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1.  A Randomized Trial of Selenium Supplementation and Risk of Type-2 Diabetes, as Assessed by Plasma Adiponectin 
PLoS ONE  2012;7(9):e45269.
Background
Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen.
Methods
In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 µg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available.
Results
Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0–27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96).
Conclusions
These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status.
Trial Registration
Controlled-Trials.com ISRCTN25193534
doi:10.1371/journal.pone.0045269
PMCID: PMC3446875  PMID: 23028897
2.  Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597 
Journal of Clinical Oncology  2013;31(33):4179-4187.
Purpose
Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non–small-cell lung cancer (NSCLC) receiving selenium supplementation.
Patients and Methods
Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence.
Results
The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected.
Conclusion
Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC.
doi:10.1200/JCO.2013.49.2173
PMCID: PMC3821010  PMID: 24002495
3.  Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
Context
Secondary analyses of two randomized controlled trials (RCTs) and supportive epidemiologic and preclinical indicated the potential of selenium and vitamin E for preventing prostate cancer.
Objective
To determine whether selenium or vitamin E or both could prevent prostate cancer with little or no toxicity in relatively healthy men.
Design, Setting, and Participants
Randomization of a planned 32,400 men to selenium, vitamin E, selenium plus vitamin E, and placebo in a double-blinded fashion. Participants were recruited and followed in community practices, local hospitals and HMOs, and tertiary cancer centers in the United States, Canada and Puerto Rico. Baseline eligibility included 50 years or older (African American) or 55 years or older (all others), a serum prostate-specific antigen (PSA) ≤ 4 ng/mL, and a digital rectal examination (DRE) not suspicious for prostate cancer. Between 2001 and 2004, 35,533 men (10% more than planned because of a faster-than-expected accrual rate) were randomly assigned to the four study arms, which were well balanced with respect to all potentially important risk factors.
Interventions
Oral selenium (200 µg/day from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/day of all rac-α-tocopheryl acetate) and matched selenium placebo, or the two combined or placebo plus placebo for a planned minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer (as determined by routine community diagnostic standards) and prespecified secondary outcomes including lung, colorectal and overall cancer.
Results
Study supplements were discontinued at the recommendation of the Data and Safety Monitoring Committee at a planned 7-year interim analysis because the evidence convincingly demonstrated no benefit from either study agent (p < 0.0001) and no possibility of a benefit to the planned degree with additional follow-up. As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17 and 7.33). Hazard ratios (number of prostate cancers, 99% confidence intervals [CIs]) for prostate cancer were 1.13 for vitamin E (n=473; CI, 0.91–1.41), 1.04 for selenium (n=432; CI, 0.83–1.30), and 1.05 for the combination (n=437; CI, 0.83–1.31) compared with placebo (n=416). There were no significant differences (all p-values > 0.15) in any prespecified cancer endpoints. There were nonsignificant increased risks of prostate cancer in the vitamin E arm (p=0.06; relative risk [RR]=1.13; 99% CI, 0l95–1.35) and of Type 2 diabetes mellitus in the selenium arm (p=0.16; RR=1.07; 99% CI, 0.94–1.22), but they were not observed in the combination arm.
Conclusion
Selenium or vitamin E, alone or in combination, did not prevent prostate cancer in this population at the doses and formulations used.
doi:10.1001/jama.2008.864
PMCID: PMC3682779  PMID: 19066370
4.  Vitamin E and the Risk of Prostate Cancer: Updated Results of The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
JAMA  2011;306(14):1549-1556.
Context
The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a non-statistically significant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.
Objective
To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.
Design, Setting and Participants
SELECT randomized 35,533 men from 427 study sites in the United States, Canada and Puerto Rico in a double-blind manner between August 22, 2001 and June 24, 2004. Eligible men were 50 years or older (African Americans) or 55 years or older (all others) with a PSA ≤4.0 ng/mL and a digital rectal examination not suspicious for prostate cancer. Included in the analysis are 34,887 men randomly assigned to one of four treatment groups: selenium (n=8752), vitamin E (n=8737), both agents (n=8702), or placebo (n=8696). Data reflect the final data collected by the study sites on their participants through July 5, 2011.
Interventions
Oral selenium (200 μg/day from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer incidence.
Results
This report includes 54,464 additional person-years of follow-up since the primary report. Hazard ratios (99% confidence intervals [CI]) and numbers of prostate cancers were 1.17(99% CI 1.004-1.36, p=.008, n=620) for vitamin E, 1.09 (99% CI 0.93-1.27, p=.18, n=575) for selenium, 1.05 (99%CI 0.89-1.22, p=.46, n=555) for selenium + vitamin E vs. 1.00 (n=529) for placebo.The absolute increase in risk compared with placebo for vitamin E, selenium and the combination were 1.6, 0.9 and 0.4 cases of prostate cancer per 1,000 person-years.
Conclusions
Dietary supplementation with Vitamin E significantly increases the risk of prostate cancer among healthy men.
Trial registration
clinicaltrials.gov identifier: NCT00006392
doi:10.1001/jama.2011.1437
PMCID: PMC4169010  PMID: 21990298
5.  Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer 
Background
Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.
Methods
Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 μg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided.
Results
The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051).
