Faculty Bibliography

BACKGROUND:Screening has become one of our best tools for early detection and prevention of cancer. The group-randomized trial is the most rigorous experimental design for evaluating multilevel interventions. However, identifying the proper sample size for a group-randomized trial requires reliable estimates of intraclass correlation (ICC) for screening outcomes, which are not available to researchers. We present crude and adjusted ICC estimates for cancer screening outcomes for various levels of aggregation (physician, clinic, and county) and provide an example of how these ICC estimates may be used in the design of a future trial. METHODS:Investigators working in the area of cancer screening were contacted and asked to provide crude and adjusted ICC estimates using the analysis of variance method estimator. RESULTS:Of the 29 investigators identified, estimates were obtained from 10 investigators who had relevant data. ICC estimates were calculated from 13 different studies, with more than half of the studies collecting information on colorectal screening. In the majority of cases, ICC estimates could be adjusted for age, education, and other demographic characteristics, leading to a reduction in the ICC. ICC estimates varied considerably by cancer site and level of aggregation of the groups. CONCLUSIONS:Previously, only two articles had published ICCs for cancer screening outcomes. We have complied more than 130 crude and adjusted ICC estimates covering breast, cervical, colon, and prostate screening and have detailed them by level of aggregation, screening measure, and study characteristics. We have also demonstrated their use in planning a future trial and the need for the evaluation of the proposed interval estimator for binary outcomes under conditions typically seen in GRTs.

We review design and analytic methods available for multilevel interventions in cancer research with particular attention to study design, sample size requirements, and potential to provide statistical evidence for causal inference. The most appropriate methods will depend on the stage of development of the research and whether randomization is possible. Early on, fractional factorial designs may be used to screen intervention components, particularly when randomization of individuals is possible. Quasi-experimental designs, including time-series and multiple baseline designs, can be useful once the intervention is designed because they require few sites and can provide the preliminary evidence to plan efficacy studies. In efficacy and effectiveness studies, group-randomized trials are preferred when randomization is possible and regression discontinuity designs are preferred otherwise if assignment based on a quantitative score is possible. Quasi-experimental designs may be used, especially when combined with recent developments in analytic methods to reduce bias in effect estimates.

INTRODUCTION/BACKGROUND:Data on overweight and obesity prevalence among children enable state and local officials to develop, target, fund, and evaluate policies and programs to address childhood overweight. During the 2004-2005 school year, the Ohio Department of Health (ODH) conducted surveillance of elementary school-aged children through coordination with the ODH oral health survey to create a system that would provide county and state estimates of obesity and overweight prevalence. METHODS:We used a stratified, cluster-sampling survey design. Schools were considered clusters and were sampled from strata determined by their county and by their participation rate in the Free and Reduced Price Meal program. We selected public elementary schools by probability proportional to size sampling without replacement. We requested consent from the guardian or parent of each third-grade student. Trained health care professionals used state-purchased equipment to weigh students and measure their height. We removed implausible observations and calculated sex-specific, body mass index (BMI)-for-age percentiles using Centers for Disease Control and Prevention growth charts. RESULTS:Of eligible schools, 374 agreed to height and weight screening; 41 were considered substitutes. Of 26,590 enrolled students, 17,557 (66.0%) returned consent forms, and 15,209 (57.2%) provided consent. BMI estimates were generated for 14,451 students, resulting in an overall response rate of 54.3%. The overall oral health response rate was 52.8%. CONCLUSION/CONCLUSIONS:By adding BMI screening to Ohio's third-grade oral health survey and incorporating trained volunteer screeners, the ODH successfully implemented overweight and obesity surveillance using minimal resources. Future efforts should focus on improving student response rate.

BACKGROUND:Mutations in the P53 gene are among the most common genetic abnormalities in human lung cancer. Codon 273 in the sequence-specific DNA binding domain is one of the most frequently mutated sites. METHODOLOGY/METHODS:To investigate the role of mutant p53 in lung tumorigenesis, a lung specific p53(273H) transgenic mouse model was developed. Rates of lung cancer formation in the transgenic animals and their littermates were evaluated by necropsy studies performed in progressive age cohorts ranging from 4 to 24 months. In order to establish the influence of other common genetic abnormalities in lung tumor formation in the animals, K-Ras gene mutation and p16INK4a (p16) promoter methylation were evaluated in a total of 281 transgenic mice and 189 non-transgenic littermates. PRINCIPAL FINDINGS/RESULTS:At the age extremes of 4-12 and 22-24 months no differences were observed, with very low prevalence of tumors in animals younger than 12 months, and a relatively high prevalence at age 22 months or older. However, the transgenic mice had a significant higher lung tumor rate than their non-transgenic counterparts during the age of 13-21 months, suggesting an age-related shift in lung tumor formation induced by the lung-specific expression of the human mutant p53. Histopathology suggested a more aggressive nature for the transgenic tumors. Older mice (>13 months) had a significantly higher rate of p16 promoter methylation (17% v 82%). In addition, an age related effect was observed for K-Ras codons 12 or 13 mutations, but not for codon 61 mutations. CONCLUSIONS/SIGNIFICANCE/CONCLUSIONS:These results would suggest that the mutant p53(273H) contributes to an acceleration in the development of spontaneous lung tumors in these mice. Combination with other genetic and epigenetic alterations occurring after the age of 13 months is intimately linked to its oncogenic potential.

