The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke.

There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors ('statins') have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcome will be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose-toxicity model is calibrated such that the method will eventually select a dose that causes 7-13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: dose-response analysis of thyroid follicular adenomas detected during first screening in Ukraine (1998-2000).

The Chornobyl (Chernobyl) accident in 1986 exposed many individuals to radioactive iodines, chiefly (131)I, the effects of which on benign thyroid diseases are largely unknown. To investigate the risk of follicular adenoma in relation to radiation dose after Chornobyl, the authors analyzed the baseline data from a prospective screening cohort study of those exposed as children or adolescents. A stratified random sample was selected from all individuals who were younger than 18 years, had thyroid radioactivity measurements taken within 2 months after the accident, and resided in the three heavily contaminated areas in Ukraine. This analysis is based on the 23 cases diagnosed in 12,504 subjects for whom personal history of thyroid diseases was known. The dose-response relation was linear with an excess relative risk of 2.07 per gray (95% confidence interval: 0.28, 10.31). The risk was significantly higher in women compared with men, with no clear modifying effects of age at exposure. In conclusion, persons exposed to radioactive iodines as children and adolescents have an increased risk of follicular adenoma, though it is smaller than the risk of thyroid cancer in the same cohort. Compared with results from other studies, this estimate is somewhat smaller, but confidence intervals overlap, suggesting compatibility.

Factors associated with elevated serum concentrations of anti-TPO antibodies in subjects with and without diffuse goitre. Results from the Ukrainian-American Cohort Study of thyroid cancer and other thyroid diseases following the Chornobyl accident.

OBJECTIVES: To examine factors associated with the prevalence of elevated anti-thyroid peroxidase antibodies (ATPO) among iodine-deficient adolescents and young adults and test whether associations vary according to the presence of diffuse goitre. DESIGN: Subjects were members of the Ukrainian-American Cohort Study exposed to the Chornobyl accident whose (131)I thyroid dose estimates were below 0.2 Gy. MEASUREMENTS: The odds ratios (ORs) for ATPO above 60 U/ml were estimated using logistic regression models for a number of factors in the total population (N = 5133), and separately for thyroid disease-free subjects (N = 3875), those with diffuse goitre (N = 921), and diffuse goitre without autoimmune thyroiditis (AIT; N = 883). RESULTS: Elevated ATPO was found in 9.9% of the total population and ORs were significantly higher in females, older individuals, those examined in earlier calendar years, residents of Kyiv and Chernihiv oblasts, subjects with a family history of thyroid disease, higher thyroid ultrasound volume, suppressed or elevated TSH, blood collection in March to May, very low thyroglobulin (Tg), and shorter serum storage time. When thyroid disease-free subjects and those with diffuse goitre were compared, there were few differences in antibody prevalence, and after excluding individuals with AIT, the only difference was an increased prevalence of elevated ATPO at low urinary iodine in those with goitre alone. CONCLUSIONS: Although a number of factors are associated with the prevalence of elevated ATPO in our study group, with the exception of urinary iodine these factors are independent of goitre, and differences between thyroid disease-free subjects and those with diffuse goitre are largely due to AIT.

A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: thyroid cancer in Ukraine detected during first screening.

BACKGROUND: The Chornobyl accident in 1986 exposed thousands of people to radioactive iodine isotopes, particularly (131)I; this exposure was followed by a large increase in thyroid cancer among those exposed as children and adolescents, particularly in Belarus, the Russian Federation, and Ukraine. Here we report the results of the first cohort study of thyroid cancer among those exposed as children and adolescents following the Chornobyl accident. METHODS: A cohort of 32 385 individuals younger than 18 years of age and resident in the most heavily contaminated areas in Ukraine at the time of the accident was invited to be screened for any thyroid pathology by ultrasound and palpation between 1998 and 2000; 13 127 individuals (44%) were actually screened. Individual estimates of radiation dose to the thyroid were available for all screenees based on radioactivity measurements made shortly after the accident and on interview data. The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model. RESULTS: Forty-five pathologically confirmed cases of thyroid cancer were found during the 1998-2000 screening. Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate (P<.001), yielding an estimated excess relative risk of 5.25 per Gy (95% confidence interval [CI] = 1.70 to 27.5). Greater age at exposure was associated with decreased risk of radiation-related thyroid cancer, although this interaction effect was not statistically significant. CONCLUSION: Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population.

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: objectives, design and methods.

The thyroid gland in children is one of the organs that is most sensitive to external exposure to X and gamma rays. However, data on the risk of thyroid cancer in children after exposure to radioactive iodines are sparse. The Chornobyl accident in Ukraine in 1986 led to the exposure of large populations to radioactive iodines, particularly (131)I. This paper describes an ongoing cohort study being conducted in Belarus and Ukraine that includes 25,161 subjects under the age of 18 years in 1986 who are being screened for thyroid diseases every 2 years. Individual thyroid doses are being estimated for all study subjects based on measurement of the radioactivity of the thyroid gland made in 1986 together with a radioecological model and interview data. Approximately 100 histologically confirmed thyroid cancers were detected as a consequence of the first round of screening. The data will enable fitting appropriate dose-response models, which are important in both radiation epidemiology and public health for prediction of risks from exposure to radioactive iodines from medical sources and any future nuclear accidents. Plans are to continue to follow-up the cohort for at least three screening cycles, which will lead to more precise estimates of risk.

Evaluation of linearity in the clinical laboratory.

CONTEXT: Clinical laboratory assessment of test linearity is often limited to satisfying regulatory requirements rather than integrating this tool into the laboratory quality assurance program. Although an important part of quality control and method validation for clinical laboratories, linearity of clinical tests does not get the attention it deserves. OBJECTIVE: This article evaluates the concepts and importance of linearity evaluations for clinical tests. DESIGN: We describe the theory and procedural steps of each linearity evaluation. We then evaluate the statistical methods for each procedure. RESULTS: Visual assessment, although simple, is subjective. The lack-of-fit error and the 1986 NCCLS EP6-P G test are sensitive to imprecision and assume that the data are first order. Regression analysis, as developed as the polynomial method, is partly based on the experiences of the College of American Pathologists Instrumentation Resource Committee and has proved to be a robust statistical method. CONCLUSIONS: We provide general guidelines for handling non-linear results from a linearity evaluation. Handling linearity data in an objective manner will aid clinical laboratorians whose goal is to improve the quality of the tests they perform.