Conclusions
We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type– and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
doi:10.1093/jnci/djn512
PMCID: PMC2734116  PMID: 19244175
6.  Phase III Trial of Selenium to Prevent Prostate Cancer in Men with High-Grade Prostatic Intraepithelial Neoplasia: SWOG S9917 
The threat of prostate cancer (PC) and the significant and often negative impact of its treatment underscore the importance of prevention. High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a potential premalignant lesion marking an increased risk of PC, and substantial evidence suggests that men with HGPIN are in need of PC prevention. In vitro, in vivo, epidemiologic, and clinical trial evidence that selenium supplementation protects against PC motivated the study we report here: A double-blind, randomized, placebo-controlled trial of selenium 200 (mcg/day) as selenomethionine in men with HGPIN. The primary endpoint was progression of HGPIN to PC over a three-year period. This NCI Intergroup trial was coordinated by the Southwest Oncology Group (SWOG). Of 619 enrolled patients, 423 randomized men with HGPIN (212, selenium; 211, placebo) were eligible (by central pathology review) and included in the primary analysis. Three-year cancer rates were 36.6% (placebo) versus 35.6% (selenium; P = 0.73, adjusted). The majority of patients who developed cancer on trial (70.8%, selenium, and 75.5%, placebo) had a Gleason score of ≤ 6; there were no differences in Gleason scores between the two arms. Subset analyses included the finding of a nonsignificantly reduced PC risk (relative risk = 0.82; 95% confidence interval, 0.40–1.69) in selenium versus placebo patients in the lowest quartile of baseline plasma selenium level (< 106 ng/ml). Overall, and in all other subsets defined by baseline blood selenium levels, selenium supplementation had no effect on PC risk. The 36% PC rate in men with HGPIN indicates the association of this lesion with an elevated PC risk. Future study in this setting should focus on selenium-deficient populations and selenium pharmacogenetics.
doi:10.1158/1940-6207.CAPR-10-0343
PMCID: PMC3208719  PMID: 21896650
Chemoprevention; selenium; prostate cancer; intraepithelial neoplasia; prevention; clinical trials
7.  Phase 3 clinical trial investigating the effect of selenium supplementation in men at high risk for prostate cancer 
The Prostate  2012;73(3):328-335.
Purpose
This study was conducted to investigate the effect of Se supplementation on prostate cancer incidence in men at high risk for prostate cancer.
Methods
A Phase 3 randomized, double-blind, placebo-controlled clinical trial was conducted in 699 men at high risk for prostate cancer (prostate specific antigen (PSA) >4 ng/ml and/or suspicious digital rectal examination and/or PSA velocity >0.75ng/ml/year), but with a negative prostate biopsy. Participants were randomized to receive daily oral placebo (N = 232), 200 µg selenium (N =234), or 400 µg selenium (N=233) as selenized yeast. They were followed every six months for up five years. The time to diagnosis of prostate cancer was compared between treatment groups using the Cox-proportional hazards model.
Result
Compared to placebo, the hazard ratios [95% confidence intervals] for risk of developing prostate cancer in the selenium 200 µg/day or the selenium 400 µg/day group were 0.94 [0.52, 1.7] and 0.90 [0.48, 1.7] respectively. PSA velocity in the selenium arms was not significantly different from that observed in the placebo group (p=0.18 and p=0.17, respectively).
Conclusion
Selenium supplementation appeared to have no effect on the incidence of prostate cancer in men at high risk. In conjunction with results of other studies, these data indicate that selenium supplementation may not have a role in prostate cancer chemoprevention.
doi:10.1002/pros.22573
PMCID: PMC4086804  PMID: 22887343
8.  Selenium supplementation has no effect on serum glucose levels in men at high risk for Prostate Cancer 
Journal of diabetes  2013;5(4):465-470.
Background
Current literature regarding the effect of selenium supplementation on risk of diabetes is inconclusive. Hence a longitudinal study was conducted to investigate the effect of selenium supplementation on serum glucose levels in elderly men.
Methods
Data were obtained from 699 men participating in a randomized, double-blind, placebo-controlled Phase 3 clinical trial investigating the effect of two doses of selenium (200 and 400 μg/day) compared to placebo on incidence of prostate cancer. Subjects were followed every six months for up to five years. Serum glucose levels were obtained every six months. Mixed effects regression models were used to assess if rate of change of serum glucose levels was significantly different in the selenium supplemented groups as compared to placebo. Sensitivity analyses were performed to assess the robustness of findings and to minimize the possibility of residual bias due to fasting status.
Results
Of the total 2893 glucose measurements, 734 were carried out when the subject had been fasting for ≥ 8 hours. The changes in serum glucose levels during the course of the trial were not statistically significantly different as compared to placebo for the selenium 200 μg/day (p = 0.98) or selenium 400 μg/day (p = 0.81) treatment groups. Sensitivity analyses demonstrated comparable results for models using the total population and models restricted to subjects with only fasting glucose data.
Conclusion
These results do not support a relationship between selenium supplementation and risk of diabetes. Hence recommendations regarding selenium supplementation based on increased risk of diabetes seem premature.
doi:10.1111/1753-0407.12041
PMCID: PMC3966548  PMID: 23489776
selenium supplementation; serum glucose; prostate cancer
9.  Optimal Management of High-Risk T1G3 Bladder Cancer: A Decision Analysis 
PLoS Medicine  2007;4(9):e284.
