Results of the cancer screening feasibility study in China: a multicentered randomized controlled trial of lung and colorectal cancer screening.

Background: To provide an understanding of important aspects of the participant recruitment and data collection, become aware of any potential problems, and obtain necessary information in order to design a large-scale randomized controlled trial (RCT) for lung cancer and colorectal cancer (CRC) screening in China. Methods: This feasibility study was a multicentered, open-label, pilot randomized trial. A total of 2696 participants who were at high risk of lung cancer were recruited from three screening centers and randomly allocated to arm 1 (n = 894), annual low-dose computed tomography (LDCT) plus a baseline colonoscopy; arm 2 (n = 902), biennial LDCT plus annual fecal immunochemical test (FIT) with OC-Sensor (OC-FIT); and arm 3 (n = 900), annual Insure-FIT plus Septin 9 blood test. Information on randomization, compliance, positivity rate, cancer case detection, and contamination with screening for lung cancer and CRC were collected. Results: Participant characteristics were similar across study arms. The compliance rate of annual LDCT screening in arm 1 was 86.4% (95% CI: 83.9%, 88.5%) at baseline (T0), and 69.0% (95% CI: 65.8%, 72.0%) and 70.7% (95% CI: 67.6%, 73.7%) at the following two rounds (T1 and T2). The compliance rates of biennial LDCT screening in arm 2 were similar to those in arm 1 in the corresponding rounds. The compliance rate was 55.5% (95% CI: 52.2%, 58.8%) for colonoscopy in arm 1, while the compliance rates of OC-FIT, Insure-FIT, and the Septin 9 test in arms 2 and 3 were all approximately 90% at T0, decreasing to 65%-80% at T1 and T2. The positivity rate, cancer case detection rate, and contamination rate of screening for lung cancer and CRC were also reported. Conclusion: In this pilot study, the feasibility of an RCT in China of lung cancer and CRC screening was demonstrated.

The Evolving Design of NIH-Funded Cardio-Oncology Studies to Address Cancer Treatment-Related Cardiovascular Toxicity.

Cardiovascular (CV) toxicity from cancer therapy is a significant and growing concern. Conventional oncology clinical trial designs focused singularly on cancer treatment efficacy have not provided sufficient information on both CV risk factors and outcomes. Similarly, traditional CV trials evaluating standard interventions typically exclude cancer patients, particularly those actively receiving cancer therapy. Neither trial type simultaneously evaluates the balance between CV toxicity and cancer outcomes. However, there is increasing collaboration among oncologists and cardiologists to design new cardio-oncology trials that address this important need. In this review, we detail five ongoing, oncology-based trials with integrated CV endpoints. Key design features include: 1) a careful assessment of baseline risk factors for CV disease; 2) an introduction of cardioprotective interventions at various timepoints in cancer therapy; 3) a balance of the risk of subclinical CV injury with the need for ongoing cancer treatment; and 4) an understanding of the time profile for development of clinically apparent CV toxicity. Additional critical priorities in cardio-oncology clinical research include harmonization of data collection and definitions for all physician- and patient-reported exposures and outcomes.

Predictive Value Tools as an Aid in Chemopreventive Agent Development.

BACKGROUND: Over 25 years, the National Cancer Institute's Division of Cancer Prevention has entered some 800 agents into a chemopreventive agent testing program. Two critical steps involve: 1) in vitro/in vivo morphologic assays and 2) animal tumor assays (incidence/multiplicity reduction). We sought to determine how accurately the earlier-stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. METHODS: Focusing on 210 agents tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the six most commonly used morphologic assays predicted drug efficacy in animal tumor assays. Using multimodel inference, three statistical models were generated to evaluate the ability of these six morphologic assays to predict tumor outcomes in three different sets of animal tumor assays: 1) all tumor types, 2) mammary cancer only, and 3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the three different sets of animal tumor assays. RESULTS: We demonstrated differences in the predictive value of specific morphologic assays for positive animal tumor assay results. Some of the morphologic assays were strongly predictive of meaningful positive efficacy outcomes in animal tumor assays representing specific cancer types, particularly the aberrant crypt focus (ACF) assay for colon cancer. Moreover, less strongly predictive assays can be combined and sequenced, resulting in enhanced composite predictive ability. CONCLUSIONS: Predictive models such as these could be used to guide selection of preventive agents as well as morphologic and animal tumor assays, thereby improving the efficiency of our approach to chemopreventive agent development.

