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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. [ABSTRACT FROM AUTHOR]

Background: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial originally reported no mortality benefit of ovarian cancer screening after a median of 12.4years of follow-up. The UKCTOCS screening trial failed to show a statistically significant mortality reduction in the primary analysis but reported an apparent increased mortality benefit in trial years 7-14 compared to 0-7. Here we report an updated analysis of PLCO with extended mortality follow-up., Methods: Participants were randomized from 1993 to 2001 at ten U.S. centers to an intervention or usual care arm. Intervention arm women were screened for ovarian cancer with annual trans-vaginal ultrasound (TVU) (4years) and CA-125 (6years), with a fixed cutoff at 35U/mL for CA-125. The original follow-up period was for up to 13years (median follow-up 12.4years); in this analysis follow-up for mortality was extended by up to 6years., Results: 39,105 (intervention) and 39,111 (usual care) women were randomized, of which 34,253 and 34,304, respectively, had at least one ovary at baseline. Median follow-up was 14.7years in each arm and maximum follow-up 19.2years in each arm. A total of 187 (intervention) and 176 (usual care) deaths from ovarian cancer were observed, for a risk-ratio of 1.06 (95% CI: 0.87-1.30). Risk-ratios were similar for study years 0-7 (RR=1.04), 7-14 (RR=1.06) and 14+ (RR=1.09). The risk ratio for all-cause mortality was 1.01 (95% CI: 0.97-1.05). Ovarian cancer specific survival was not significantly different across trial arms (p=0.16)., Conclusion: Extended follow-up of PLCO indicated no mortality benefit from screening for ovarian cancer with CA-125 and TVU., Competing Interests: Statement The authors report no conflicts of interest., (Published by Elsevier Inc.)

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers., (Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Chest radiographs (CXRs) are commonly performed for diagnostic and other purposes. There is little literature either on the prevalence in the general population of various abnormalities seen on CXRs or on the risks associated with these abnormalities., Methods: We followed up > 70,000 men and women who were enrolled in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Subjects received four annual posteroanterior CXRs for the early detection of lung cancer. Radiologists noted the presence of non-cancer-related abnormalities as well as nodules/masses that were suspicious for lung cancer. Subjects were followed up for mortality and cancer incidence., Results: Abnormalities that were not suspicious for lung cancer were observed on 35% of examinations, compared to 8% of examinations with findings that were suspicious for cancer. The most commonly reported noncancer abnormalities were granuloma (10.7% of examinations), scarring/pulmonary fibrosis (8.2% of examinations), bone/soft tissue lesions (5.5% of examinations), cardiac abnormalities (4.4% of examinations), pleural fibrosis (3.6% of examinations), and COPD/emphysema (2.5% of examinations). Most noncancer abnormalities were more prevalent in men, older subjects, and smokers. Controlling for age, smoking, and other factors, scarring/pulmonary fibrosis was significantly associated with an increased risk of lung cancer with a hazard ratio (HR) of 2.0, while cardiac abnormalities (HR, 2.1), scarring/pulmonary fibrosis (HR, 1.4), COPD (HR, 1.7), and pleural fluid (HR, 2.3) were significantly associated with increased overall (ie, non-lung cancer) mortality., Conclusion: Abnormalities that are not suspicious for lung cancer are common in a population undergoing screening. Some of these abnormalities are associated with an increased risk for lung cancer incidence and/or overall mortality.