Background
Controversy exists about the most appropriate treatment for high-risk superficial (stage T1; grade G3) bladder cancer. Immediate cystectomy offers the best chance for survival but may be associated with an impaired quality of life compared with conservative therapy. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) for both of these treatments for men and women of different ages and comorbidity levels.
Methods and Findings
We evaluated two treatment strategies for high-risk, T1G3 bladder cancer using a decision-analytic Markov model: (1) Immediate cystectomy with neobladder creation versus (2) conservative management with intravesical bacillus Calmette-Guérin (BCG) and delayed cystectomy in individuals with resistant or progressive disease. Probabilities and utilities were derived from published literature where available, and otherwise from expert opinion. Extensive sensitivity analyses were conducted to identify variables most likely to influence the decision. Structural sensitivity analyses modifying the base case definition and the triggers for cystectomy in the conservative therapy arm were also explored. Probabilistic sensitivity analysis was used to assess the joint uncertainty of all variables simultaneously and the uncertainty in the base case results. External validation of model outputs was performed by comparing model-predicted survival rates with independent published literature. The mean LE of a 60-y-old male was 14.3 y for immediate cystectomy and 13.6 y with conservative management. With the addition of utilities, the immediate cystectomy strategy yielded a mean QALE of 12.32 y and remained preferred over conservative therapy by 0.35 y. Worsening patient comorbidity diminished the benefit of early cystectomy but altered the LE-based preferred treatment only for patients over age 70 y and the QALE-based preferred treatment for patients over age 65 y. Sensitivity analyses revealed that patients over the age of 70 y or those strongly averse to loss of sexual function, gastrointestinal dysfunction, or life without a bladder have a higher QALE with conservative therapy. The results of structural or probabilistic sensitivity analyses did not change the preferred treatment option. Model-predicted overall and disease-specific survival rates were similar to those reported in published studies, suggesting external validity.
Conclusions
Our model is, to our knowledge, the first of its kind in bladder cancer, and demonstrated that younger patients with high-risk T1G3 bladder had a higher LE and QALE with immediate cystectomy. The decision to pursue immediate cystectomy versus conservative therapy should be based on discussions that consider patient age, comorbid status, and an individual's preference for particular postcystectomy health states. Patients over the age of 70 y or those who place high value on sexual function, gastrointestinal function, or bladder preservation may benefit from a more conservative initial therapeutic approach.
Using a Markov model, Shabbir Alibhai and colleagues develop a decision analysis comparing cystectomy with conservative treatment for high-risk superficial bladder cancer depending on patient age, comorbid conditions, and preferences.
Editors' Summary
Background.
Every year, about 67,000 people in the US develop bladder cancer. Like all cancers, bladder cancer arises when a single cell begins to grow faster than normal, loses its characteristic shape, and moves into surrounding tissues. Most bladder cancers develop from cells that line the bladder (“transitional” cells) and most are detected before they spread out of this lining. These superficial or T1 stage cancers can be removed by transurethral resection of bladder tumor (TURBT). The urologist (a specialist who treats urinary tract problems) passes a small telescope into the bladder through the urethra (the tube through which urine leaves the body) and removes the tumor. If the tumor cells look normal under a microscope (so-called normal histology), the cancer is unlikely to return; if they have lost their normal appearance, the tumor is given a “G3” histological grade, which indicates a high risk of recurrence.
Why Was This Study Done?
The best treatment for T1G3 bladder cancer remains controversial. Some urologists recommend immediate radical cystectomy— surgical removal of the bladder, the urethra, and other nearby organs. This treatment often provides a complete cure but can cause serious short-term health problems and affects long-term quality of life. Patients often develop sexual dysfunction or intestinal (gut) problems and sometimes find it hard to live with a reconstructed bladder. The other recommended treatment is immunotherapy with bacillus Calmette-Guérin (BCG, bacteria that are also used to vaccinate against tuberculosis). Long-term survival is not always as good with this conservative treatment but it is less likely than surgery to cause short-term illness or to reduce quality of life. In this study, the researchers have used decision analysis (a systematic evaluation of the important factors affecting a decision) to determine whether immediate cystectomy or conservative therapy is the optimal treatment for patients with T1G3 bladder cancer. Decision analysis allowed the researchers to account for quality-of-life factors while comparing the health benefits of each treatment for T1G3 bladder cancer.
What Did the Researchers Do and Find?
Using a decision analysis model called a Markov model, the researchers calculated the months of life gained, and the quality of life expected to result, from each of the two treatments. To estimate the life expectancy (LE) associated with each treatment, the researchers incorporated the published probabilities of various outcomes of each treatment into their model. To estimate quality-adjusted life expectancy (QALE, the number of years of good quality life), they incorporated “utilities,” measures of relative satisfaction with outcomes. (A utility of 1 represents perfect health; death is assigned a value of 0, and outcomes considered less than ideal, but better than death, fall in between). For a sexually potent 60-year-old man with bladder cancer but no other illnesses, the average LE predicted by the model was nearly eight months longer with immediate cystectomy than with conservative treatment (both LEs predicted by this model matched those seen in clinical trials); the average QALE with cystectomy was 4.2 months longer than with conservative treatment. Having additional diseases decreased the benefit of immediate cystectomy but the treatment still gave a longer LE until the patient reached 70 years old, when conservative treatment became better. For QALE, this change in optimal treatment appeared at age 65. Finally, conservative treatment gave a higher QALE than immediate cystectomy for patients concerned about preserving sexual function or averse to living with intestinal problems or a reconstructed bladder.