In North America, some ovarian cancers express the oncogenes of preventable human papillomavirus HPV-18.

Some researchers in other regions have recommended human papillomavirus (HPV) vaccination to reduce risk of ovarian cancer, but not in North America, where evidence has previously suggested no role for HPV in ovarian cancer. Here we use a large sample of ovarian cancer transcriptomes (RNA-Seq) from The Cancer Genome Atlas (TCGA) database to address whether HPV is involved with ovarian cancer in North America. We estimate that a known high-risk type of HPV (type 18) is present and active in 1.5% of cases of ovarian epithelial cancers in the US and Canada. Our detection methods were verified by negative and positive controls, and our sequence matches indicated high validity, leading to strong confidence in our conclusions. Our results indicate that previous reports of zero prevalence of HPV in North American cases of ovarian cancer should not be considered conclusive. This is important because currently used vaccines protect against the HPV-18 that is active in ovarian tumors and, therefore, may reduce risk in North America of cancers of the ovaries as well as of the cervix and several other organ sites.

Results of the two incidence screenings in the National Lung Screening Trial.

BACKGROUND: The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS: We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS: At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS: Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

Results of initial low-dose computed tomographic screening for lung cancer.

BACKGROUND: Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. METHODS: At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. RESULTS: A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. CONCLUSIONS: The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

Reduced lung-cancer mortality with low-dose computed tomographic screening.

BACKGROUND: The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer. METHODS: From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009. RESULTS: The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02). CONCLUSIONS: Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

The National Lung Screening Trial: overview and study design.

The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

CT quality assurance in the lung screening study component of the National Lung Screening Trial: implications for multicenter imaging trials.

OBJECTIVE: The purpose of this study was to describe the effect of implementing an imaging quality assurance program on CT image quality in the Lung Screening Study component of the National Lung Screening Trial. MATERIALS AND METHODS: The National Lung Screening Trial is a multicenter study in which 53,457 subjects at increased risk of lung cancer were randomized to undergo three annual chest CT or radiographic screenings for lung cancer to determine the relative effect of use of the two screening tests on lung cancer mortality. Of the 26,724 subjects randomized to the CT screening arm of the National Lung Screening Trial, the Lung Screening Study randomized 17,309 through 10 screening centers. The others were randomized through the American College of Radiology Imaging Network. Quality assurance procedures were implemented that included centralized review of a random sample of 1,504 Lung Screening Study CT examinations. Quality defect rates were tabulated. RESULTS: Quality defect rates ranged from 0% (section reconstruction interval) to 7.1% (reconstructed field of view), and most errors were sporadic. However, a recurrently high effective tube current-time product setting at one center, excessive streak artifact at one center, and excessive section thickness at one center were detected and corrected through the quality assurance process. Field-of-view and scan length errors were less frequent over the second half of the screening period (p < 0.01 for both parameters, two-tailed, paired Student's t test). Error rates varied among the screening centers and reviewers for most parameters evaluated. CONCLUSION: Our experience suggested that centralized monitoring of image quality is helpful for reducing quality defects in multicenter trials.

Cumulative incidence of false-positive results in repeated, multimodal cancer screening.

PURPOSE: Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program. METHODS: Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period. RESULTS: After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%) for men, and 48.8% (95% CI, 48.1%-49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%) for men and 22.1% (95% CI, 21.4%-22.7%) for women. CONCLUSIONS: For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.

Lung cancer: interobserver agreement on interpretation of pulmonary findings at low-dose CT screening.