Objectives: To characterize the role of demographic and clinical parameters in the measurements of prostate-specific antigen (PSA), free PSA (fPSA), and percent free PSA (%fPSA)., Methods: This was a cohort study of volunteers to a randomized screening trial. A central laboratory determined PSA and fPSA for the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A baseline evaluation of free and total PSA was done for 7183 white, black, Asian, Hispanic, and other male volunteers, aged 55 to 74 years. Comparisons were made across racial and ethnic groups and across a set of clinical parameters from a baseline questionnaire., Results: The median levels of serum PSA were less than 2.1 ng/mL in each age-race grouping of the study participants. The levels of free and total PSA were higher in black (n = 868, 12%) participants than in white (n = 4995, 70%) and Asian (n = 849, 11.8%) participants. Individuals who identified themselves as ethnically Hispanic (n = 339, 4.7%) had median PSA levels higher than whites who were not Hispanic. The free and total PSA levels increased with age, particularly among men 70 to 74 years old. However, the %fPSA levels showed less variation among the four racial groups or by age. The free and total PSA levels were higher among those who had a history of benign prostatic disease., Conclusions: Demographic (age and race/ethnicity) and clinical (history of benign prostatic disease) variables had a moderate effect on the measures of PSA and fPSA and very little effect on %fPSA.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which is randomizing 74,000 screening arm participants (37,000 men, 37,000 women; ages 55-74) and an equal number of nonscreened controls, is a unique setting for the investigation of the etiology of cancer and other diseases and for the evaluation of potential molecular markers of early disease. At entry, baseline information is collected by questionnaire on dietary intake, tobacco and alcohol use, reproductive history (for women), family history of cancer, use of selected drugs, and other selected risk factors. Blood samples collected at the baseline screening exam are aliquoted to serum, plasma, red blood cell, and buffy coat fractions. At the next two annual screening visits, serum samples are collected. At the third annual reexamination, cryopreserved whole blood is obtained, in addition to serum, plasma, red blood cell, and buffy coat fractions. At the fourth and fifth years, serum, plasma, and buffy coat are collected. All blood samples are shipped to a central repository for long-term storage at -70 degrees C. Dietary questionnaires and buccal cells for DNA analysis are obtained from nonscreened controls. Cancer cases are identified through annual follow-up questionnaires, and all deaths are identified through vital status tracing mechanisms. Procedures are being developed to obtain archival pathologic material for selected cases of cancer and related diseases. Initial investigations are focusing on the etiology of colorectal cancer and on the operative characteristics of tests for the early detection of colorectal and prostate cancer.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is enrolling 148,000 men and women ages 55-74 at ten screening centers nationwide with balanced randomization to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for prostate-specific antigen. For lung cancer, men and women receive a posteroanterior view chest X-ray. For colorectal cancer, men and women undergo a 60-cm flexible sigmoidoscopy. For ovarian cancer, women receive a blood test for the CA125 tumor marker and transvaginal ultrasound. Members of the control arm continue with their usual care. Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary endpoint is mortality from the four PLCO cancers, which accounts for about 53% of all cancer deaths in men and 41% of cancer deaths in women in the United States each year. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Changes in the eligibility criteria followed. As of April 2000, enrollment exceeded 144,500. Data are scanned into designated on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences. The PLCO trial is formally endorsed by the American Cancer Society and has been ranked by the American Urological Association as one of the most important prostate cancer studies being conducted. Special efforts to enroll black participants are cosponsored by the U.S. Centers for Disease Control and Prevention.

The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large and complex multi-institutional, multifaceted organization with a 20-year horizon. The implementation of the trial began with the creation of an organizational structure that supports strong leadership, cooperation, and effective communication among the trial collaborators including an operational framework for the development, review, and pretest of instruments, data collection, and management procedures; the setting of high-quality standards for training of trial staff; and the development of a comprehensive assessment plan for evaluation of all trial activities. This paper describes the process and methods used in the coordination and management of the PLCO trial. These include the role of the steering committee and its subcommittees and working groups, the establishment of regular and ad hoc communications among collaborators, the training of screening center coordinators and examiners, the PLCO manual of operations and procedures, and the development and implementation of a comprehensive quality assurance plan.

Rationale and Objectives: Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point., Materials and Methods: The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed., Conclusion: Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

Frequently, the medical and lay community has assumed that earlier diagnosis of cancer of any type automatically confers benefit and that any diagnostic test that can identify early stages of disease must therefore be useful for screening. However, there is an emerging science of screening which affords a more rigorous approach to public health recommendations in the application of new technologies to screening and early detection. A number of public health groups and agencies are using an evidence-based approach in making recommendations. Using this approach, early detection methods for ovarian cancer would meet only the weakest level of evidence to support their routine application in asymptomatic women. For this reason, the National Cancer Institute has recently launched a large randomized clinical trial to test the effectiveness of screening for ovarian cancer.

Screening for prostate cancer and subsequent treatment is of unknown benefit but carries known treatment related morbidity and mortality risks. The recent enthusiasm for screening in the United States contrasts sharply with the more cautious attitudes of the European and Canadian medical communities. Current data from screening series without randomization and controls are inadequate to determine screening benefit. The prostate, lung, colorectal and ovarian cancer (randomized, controlled) screening trial of the National Cancer Institute, to include 74,000 men (and 74,000 women) 60 to 74 years old, has a design power of 90% to determine a 20% reduction of prostate cancer mortality from a baseline and 3 subsequent annual screens using prostate specific antigen and digital rectal examination. Randomization of participants into this trial began on November 16, 1993. Ten screening centers nationwide, a coordinating center, a laboratory and a biorepository are participating under contract.

Objective: To critically evaluate the evidence for recommending the screening of asymptomatic men for prostate cancer with a blood test to detect a prostate-specific antigen (PSA)., Data Sources: Relevant articles on screening for prostate cancer were identified from MEDLINE searches, from the authors' files, and from the bibliographies of identified articles., Study Selection: In the absence of controlled prospective trials, the studies are primarily retrospective and contain information about the sensitivity, specificity, and predictive values of tests used to screen for prostate cancer; the natural history of untreated prostate cancer; the morbidity, mortality, and costs of definitive treatment; and reviews of screening study biases., Data Extraction: Potential treatment-related mortality and costs that could be incurred by screening were estimated using defined assumptions., Results: Although screening for prostate cancer has the potential to save lives, because of possible overdiagnosis, screening and subsequent therapy could actually have a net unfavorable effect on mortality or quality of life or both. Given the performance characteristics of the test, widespread screening efforts would probably cost billions of dollars., Conclusions: The net benefit from widespread screening is unclear. A randomized prospective study of the effect of screening on prostate cancer mortality has therefore been initiated by the National Cancer Institute.