What Do These Findings Mean?
As with all mathematical models, these results depend on the assumptions included in the model. In particular, because published probability and utility values are not available for some of the possible outcomes of the two treatments, the LE and QALE calculations could be inaccurate. Also, assigning numerical ratings to life experiences is generally something of a simplification, which could affect the reliability of the QALE (but not the LE) results. Nevertheless, these findings provide useful guidance for urologists trying to balance the benefits of immediate cystectomy or conservative treatment against the potential short-term and long-term effects of these treatments on patients' quality of life. Specifically, the results indicate that decisions on treatment for T1G3 bladder cancer should be based on a consideration of the patient's age and any coexisting disease coupled with detailed discussions with the patient about their attitudes regarding the possible health-related effects of cystectomy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040284.
MedlinePlus encyclopedia page on bladder cancer (in English and Spanish)
Information for patients and professionals from the US National Cancer Institute on bladder cancer (in English and Spanish)
Information for patients on bladder cancer from the UK charity Cancerbackup
Online course on Decision Analysis in Health Care from George Mason University
doi:10.1371/journal.pmed.0040284
PMCID: PMC1989749  PMID: 17896857
10.  Moving a Randomized Clinical Trial into an Observational Cohort 
Clinical trials (London, England)  2012;10(1):131-142.
Background
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double blind, placebo-controlled prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo. The independent Data and Safety Monitoring Committee recommended the discontinuation of study supplements because of the lack of efficacy for risk reduction and because futility analyses demonstrated no possibility of benefit of the supplements to the anticipated degree (25% reduction in prostate cancer incidence) with additional follow-up. Study leadership agreed that the randomized trial should be terminated but believed that the cohort should be maintained and followed as the additional follow-up would contribute important information to the understanding of the biologic consequences of the intervention. Since the participants no longer needed to be seen in person to assess acute toxicities or to be given study supplements, it was determined that the most efficient and cost-effective way to follow them was via a central coordinated effort.
Purpose
A number of changes were necessary at the local Study Sites and SELECT Statistical Center to transition to following participants via a Central Coordinating Center. We describe the transition process from a randomized clinical trial to the observational Centralized Follow-up (CFU) study.
Methods
The process of transitioning SELECT, implemented at more than 400 Study Sites across the United States, Canada and Puerto Rico, entailed many critical decisions and actions including updates to online documents such as the SELECT Workbench and Study Manual, a protocol amendment, reorganization of the Statistical Center, creation of a Transition Committee, development of materials for SELECT Study Sites, development of procedures to close Study Sites, and revision of data collection procedures and the process by which to contact participants.
Results
At the time of the publication of the primary SELECT results in December 2008, there were 32,569 men alive and currently active in the trial. As of December 31, 2011, 17,761 participants had been registered to the CFU study. This number is less than had been anticipated due to unforeseen difficulties with local Study Site IRBs. However, from this cohort we estimate that an additional 580 prostate cancer cases and 215 Gleason 7 or higher cancers will be identified. Over 109,000 individual items have been mailed to participants. Active SELECT ancillary studies have continued. The substantial SELECT biorepository is available to researchers; requests to use the specimens are reviewed for feasibility and scientific merit. As of April 2012, 12 proposals had been approved.
Limitations
The accrual goal of the follow-up study was not met, limiting our power to address the study objectives satisfactorily. The CFU study is also dependent on a number of factors including continued funding, continued interest of investigators in the biorepository and the continued contribution of the participants. Our experience may be less pertinent to investigators who wish to follow participants in a treatment trial or participants in prevention trials in other medical areas.
Conclusions
Extended follow-up of participants in prevention research is important to study the long-term effects of the interventions, such as those used in SELECT. The approach taken by SELECT investigators was to continue to follow participants centrally via an annual questionnaire and with a web-based option. The participants enrolled in the CFU study represent a large, well-characterized, generally healthy cohort. The CFU has enabled us to collect additional prostate and other cancer endpoints and longer follow-up on the almost 18,000 participants enrolled. The utility of the extensive biorepository that was developed during the course of the SELECT is enhanced by longer follow-up.
doi:10.1177/1740774512460345
PMCID: PMC3636982  PMID: 23064404
11.  Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
Nutrients  2013;5(4):1122-1148.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention.
doi:10.3390/nu5041122
PMCID: PMC3705339  PMID: 23552052
selenium; SELECT; prostate cancer; chemoprevention
12.  Randomized, double-blind, placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania: effects on maternal and child outcomes2 
Background
In observational studies, adequate selenium status has been associated with better pregnancy outcomes and slowed HIV disease progression.
Objective
We investigated the effects of daily selenium supplements on CD4 cell counts, viral load, pregnancy outcomes, and maternal and infant mortality among 913 HIV-infected pregnant women.
Design
In this randomized, double-blind, placebo-controlled trial, eligible women between 12 and 27 wk of gestation were given daily selenium (200 μg as selenomethionine) or placebo as supplements from recruitment until 6 mo after delivery. All women received prenatal iron, folic acid, and multivitamin supplements irrespective of experimental assignment.