PURPOSE: To evaluate agreement among radiologists on the interpretation of pulmonary findings at low-dose computed tomographic (CT) screening examinations for lung cancer. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. HIPAA guidelines were followed. Sixteen radiologists from the 10 National Lung Screening Trial screening centers of the National Cancer Institute's Lung Screening Study network reviewed image subsets from 135 baseline low-dose screening CT examinations in 135 trial participants (89 men, 46 women; mean age, 62.7 years +/- 5.4 [standard deviation]). Interpretations were classified into one of four of the following categories: noncalcified nodule 4 mm or larger in greatest transverse dimension (positive screening result); noncalcified nodule smaller than 4 mm in greatest transverse dimension (negative screening result); calcified, benign nodule (negative screening result); or no nodule (negative screening result). A recommendation for follow-up evaluation was obtained for each case. Interobserver agreement was evaluated by using the multirater kappa statistic and by using response frequencies and descriptive statistics. RESULTS: Multirater kappa values ranged from 0.58 (for agreement among all four classifications; 95% confidence interval: 0.55, 0.61) to 0.64 (for agreement on classification as a positive or negative screening result; 95% confidence interval: 0.62, 0.65). The average percentage of reader pairs in agreement on the screening result per case (percentage agreement) was 82%. There was wide variation in the total number of abnormalities detected and classified as pulmonary nodules, with differences of up to more than twofold among radiologists. For cases classified as positive, multirater kappa for follow-up recommendations was 0.35. CONCLUSION: Interobserver agreement was moderate to substantial; potential for considerable improvement exists. Clinical trial registration no. NCT00047385.

Expression of xyloglucan endotransglycosylases of Gerbera hybrida and Betula pendula in Pichia pastoris.

The plant enzyme xyloglucan endotransglycosylase (XET; EC 2.4.1.207, xyloglucan:xyloglucosyl transferase) participates in selective modification of plant cell walls during cell growth. XETs are potential catalysts in various applications. Here, sequences encoding two XETs from Gerbera hybrida and Betula pendula are reported. The encoded proteins, which are 51% identical at the amino acid level, were expressed in the yeast Pichia pastoris in secreted form with the aid of mating factor alpha signal sequence. XET production in shake flask cultivations was better at 22 degrees C than at 30 degrees C. Both the yield of protein of expected molecular mass and the XET activity improved at the lower temperature. Under all cultivation conditions studied, higher amounts of XET from B. pendula (BXET) were expressed than XET from G. hybrida (GXET). Both XET enzymes were produced in 16l fed-batch bioreactor cultures. GXET was produced in methanol-limited fed-batch cultivation in minimal medium, and BXET in temperature-limited fed-batch (TLFB) in minimal or complex medium. Production was highest in TLFB in complex medium. BXET was purified from the culture filtrate and characterized. Based on the specific activity of the purified protein, 60-70 mg l(-1) BXET was produced in the TLFB in complex medium.

Ovarian cancer screening in women with a family history of breast or ovarian cancer.

OBJECTIVE: To evaluate positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer. METHODS: In the screening arm of a randomized controlled trial of screening compared with usual care, 28,460 women with family history data received baseline and annual CA 125 and transvaginal ultrasonography examinations. We analyzed CA 125 and transvaginal ultrasonography results from the first four rounds of screening. We classified women as average (n=22,687), moderate (n=2,572), or high (n=2,163) risk based on family history, or high risk due to a personal history of breast cancer (n=1,038). Cancers were identified by active follow-up of women with abnormal screening results and annual questionnaires. We calculated positive predictive values for screening combinations. RESULTS: Similar proportions (4.8-5.0%) of women in each group had abnormal screening results. Higher-risk women were more likely than lower-risk women to undergo biopsy after a positive screen. Screening identified 43 invasive ovarian cancers. The positive predictive values for abnormal screening results were 0.7% in average-risk, 1.3% in moderate-risk, and 1.6% in high-risk groups; one ovarian cancer occurred among the breast cancer survivors. The positive predictive values for postbaseline abnormal screening results were also higher in the higher-risk groups. The positive predictive values did not significantly differ across risk groups. CONCLUSION: Probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens were similar across groups based on family history of breast or ovarian cancer. However, ovarian cancer was more likely to be diagnosed after an abnormal screening result among women at higher family history-based risk than among women at lower risk. LEVEL OF EVIDENCE: I.

Prostate specific antigen changes as related to the initial prostate specific antigen: data from the prostate, lung, colorectal and ovarian cancer screening trial.

