample size calculation at the planning stage of a clinical trial may also be questionable. Adjustment of the sample size during the mid-course of a clinical trial has become a popular strategy lately. In this paper we propose a procedure for calculating additional sample size needed based on conditional power, and adjusting the final-stage critical value to protect the overall type-I error rate. Compared to other previous procedures, the proposed procedure uses the definition of the conditional type-I error directly without appealing to an extra special function for it. It has better flexibility in setting up interim decision rules and the final-stage test is a likelihood ratio test.

Journal Article↗
PubMedDate not supplied

Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis.

PURPOSE: Based largely on in vitro investigations and animal studies, investigators believe that disruptions of transforming growth factor-beta (TGF-beta) signaling contribute to the development and progression of human colorectal cancer. The purpose of this study was to directly assess the status of the TGF-beta signaling pathway in colorectal cancer and determine the effects of its disruption on clinical behavior and outcome. MATERIALS AND METHODS: Smad proteins are the principal intracellular components of the TGF-beta signaling pathway. We conducted a high-throughput analysis of the expression patterns of Smad2, phosphorylated (activated) Smad2 (pSmad2), and Smad4 in more than 600 human colorectal cancer specimens assembled in tissue microarrays. RESULTS: The vast majority (93.8%; 95% CI: 92%-96%) of colorectal cancers expressed phosphorylated Smad2, indicating the ability of the tumors to survive and proliferate within a microenvironment that contains bioactive TGF-beta. Twelve of 633 (1.9%; 95% CI: 1%-3%) cases failed to express Smad2, and 15 of 641 (2.3%; 95% CI: 1%-4%) cases failed to express Smad4. Moreover, 29 of 615 (4.7%; 95% CI: 3%-7%) of cases expressed Smad2 but not its activated form (pSmad2), suggesting the presence of a TGF-beta receptor defect. Based on an analysis of 577 cases for which clinical outcome information was available, failure to express Smad2, pSmad2, or Smad4 was associated with advanced-stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months). DISCUSSION: Loss of Smad activation and/or expression occurs in approximately 10% of colorectal cancers. This subset has a poor prognosis because of its association with advanced disease and the presence of lymph node metastases at diagnosis.

Cell Division↗