Results
The selenium regimen had no significant effect on maternal CD4 cell counts or viral load. Selenium was marginally associated with a reduced risk of low birth weight [relative risk (RR) = 0.71; 95% CI: 0.49, 1.05; P = 0.09] and increased risk of fetal death (RR = 1.58; 95% CI = 0.95, 2.63; P = 0.08), but had no effect on risk of prematurity or small-for-gestational age birth. The regimen had no significant effect on maternal mortality (RR = 1.02; 95% CI = 0.51, 2.04; P = 0.96). There was no significant effect on neonatal or overall child mortality, but selenium reduced the risk of child mortality after 6 wk (RR = 0.43; 95% CI = 0.19, 0.99; P = 0.048).
Conclusion
Among HIV-infected women from Dar es Salaam, Tanzania, selenium supplements given during and after pregnancy did not improve HIV disease progression or pregnancy outcomes, but may improve child survival. This trial was registered at clinical-trials.gov as NCT00197561.
PMCID: PMC2474659  PMID: 18541571
13.  No effect of selenium supplementation on serum glucose levels in men with prostate cancer 
The American journal of medicine  2010;123(8):765-768.
Background
Literature indicates a relationship between selenium supplementation and risk of diabetes. However, since these data are inconclusive we investigated the effect of selenium supplementation on serum glucose levels in men with prostate cancer enrolled in a clinical trial testing of the effect of selenium on prostate cancer progression.
Methods
Subjects were randomized to receive placebo (N = 46), selenium 200 µg/day (N = 47) and selenium 800 µg/day (N = 47). Serum glucose levels were obtained every six months for up to five years. Longitudinal analysis was carried out to assess if rate of change of serum glucose levels was significantly different in the selenium supplemented groups as compared to placebo. Sensitivity analyses were performed to assess the robustness of findings.
Results
Changes in serum glucose levels during the course of the trial were not statistically significantly different as compared to placebo for the selenium 200 µg/day (p = 0.56) or selenium 800 µg/day (p = 0.91) treatment groups.
Conclusion
These results do not support a relationship between selenium supplementation and changes in serum glucose levels. Recommendations regarding selenium supplementation and risk of diabetes will require more definitive studies.
doi:10.1016/j.amjmed.2010.02.018
PMCID: PMC2913148  PMID: 20670733
Selenium supplementation; serum glucose; prostate cancer
14.  Design and baseline characteristics of participants in a phase III randomized trial of celecoxib and selenium for colorectal adenoma prevention 
Cyclooxygenase (COX) inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women aged 40-80 years were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November, 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared to placebo, as determined by surveillance colonoscopy performed 3-5 years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December, 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n=1,621) was completed in November, 2008. A further 200 patients with 1+ advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n=1,824) was completed in January, 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; BMI 29.1 ±5.1; 47% taking low-dose aspirin while on trial; 20% with 3+ adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type 2 diabetes will also be reported (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00078897.)
doi:10.1158/1940-6207.CAPR-12-0204
PMCID: PMC3518663  PMID: 23060037
colorectal adenoma; celecoxib; selenium; randomized trial
15.  Selenium and Lung Cancer: A Systematic Review and Meta Analysis 
PLoS ONE  2011;6(11):e26259.
Background
Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies.
Methods and Findings
Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum<106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61–1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70–3.24); and all-cause-death, OR 0.93 (95%CI 0.79–1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy.
Conclusions
Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context.
doi:10.1371/journal.pone.0026259
PMCID: PMC3208545  PMID: 22073154
16.  Association of selenium status and blood glutathione concentrations in blacks and whites 
Nutrition and cancer  2011;63(3):367-375.
Selenium deficiency has been linked with increased cancer risk and, in some studies, selenium supplementation was protective against certain cancers. Previous studies suggest that selenium chemoprevention may involve reduced oxidative stress through enhanced glutathione (GSH). Our objectives were to examine the relationships between selenium and GSH in blood and modifying effects of race and sex in free living adults and individuals supplemented with selenium. Plasma selenium concentrations and free and bound GSH concentrations and γ-glutamyl cysteine ligase (GCL) activity in blood were measured in 336 healthy adults, (161 blacks, 175 whites). Plasma selenium and blood GSH were also measured in 36 healthy men from our previously conducted placebo-controlled trial of selenium-enriched yeast (247 μg/day for 9 months). In free-living adults, selenium concentrations were associated with increased blood GSH concentration and GCL activity (P<0.05). Further, selenium was significantly higher in whites than in blacks (P<0.01). After 9 months of supplementation, plasma selenium was increased 114% in whites and 50% in blacks (P<0.05) and blood GSH was increased 35% in whites (P<0.05) but was unchanged in blacks. These results indicate a direct association between selenium and GSH in blood of both free-living and selenium-supplemented individuals, with race being an important modifying factor.
doi:10.1080/01635581.2011.535967
PMCID: PMC3087599  PMID: 21462082
17.  SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients 
Trials  2014;15(1):339.
Background
Cardiac surgery has been shown to result in a significant decrease of the antioxidant selenium, which is associated with the development of multiorgan dysfunction and increased mortality. Thus, a large-scale study is needed to investigate the effect of perioperative selenium supplementation on the occurrence of postoperative organ dysfunction.