PURPOSE: Annual screening with PSA, although of unproven benefit, is currently used for prostate cancer early detection. A large fraction of screened men have low (less than 2 ng/ml) initial PSA. The yield over time of positive PSA screens (ie more than 4 ng/ml) in these men has not been well characterized in large cohorts in the United States. MATERIALS AND METHODS: Men in the screening arm of the PLCO received baseline PSA and annual tests for 5 years. 30,495 of these men had baseline PSA 4 ng/ml or less. We estimated the cumulative probability of converting to PSA greater than 4 at years 1 through 5 as a function of baseline PSA. RESULTS: Among men with baseline PSA less than 1 ng/ml, 1.5% converted by year 5 (95% CI 1.2-1.7). Among men with baseline PSA of 1.0 to 1.99 ng/ml, 1.2% (95% CI 0.9-1.3) and 7.4% (95% CI 6.8-8.1) converted by year 1 and 5, respectively. A total of 33.5% and 79% of men with initial PSA of 2.0 to 2.99 and 3.0 to 4.0, respectively, converted by year 5. Of men with baseline PSA less than 1 ng/ml converting to PSA more than 4 ng/ml, 8% were diagnosed with cancer within 2 years of conversion. About 10% of men with baseline PSA less than 1 ng/ml and negative baseline DRE had a positive DRE within 3 years. CONCLUSIONS: For men choosing PSA screening, screening every 5 years for baseline PSA less than 1 ng/ml and every 2 years for PSA 1 to 2 ng/ml could result in a 50% reduction in PSA tests and in less than 1.5% of men missing earlier positive screens, but with an unknown effect on prostate cancer mortality.

Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial.

OBJECTIVE: Ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 was evaluated in the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial. STUDY DESIGN: This was a randomized controlled trial of screening versus usual care. Baseline screening results are reported. RESULTS: Of 39,115 women randomized to receive screening, 28,816 received at least 1 test. Abnormal TVU was found in 1338 (4.7%), and abnormal CA-125 in 402 (1.4%). Twenty-nine neoplasms were identified (26 ovarian, 2 fallopian, and 1 primary peritoneal neoplasm). Nine were tumors of low malignant potential and 20 were invasive. The positive predictive value for invasive cancer was 3.7% for an abnormal CA-125, 1.0% for an abnormal TVU, and 23.5% if both tests were abnormal. CONCLUSION: The effect of screening on ovarian cancer mortality in the PLCO cohort has yet to be evaluated and will require longer follow-up. Screening identified both early- and late-stage neoplasms, and the predictive value of both tests was relatively low.

Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

Estimating the cumulative risk of a false-positive test in a repeated screening program.

The goal of screening tests for a chronic disease such as cancer is early detection and treatment with a consequent reduction in mortality from the disease. Screening tests, however, might produce false positive and false-negative results. With an increasing number of screening tests, it is clear that the risk of a false-positive screen, a finding with potentially significant emotional, financial, and health costs, also increases. Elmore et al. (1998, New England Journal of Medicine 338, 1089-1096), Christiansen et al. (2000, Journal of the National Cancer Institute 92, 1657-1666), and Gelfand and Wang (2000, Statistics in Medicine 19, 1865-1879) investigated this problem under the somewhat unrealistic assumption that the choice of making the decision to drop out at the kth screen does not depend upon the results of the earlier k - 1 screens. In this article we obtain sufficient and necessary conditions for their assumption to hold and use one of them to provide a method for testing the validity of the assumption. A new model which does not depend on their assumption is introduced. The maximum likelihood estimator of the cumulative risk of receiving a false-positive screen under the new model is derived and its asymptotic normality is proved. The extension of the new model by incorporating covariate information is also considered. We apply our testing method and the new model to data from the breast cancer screening trial of the Health Insurance Plan of Greater New York.

Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan vs chest radiograph: the Lung Screening Study of the National Cancer Institute.