BACKGROUND. Ovarian cancer is the fifth most common cause of cancer-related death in American women. The median age at diagnosis is about 62 years; incidence rises rapidly after age 60. Pelvic examination has been the primary method for detection of ovarian carcinoma. It is insensitive for the detection of early disease, however: most women present with disease beyond the pelvis (Stages III and IV) and are not curable with existing techniques. Two new technologies may be useful as screening tools for earlier detection of ovarian cancer. CA 125 is an antigenic determinant expressed on an ovarian cancer cell line. Transvaginal ultrasound (TVUS) images the ovaries from within the vagina and can be performed by a technician in about 10 minutes. In small preoperative studies of women with ovarian masses, serum CA 125 levels have been elevated (typically above 35 U/ml) in over two-thirds of cases and in up to 50% of Stage I cases. The test is not absolutely specific: elevations have been reported with pregnancy, endometriosis, menstruation, benign ovarian tumors, and with cancers of the breast, colon, pancreas, lung, stomach, and liver. Nevertheless, the specificity of CA 125 in postmenopausal women has been reported at about 95% or more. TVUS provides higher resolving power for ovarian abnormalities than transabdominal ultrasound or physical examination; however, experience with it is limited. CA 125 and TVUS may be complementary. CONCLUSIONS. For these reasons, the National Cancer Institute is planning a randomized trial of all three tests versus routine medical care in women of ages 60-74 years. This is part of a larger trial to determine the efficacy of screening for lung, colorectal, and ovarian cancers in women, and for lung, colorectal, and prostatic cancers in men. Seventy-four thousand women will be randomized in the study.

Receiver operating characteristic curves (ROCs) for mammography and clinical palpation individually and in combination are generated using screening data from Breast Cancer Detection Demonstration Project (BCDDP) No. 25. Detailed standard records of disease features observed on screening were kept by all examiners. And actual disease states at examination were determined for each case by pathology or follow-up. The ROCs are produced from these objective data without the usual concern for examiners' ultimate diagnostic conclusions. Comparative analysis of the ROCs illustrates the clear superiority of mammography over clinical palpation as an individual screening modality as well as the further superiority of the combined use of both modalities.

The radiocarcinogenic implications of published breast-screening policies were compared. With the use of radioepidemiologic data published recently by the National Institutes of Health, expected excess breast cancers were projected. With a base-line mammogram at age 35 and annual mammography after age 40, as few as 150 or as many as 1,000 radiogenic breast cancers were projected for a screening population of 1 million women, depending on the mammographic system employed and the screening schedule.

A decision theoretic model was used to investigate the relative importance of risk level, radiation hazard, mammographic accuracy, and cost in mammographic screening decision. The model uses woman-specific medical and family history facts and clinic-specific information regarding mammographic accuracy and practice to profile both woman and clinic, and to formulate periodic screening recommendations. Model parameters were varied extensively to investigate the sensitivity of screening schedules to input values. Multivariate risk was estimated within the program using published data from the Breast Cancer Detection Demonstration Project 5-year follow-up study. Radiation hazard estimates were developed from published radiation physics and radioepidemiologic risk data. Benchmark values for mammographic sensitivity and specificity under screening conditions were calculated from Breast Cancer Detection Demonstration Project data. Procedural costs used in the analysis were varied around values reflecting conditions at the Washington University Medical Center. Mortality advantages of early versus late breast cancer detection were accounted for using Health Insurance Plan of New York case survival rates. Results are compared with published screening policies to provide insight into implicit assumptions behind those policies. This analysis emphasizes the importance of accounting for variations in clinical accuracy under screening circumstances, in costs, in radiation exposure, and in woman-specific risk when recommending mammographic screening.

Preliminary investigations were conducted into the potential of magnetic resonance (MR) images for tissue classification of the breast on the basis of relative signal intensity. Multispectral techniques originally developed by the National Aeronautics and Space Administration for satellite image analysis were used in sequence selection, image data correction, image standardization, and image interpretation. Numerous sequence combinations with varying repetition times (TR) and echo times (TE) were considered, and a triplet was selected consisting of long TR/long TE, short TR/short TE, and an opposed phase sequence with intermediate TR and TE. Correction to remove system-imposed intensity inhomogeneities was required for all images. Image standardization based on fat and pectoral muscle signals was necessary for intercase comparisons. Multispectral images obtained based on this analysis suggest the feasibility of intensity-based image classification.