We hypothesized that IFN-alpha would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with bortezomib and IFN-alpha induced synergistic apoptosis in melanoma and other solid tumor cell lines. Apoptosis was associated with processing of procaspase-3, procaspase-7, procaspase-8, and procaspase-9 and with cleavage of Bid and poly(ADP-ribose) polymerase. Bortezomib plus IFN-alpha was effective at inducing apoptosis in melanoma cells that overexpressed Bcl-2 or Mcl-1, suggesting that this treatment combination can overcome mitochondrial pathways of cell survival and resistance to apoptosis. The proapoptotic effects of this treatment combination were abrogated by a caspase-8 inhibitor, led to increased association of Fas and FADD before the onset of cell death, and were significantly reduced in cells transfected with a dominant-negative FADD construct or small interfering RNA targeting Fas. These data suggest that bortezomib and IFN-alpha act through the extrinsic pathway of apoptosis via FADD-induced caspase-8 activation to initiate cell death. Finally, bortezomib and IFN-alpha displayed statistically significant antitumor activity compared with either agent alone in both the B16 murine model of melanoma and in athymic mice bearing human A375 xenografts. These data support the future clinical development of bortezomib and IFN-alpha for malignant melanoma.

BACKGROUND:Removal of rings is recommended before surgeons aseptically prepare for surgical procedures. OBJECTIVES/OBJECTIVE:This study was undertaken to determine whether there is a difference between bacterial counts under surgical gloves of ring wearers compared with nonring wearers after proper aseptic hand preparation and 3 hours of wear. METHODS:Twenty volunteer veterinary medical students were divided into 2 groups: One group wore a smooth ring band (without projections or mounted stones) on their ring finger, and the other group did not wear a ring. A modified glove juice method was used to obtain bacterial counts (colony-forming units/mL) inside surgically gloved hands prior to a proper aseptic hand preparation and 3 hours after hand preparation and wear. Each of the pre- and postsurgical glove juice samples were inoculated onto Letheen agar plates, which were incubated aerobically under atmospheric conditions for 48 hours at 35 degrees C. Gloves were tested for perforations using a water pressure test. RESULTS:No differences, or significant change, in bacterial counts were found before or after surgery between all ring hands and nonring hands or between ring and nonring hands for ringed participants. No differences in bacterial counts were found within perforated versus nonperforated gloves. CONCLUSION/CONCLUSIONS:There is no compelling evidence to suggest that surgeons wearing rings possess higher bacterial counts under their gloves during surgery.

Interferon-alpha (IFN-alpha) is used as an adjuvant therapy in patients with malignant melanoma and who have undergone surgical resection of high-risk lesions. Defective expression or activation of STAT1 or STAT2 has been shown to correlate with IFN-alpha or resistance in vitro; however, recent data from our laboratory suggest that the anti-tumor effects of IFN-alpha are dependent on STAT1 signaling within host immune cells. We measured STAT1 and STAT2 expression in 28 melanoma biopsies (8 cutaneous lesions; 1 lung metastasis; 19 nodal metastases) obtained from patients prior to the initiation of adjuvant IFN-alpha therapy. Disease recurrence following IFN-alpha treatment did not correlate with the staining intensity of either STAT1 (P = 0.61) or STAT2 (P = 0.52). Tumors with minimal STAT1 or STAT2 expression (< 20% positive) were present in four patients with tumor-positive lymph nodes, who exhibited prolonged relapse-free survival (> 44 months) following adjuvant therapy. Conversely, high levels of STAT1 were present in a patient who recurred during the course of IFN-alpha therapy. A case study of one patient who experienced recurrent disease during IFN-alpha treatment revealed that STAT1 levels were greater in the recurrent tumor when compared to the original lesion. These studies provide direct evidence to suggest that levels of STAT1 and STAT2 within the tumor do not influence a patient's response to adjuvant IFN-alpha.

Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210(E255K) and Ba/F3p210(T315I). The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210(E255K) and Ba/F3p210(T315I) were 14 +/- 4 and 30 +/- 2 microM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 microM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.

CONTEXT/BACKGROUND:Articles in the medical literature and lay press have supported a belief that individuals, including those dying of cancer, can temporarily postpone their death to survive a major holiday or other significant event, but results and effects have been variable. OBJECTIVE:To determine whether, for the patient dying of cancer, a "death takes a holiday" effect showing a reduction in deaths in the week before a significant event was associated with Christmas, the US holiday of Thanksgiving, or the date of the individual's birthday. DESIGN, SETTING, AND SUBJECTS/METHODS:Analysis of death certificate data for all 1,269,474 persons dying in Ohio from 1989-2000, including 309,221 persons dying with cancer noted as the leading cause of death. MAIN OUTCOME MEASURE/METHODS:We measured the total number of cancer deaths in the 2 weeks centered on the event of interest and the proportion of these deaths that occurred in the week before the event to determine whether this proportion was significantly different from 0.5 by using an exact binomial test. RESULTS:The proportion of persons dying of cancer in the week before Christmas, Thanksgiving, and the individual's birthday was not significantly different from the proportion dying in the week after the event (P = .52, .26, and .06, respectively). However, among black individuals there was an increase in cancer deaths in the week before Thanksgiving (P = .01), whereas women showed an increase in cancer deaths in the week before their birthday (P = .05). There was no statistically significant excess of deaths in the postevent week in any subgroup. CONCLUSION/CONCLUSIONS:We found no evidence, in contrast to previous studies, that cancer patients are able to postpone their deaths to survive significant religious, social, or personal events.