BACKGROUND: Low-radiation-dose spiral CT (LDCT) scanning is capable of detecting lung neoplasms in asymptomatic individuals. To determine whether such detection can reduce lung cancer mortality, a randomized controlled trial (RCT) of LDCT scanning is necessary. METHODS: The feasibility of conducting an RCT in asymptomatic individuals who are at high risk for lung cancer was explored in the Lung Screening Study (LSS), a 12-month special project of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. During the fall of 2000, six PLCO screening centers recruited a total of 3,318 heavy or long-term smokers who were not participants in the PLCO trial and randomized them to receive either a screening LDCT scan (1,660 participants) or screening posteroanterior view chest radiograph (CXR) [1,658 participants]. RESULTS: The screens were completed on 96% of subjects in the LDCT scan arm and 93% of subjects in the CXR arm. A total of 20.5% of screened subjects in the LDCT scan arm and 9.8% of those in the CXR arm had findings that were suspicious for lung cancer. Thirty lung cancers in subjects in the LDCT arm and 7 lung cancers in patients in the CXR arm were diagnosed following a positive screening result. Additional data from the LSS indicated that, among persons who were at elevated risk for lung cancer, CT scan use was not pervasive, interest in participating in an RCT of LDCT scanning was strong, and few subjects randomized to CXR either refused their examination or sought a CT scan after their study CXR. INTERPRETATION: The results of the LSS demonstrated convincingly the feasibility of an RCT of LDCT scanning in the United States.

Primary recovery of a genetically engineered Trichoderma reesei endoglucanase I (Cel 7B) fusion protein in cloud point extraction systems.

Here we present data to demonstrate how partitioning of a hydrophilic enzyme can be directed to the hydrophobic detergent-enriched phase of an aqueous two-phase system by addition of short stretches of amino acid residues to the protein molecule. The target enzyme was the industrially important endoglucanase I, EGI (endo-1,4-beta-D-glucan-4-glucanohydrolase, EC 3.2.1.4, Cel7B) of Trichoderma reesei. We investigated the partitioning of three EGI variants containing various C-terminal peptide extensions including Trp-Pro motifs of different lengths and localizations. Additionally, a recently developed system composed of the thermoseparating copolymer HM-EOPO was utilized to study the effects of fusion tags. The addition of peptides containing tryptohan residues enhanced the partitioning of EGI to the HM-EOPO-rich phase. The system composed of a nonionic detergent (Agrimul NRE1205) resulted in the highest partition coefficient (K = 31) and yield (90%) with the construct EGI(core-P5)(WP)(4) containing (Trp-Pro)(4) after a short linker stretch. A recombinant strain of T. reesei Rut-C30 for large-scale production was constructed in which the fusion protein EGI(core-P5)(WP)(4) was expressed from the strong promoter of the cellulase gene cbh1. The fusion protein was successfully expressed and secreted from the fungus during shake-flask cultivations. Cultivation in a 28-L bioreactor however, revealed that the fusion protein is sensitive to proteases. Consequently, only low production levels were obtained in large-scale production trials.

Toenail selenium concentration and lung cancer in male smokers (Finland).

BACKGROUND: The objective of this investigation was to evaluate the association between toenail selenium concentration and lung cancer risk in male smokers. METHODS: We conducted a nested case-control study within the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study cohort. This substudy included 250 randomly selected incident lung cancer cases and 250 controls matched on age (up to +/- 5 years), intervention group assignment, and date of randomization (+/- 15 days). Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using conditional logistic regression methods. Finland began fortification of agricultural fertilizers in the fall of 1984, increasing the dietary intake, plasma, and toenail selenium concentrations for the population. The present analyses were based on the calculated residual of toenail selenium after regressing it on date of randomization. The selenium residual and the interaction of the residual with date of randomization were included in models with smoking status and body mass index as covariates. RESULTS: We observed a suggestion of a protective association for higher selenium status among men who entered the trial early (when the range of selenium values included very low levels). The OR for men with adjusted toenail selenium concentrations at the 75th percentile compared to those with the lowest selenium concentrations ranged between 0.20 (0.09-0.44) for men randomized earliest in the trial and 0.61 (0.27-1.41) for men randomized in the fifth year. CONCLUSIONS: These results suggest that low selenium status may be associated with increased risk for lung cancer.