Methods/Design
We plan a prospective, randomized double-blind, multicenter controlled trial, which will be conducted in North and South America and in Europe. In this trial we will include 1,400 high-risk patients, who are most likely to benefit from selenium supplementation. This includes patients scheduled for non-emergent combined and/or complex procedures, or with a predicted operative mortality of ≥5% according to the EuroSCORE II. Eligible patients will be randomly assigned to either the treatment group (bolus infusion of 2,000 μg sodium selenite immediately prior to surgery, followed by an additional dosage of 2,000 μg at ICU admission, and a further daily supplementation of 1,000 μg up to 10 days or ICU discharge) or to the control group (placebo administration at the same time points).
The primary endpoint of this study is a composite of 'persistent organ dysfunction’ (POD) and/or death within 30 days from surgery (POD + death). POD is defined as any need for life-sustaining therapies (mechanical ventilation, vasopressor therapy, mechanical circulatory support, continuous renal replacement therapy, or new intermittent hemodialysis) at any time within 30 days from surgery.
Discussion
The SUSTAIN-CSX™ study is a multicenter trial to investigate the effect of a perioperative high dosage sodium selenite supplementation in high-risk cardiac surgical patients.
Trial registration
This trial was registered at Clinicaltrials.gov (identifier: NCT02002247) on 28 November 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-339) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-339
PMCID: PMC4247649  PMID: 25169040
Selenium; Inflammatory response; Oxidative stress; Antioxidant capacity; Myocardial ischemia/reperfusion; Postoperative organ failure
18.  Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study 
Critical Care  2007;11(4):R73.
Introduction
Sepsis is associated with the generation of oxygen free radicals and (lacking) decreased selenium plasma concentrations. High doses of sodium selenite might reduce inflammation by a direct pro-oxidative effect and may increase antioxidant cell capacities by selenium incorporation into selenoenzymes. We investigated the effects of a continuous administration of high doses of selenium in septic shock patients.
Methods
A prospective, multicentre, placebo-controlled, randomized, double-blind study was performed with an intention-to-treat analysis in severe septic shock patients with documented infection. Patients received, for 10 days, selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) or matching placebo using continuous intravenous infusion. The primary endpoint was the time to vasopressor therapy withdrawal. The duration of mechanical ventilation, the mortality rates in the intensive care unit, at hospital discharge, and at 7, 14, 28 and 180 days and 1 year after randomization, and adverse events were recorded.
Results
Sixty patients were included (placebo, n = 29; selenium, n = 31). The median time to vasopressor therapy withdrawal was 7 days in both groups (95% confidence interval = 5–8 and 6–9 in the placebo and selenium groups, respectively; log-rank, P = 0.713). The median duration of mechanical ventilation was 14 days and 19 days in the placebo and selenium groups, respectively (P = 0.762). Mortality rates did not significantly differ between groups at any time point. Rates of adverse events were similar in the two groups.
Conclusion
Continuous infusion of selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) had no obvious toxicity but did not improve the clinical outcome in septic shock patients. Trial Registration = NCT00207844.
doi:10.1186/cc5960
PMCID: PMC2206523  PMID: 17617901
19.  The chronic autoimmune thyroiditis quality of life selenium trial (CATALYST): study protocol for a randomized controlled trial 
Trials  2014;15:115.
Background
Patients with chronic autoimmune thyroiditis have impaired health-related quality of life. The thyroid gland has a high selenium concentration, and specific selenoprotein enzyme families are crucial to immune function, and catalyze thyroid hormone metabolism and redox processes in thyroid cells. Previous randomized controlled trials have found that selenium supplementation decreases thyroid-disease-specific antibody levels. We hypothesize that selenium might be beneficial in the treatment of chronic autoimmune thyroiditis.
Methods/Design
The CATALYST trial is an investigator-initiated randomized, blinded, multicentre clinical trial of selenium supplementation versus placebo in patients with chronic autoimmune thyroiditis. Inclusion criteria: age ≥18 years; serum thyroid peroxidase antibody level ≥100 IU/ml within the previous 12 months; treatment with levothyroxine and written informed consent. Exclusion criteria: previous diagnosis of toxic nodular goitre, Graves’ hyperthyroidism, postpartum thyroiditis, Graves’ orbitopathy; previous antithyroid drug treatment, radioiodine therapy or thyroid surgery; immune-modulatory or other medication affecting thyroid function; pregnancy, planned pregnancy or breastfeeding; allergy towards any intervention or placebo component; intake of selenium supplementation >55 μg/day; inability to read or understand Danish or lack of informed consent. The trial will include 2 × 236 participants. The experimental intervention and control groups will receive 200 μg selenium-enriched yeast or matching placebo tablets daily for 12 months. The experimental supplement will be SelenoPrecise®. The primary outcome is thyroid-related quality of life assessed by the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire. Secondary outcomes include serum thyroid peroxidase antibody concentration; serum triiodothyronine/thyroxine ratio; levothyroxine dosage; adverse reactions and serious adverse reactions and events.
