Faculty Bibliography

Translational research studies often involve a central study (e.g. clinical trial, cohort of patients, etc.) and multiple investigators who are each interested in addressing different research questions using the same patient population. However, it is often impossible for the investigators to include all patients in all of the ancillary translational research substudies that are part of the main study. This arises due to time and budgetary constraints and other logistical considerations. In this paper, we propose a prospective Systematic Missing-At-Random study design (SMAR) with planned partially missing covariates collected using a nested random sampling scheme that allows an integrated statistical analysis across all domains of data. We propose an algorithm for data analysis that incorporates the features of the design. We show that the SMAR design is computationally and statistically efficient as well as cost effective using simulation studies and a published data example. An extension to a two-stage prospective-retrospective design is discussed.

RATIONALE: Whether histologic subtype of non-small cell lung cancer (NSCLC) has an important effect on prognosis after surgery is unknown. OBJECTIVES: We hypothesized that we could predict mortality more effectively by integrating precise tumor size and histology rather than relying on conventional staging. METHODS: We used the SEER (Surveillance, Epidemiology, and End Results) registry. Inclusion criteria were as follows: (1) primary squamous cell or adenocarcinoma; (2) potentially curative surgery, defined as a lobectomy or bilobectomy; (3) lymph node dissection performed; and (4) pathologic stage IA or IB. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2000, 7,965 patients were included. For both all-cause and lung cancer-associated mortality, tumor size demonstrated the strongest association (log-rank P < 0.0001 for each). When tumors were small (</=2 cm), lung cancer-associated mortality was similar for adenocarcinoma when compared with squamous cell carcinoma. When tumors were 3 cm or larger in size, lung cancer-associated mortality was higher for adenocarcinoma. The increased risk of lung cancer-associated mortality with adenocarcinoma was more pronounced in those younger than 65 years. Survival prediction using precise size and histology had much better discriminatory power than conventional TNM (tumor-node-metastasis) staging (P = 0.005). CONCLUSIONS: Staging that takes into account size, histology, late recurrence risk, and patient age is more accurate than the current TNM system and is clinically relevant because improved prediction can facilitate better decisions on the use of adjuvant chemotherapy

Specification of the study objective of superiority or non-inferiority at the design stage of a phase III clinical trial can sometimes be very difficult due to the uncertainty that surrounds the efficacy level of the experimental treatment. This uncertainty makes it tempting for investigators to design a trial that would allow testing of both superiority and non-inferiority hypotheses. However, when a conventional single-stage design is used to test both hypotheses, the sample size is based on the chosen primary objective of either superiority or non-inferiority. In this situation, the power of the test for the secondary objective can be low, which may lead to a large loss of resources. Potentially low reproducibility is another major concern for the single-stage design in phase III trials, because significant findings of confirmatory trials are required to be reproducible. In this paper, we propose a hybrid Bayesian-frequentist approach to evaluate reproducibility and power in single-stage designs for phase III trials to test both superiority and non-inferiority. The essence of the proposed approach is to express the uncertainty that surrounds the efficacy of the experimental treatment as a probability distribution. Then one can use Bayes formula with simple graphical techniques to evaluate reproducibility and power adequacy

The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP

We evaluated the mechanisms using immunohistochemistry whereby chrysotile asbestos and benzo(a)pyrene (BaP) instilled intratracheally into lung-specific dominant-negative p53 (dnp53) mice might interact in causing lung carcinomas and fibrosis. Chrysotile asbestos and benzo(a)pyrene (BaP) were instilled intratracheally into lung-specific dominant-negative p53 (dnp53) and control mice. The mice were sacrificed at 12 months and their lungs examined for lung carcinomas and fibrosis. Immunostains for proteins related to apoptosis, fibrogenesis, matrix remodeling and inflammation were performed. The dnp53 mice had increased numbers of lung adenocarcinomas with BaP alone and the combination of chrysotile and BaP (the latter was additive but not significant). Several atypical adenomatous hyperplasia lesions were found in the combined treatment group. dnp53 and FVBN control mice developed nodular buds of fibrotic lung tissue after chrysotile asbestos exposure that were localized in respiratory bronchioles; these lesions had significant increases in immunohistochemical staining for TGF-beta, MMP-7 and -9, MIG-1, and SDF-1. Fibrotic lesions in mice exposed to chrysotile had increased collagen demonstrated by picrosirius red staining. The dnp53 mice with adenocarcinomas had increased SDF-1, TGF-beta, MMP-9 and -7, Cyclin D, and MIG-1 immunostaining in the chrysotile and combined treatment groups. We conclude that BaP and the combination of BaP plus chrysotile asbestos are potent inducers of adenocarcinoma in dnp53 mice and that the inflammatory cytokines and proteases MMP-7 and -9, MIG-1, and SDF-1, and growth factors Cyclin D and TGF-beta are increased in the specific lesions

PURPOSE: To report the clinical feasibility of a trial of accelerated whole-breast intensity modulated radiotherapy, with the patient in prone position, optimally to spare the heart and lung. PATIENTS AND METHODS: Patients with stages I or II breast cancer, excised by breast conserving surgery with negative margins, were eligible for this institutional review board-approved prospective trial. Computed tomography simulation was performed with the patient prone on a dedicated breast board, in the exact position used for treatment. A dose of 40.5 Gy, delivered at 2.7 Gy in 15 fractions, was prescribed to the index breast with an additional concomitant boost of 0.5 Gy delivered to the tumor bed, for a total dose of 48 Gy to the lumpectomy site. Physics constraints consisted of limiting 5% of the heart volume to receive > or = 18 Gy and < or = 10% of the ipsilateral lung volume to receive > or = 20 Gy. RESULTS: Between September 2003 and August 2005, 91 patients were enrolled on the study. Median length of follow-up was 12 months (range, 1 to 28 months). In all patients the technique was feasible and heart and lung sparing was achieved as prescribed by the protocol. Acute toxicities consisting mostly of reversible grades 1-2 skin dermatitis (67%) and fatigue (18%) occurred in 75 patients. One patient sustained a regional recurrence rapidly followed by distant metastases. CONCLUSION: Accelerated whole breast intensity modulated radiotherapy in the prone position is feasible and it permits a drastic reduction in the volume of lung and heart tissue exposed to significant radiation.

BACKGROUND: S-Adenosylmethionine (AdoMet) is a major methyl donor for transmethylation reactions and propylamine donor for the biosynthesis of polyamines in biological systems, and therefore may play a role in lung cancer development. We hypothesized that AdoMet levels were elevated in patients with lung cancer and may prove useful as a biomarker for early lung cancer. METHODS: High-performance liquid chromatography was used to analyze plasma AdoMet levels in triplicate samples from 68 patients. This included 13 patients with lung cancer, 33 smokers with benign lung disease, and 22 healthy nonsmokers. The three groups of subjects were compared with respect to the distribution of demographic and disease characteristics and AdoMet levels. Distributions were examined using summary statistics and box plots, and nonparametric analysis of variance procedures. RESULTS: Serum AdoMet levels were elevated in patients with lung cancer as compared to smokers with benign lung disorders and healthy nonsmokers. There were no significant correlations between AdoMet levels and tumor cell types, nodule size, or other demographic variables. CONCLUSIONS: Our data demonstrate that plasma levels of AdoMet are significantly elevated in patients with lung cancer. Plasma AdoMet levels may prove to be a useful tool for the diagnosis of early lung cancer, in combination with chest CT. Registered at: clinicaltrials.gov (NCT00301119)