Discussion
In this pragmatic trial, participating patients follow their usual treatment at their usual hospitals. In order to collect high-quality data on the clinical course and quality of life, and to minimize missing data, an elaborate trial management system has been designed. 12 months intervention duration was selected in consideration of the primary outcome, thyroid-related quality of life.
Trial registration
ClinicalTrials.gov ID: NCT02013479.
doi:10.1186/1745-6215-15-115
PMCID: PMC3986429  PMID: 24716668
chronic autoimmune thyroiditis; hypothyroidism; quality of life; selenium supplementation; ThyPRO
20.  The Possible Role of Selenium Concentration in Hepatitis B and C Patients 
Background/Aim:
The compelling evidence reported that selenium is an essential trace mineral for human beings. Selenium plays a pivotal role in the restoration of immune functions. High rates of hepatitis B and C are present in Pakistan. Epidemiologic surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as viral infection. The present study was designed to evaluate the concentration of selenium in the serum of patients suffering from hepatitis B and C.
Patients and Methods:
In this cross-sectional descriptive analytical study, serum selenium concentration of 150 patients suffering from hepatitis B and C, along with 26 healthy controls, was determined by atomic absorption spectrophotometer equipped with hydride generation system, model Analytic Jena (Vario III).
Results:
The mean and standard deviation of serum selenium concentration observed in male and female patients with hepatitis C were 101.60±0.55 and 77.43±0.47 μ g/L, respectively, whereas the mean and standard deviation of serum selenium concentration observed in male and female patients with hepatitis B were 107.58±0.44 and 137.8±0.36 μg/L. Analysis of t test showed significant difference between C and B (P<0.001) patients in serum selenium concentration, when compared with the control.
Conclusion:
The obtained results indicate that serum selenium concentration of hepatitis B and C patients is less than serum selenium concentration of healthy individuals. However, serum selenium decline is relative to severity of disease. Based on findings of this study, it is proposed that selenium should be supplemented in such patients in order to optimize nutritional support and to get better treatment response.
doi:10.4103/1319-3767.93811
PMCID: PMC3326970  PMID: 22421715
Hepatitis B and C; Pakistan; selenium level
21.  Effect of Parenteral Selenium Supplementation in Critically Ill Patients: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(1):e54431.
Background
It is currently unclear whether parenteral selenium supplementation should be recommended in the management of critically ill patients. Here we conducted a systematic review and meta-analysis to assess the efficacy of parenteral selenium supplementation on clinical outcomes.
Methods/Principal Findings
Randomized trials investigating parenteral selenium supplementation administered in addition to standard of care to critically ill patients were included. CENTRAL, Medline, EMBASE, the Science Citation Index, and CINAHL were searched with complementary manual searches. The primary outcome was all-cause mortality. Trials published in any language were included. Two authors independently extracted data and assessed trial quality. A third author was consulted to resolve disagreements and for quality assurance. Twelve trials were included and meta-analysis was performed on nine trials that recruited critically ill septic patients. These comprised 965 participants in total. Of these, 148 patients (30.7%) in the treatment groups, and 180 patients (37.3%) in control groups died. Parenteral selenium treatment significantly reduced all-cause mortality in critically ill patients with sepsis (relative risk [RR] 0.83, 95% CI 0.70–0.99, p = 0.04, I2 = 0%). Subgroup analyses demonstrated that the administration schedule employing longer duration (RR 0.77, 95% CI 0.63–0.94, p = 0.01, I2 = 0%), loading boluses (RR 0.73, 95% CI 0.58–0.94, p = 0.01, I2 = 0%) or high-dose selenium treatment (RR 0.77, 95% CI 0.61–0.99, p = 0.04, I2 = 0%) might be associated with a lower mortality risk. There was no evidence of adverse events.
Conclusions/Significance
Parenteral selenium supplementation reduces risk of mortality among critically ill patients with sepsis. Owing to the varied methodological quality of the studies, future high-quality randomized trials that directly focus on the effect of adequate-duration of parenteral selenium supplementation for severe septic patients are needed to confirm our results. Clinicians should consider these findings when treating this high-risk population.
Systematic Review Registration
PROSPERO 2011; CRD42011001768
doi:10.1371/journal.pone.0054431
PMCID: PMC3555933  PMID: 23372722
22.  Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004) 
Purpose
To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer.
Methods and Materials
In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years).
Results
Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population.
Conclusions
In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.
doi:10.1016/j.ijrobp.2013.06.2044
PMCID: PMC3753507  PMID: 23958147
23.  A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: the PREADVISE trial 
Objectives
To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as a cooperative study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study.
Design
PREADViSE was designed as a double blind randomized controlled trial (RCT).
Setting
SELECT terminated after 5.5 years of accrual and follow-up due to a futility analysis. Both trials then converted into an exposure study.
Participants
In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22% reporting a family history of dementia.
Intervention
In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and/or 200 μg of selenium or placebo using a 2×2 factorial structure.
Measurements
In the RCT, participants completed the brief Memory Impairment Screen (MIS) and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the MIS-T screen. If they fail the MIS-T a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes.
Results
While this ancillary trail was open to all 427 SELECT clinical sites, only 34% chose to participate in PREADViSE. Continual staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered.
In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84% failed and were asked to contact their physicians for a more detailed memory assessment and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD.
Conclusion
Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.
doi:10.1007/s12603-012-0083-3
PMCID: PMC3636980  PMID: 23299383
Alzheimer’s disease; prevention; telephone screening; cognitive assessments; case ascertainment
24.  Selenium supplementation for patients with Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial 
Trials  2013;14:119.
Background
Graves’ hyperthyroidism is an autoimmune disease causing hyperfunction of the thyroid gland. The concentration of selenium is high in the thyroid gland and two important groups of enzymes within the thyroid are selenoproteins, that is, they depend on selenium. Selenium may have beneficial effects on autoimmune hypothyroidism and on Graves' orbitopathy, but the effects of selenium on Graves' hyperthyroidism is unknown.
We hypothesize that adjuvant selenium may be beneficial in the treatment of Graves' hyperthyroidism. The objective is to investigate if selenium supplementation plus standard treatment with anti-thyroid drugs versus standard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid drug treatment failure (that is, failure to remain euthyroid, without further treatment, one year after cessation of anti-thyroid drug treatment), faster and longer lasting remission (that is, anti-thyroid drug treatment success), and improved quality of life in patients with Graves’ hyperthyroidism.
Methods and design
The trial is an investigator-initiated, randomised, blinded, multicentre clinical trial. Inclusion criteria are: age 18 years or older; diagnosis of active Graves' hyperthyroidism within the last two months; and informed consent. Exclusion criteria are major co-morbidity; previous radioactive iodine treatment; ongoing anti-thyroid drug treatment for more than two months; treatment with immunomodulatory drugs; known allergy towards the components in the selenium and placebo pills; pregnancy or breast-feeding; and intake of selenium supplementation above 70 μg per day. We plan to include 492 participants, randomised (1:1) to two tablets of 100 μg selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily.
The primary outcome is the proportion of participants with anti-thyroid drug treatment failure (see above) at the end of the intervention period (24 to 30 months). Secondary outcomes are: thyroid-specific quality of life during the first year after randomisation; level of thyroid stimulating hormone-receptor antibodies at 18 months after randomisation and at the end of the intervention period (24 to 30 months); hyperthyroid symptoms during the first year after randomisation; eye symptoms during the first year after randomisation, and at the end of the intervention period (24 to 30 months); adverse reactions during the intervention period; and serious adverse events during the intervention period.
Discussion
It was of great importance to the initiators of this trial, that the results would be directly applicable to daily clinical practice. Therefore, it was designed as a pragmatic trial: the patients follow their usual treatment at their usual hospitals. In order to still collect high quality data on the clinical course and quality of life, an elaborate trial management system was designed to keep track of patient input, need for trial personnel input and action, and to collect data from medical chart systems. Meticulous follow-up on missing responses to the QoL measurements has been incorporated into the system, to minimise missing quality of life data. Monitoring of adverse reactions and events is achieved by thorough instruction of the participants, surveillance of patient-reported outcomes, and integration with national databases regarding hospitalizations. A very long intervention period was necessary, since patients are not considered in remission until one year after stopping anti-thyroid drugs. Usually, patients are treated for 12 to 18 months with anti-thyroid drugs, yielding a total intervention period of 24 to 30 months.
Trial registration
ClinicalTrials.gov: NCT01611896.
doi:10.1186/1745-6215-14-119
PMCID: PMC3748826  PMID: 23782950
Graves' disease; Selenium supplementation; Pragmatic trial; Quality of life; ThyPRO
25.  The effect of hypocaloric diet enriched in legumes with or without L-arginine and selenium on anthropometric measures in central obese women 
BACKGROUND:
Identifying new ways to decrease adiposity will be very valuable for health. The aim of this study was to find out whether L-Arginine (Arg) and selenium alone or together can increase the effect of hypocaloric diet enriched in legumes (HDEL) on anthropometric measures in healthy obese women.
METHODS:
This randomized, double-blind, placebo-controlled trial was undertaken in 84 healthy premenopausal women with central obesity. After 2 weeks of run-in on an isocaloric diet, participants were randomly considered to eat HDEL, Arg (5 g/d) and HDEL, selenium (200 µg/d) and HDEL or Arg, selenium and HDEL for 6 weeks. The following variables were assessed before intervention and 3 and 6 weeks after it: weight, waist circumference, hip circumference, waist to hip ratio (WHR), body mass index (BMI), and fasting nitrite/nitrate (NOx) concentrations. Other variables (arm, thigh, calf and breast circumferences, subscapular, triceps, biceps and suprailiac skinfold thicknesses, sum of skinfold thicknesses (SSF), body density (D) and estimated percent of body fat (EPF)) were assessed before and after intervention.
RESULTS:
HDEL showed a significant effect in reduction of waist, hip, arm, thigh, calf and breast circumferences, triceps, biceps, subscapular and suprailiac skinfold thicknesses, WHR, SSF, D and EPF. HDEL + Arg + selenium significantly reduced suprailiac skinfold thicknesses; and there was no significant effect of HDEL, Arg, selenium and Arg plus selenium on weight, BMI and fasting NOx.
CONCLUSIONS:
The study indicates that HDEL + Arg + selenium reduce suprailiac skinfold thicknesses which represents the abdominal obesity reduction.
PMCID: PMC3082837  PMID: 21526106
Arginine; Selenium; Diet; Reducting; Fabaceae; Obesity; Abdominal

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