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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cancer Prev Res (Phila). Author manuscript; available in PMC Nov 1, 2012.
Published in final edited form as:
PMCID: PMC3208719
NIHMSID: NIHMS313365

Phase III Trial of Selenium to Prevent Prostate Cancer in Men with High-Grade Prostatic Intraepithelial Neoplasia: SWOG S9917

Abstract

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.

Keywords: Chemoprevention, selenium, prostate cancer, intraepithelial neoplasia, prevention, clinical trials

Introduction

Prostate cancer (PC) continues to contribute significantly to cancer morbidity and mortality in the U.S. and other western industrialized countries. It is estimated that in 2011 approximately 220,000 U.S. men will be diagnosed with and 32,050 will die from PC (1), reflecting the substantial burden of PC on patients, their families, and the public health. Prevention could be an important means of limiting this burden, and chemoprevention could be a viable component of this effort (2, 3).

Targeting chemoprevention to patients with premalignant lesions marking an increased risk of short-term progression to cancer could reduce the size, duration, and cost of a chemoprevention trial versus one conducted in an average-risk population (46). According to biologic, demographic, and clinical evidence, the intraepithelial neoplasia (IEN) high-grade prostatic IEN (HGPIN) is a precursor lesion of PC (725). Men with this condition, thought to be at elevated risk for synchronous or subsequent diagnosis of PC, are suitable subjects for clinical chemoprevention (46). Finasteride and dutasteride decrease PC risk in moderate-risk men and have a similar effect on HGPIN (3, 27), but it is not known whether these agents prevent PC in men with HGPIN.

In vitro and animal-experiment data, along with prospective observational studies, have suggested that selenium has anticancer properties (2834). Although designed to study the recurrence of non-melanoma skin cancer, the Nutritional Prevention of Cancer (NPC) study of supplemental selenium (200 mcg/day) found an approximately 50% reduction in PC (a secondary endpoint) in the selenium versus the placebo arm (35, 36). Selenium in NPC was incorporated into baker's yeast; the major organoselenium component in the yeast is believed to have been selenomethionine, although not all the selenium components have been precisely characterized (37). Despite well-described limitations of the NPC study (36, 38, 39), its prostate-cancer finding derived from a clinical prevention trial and thus provided a strong rationale for the trial we report here (4042).

Also largely motivated by the NPC study, the Selenium and Vitamin E [prostate] Cancer Prevention Trial (SELECT) in selenium-replete men found no protective effect of selenium and left open the validity of the NPC results, which involved a number of selenium-deficient men (39); thus, SELECT provided strong evidence that selenium (200 mcg/day) as selenomethionine is unlikely to prevent prostate or other cancers in U.S. males with average or greater blood concentrations of selenium and at an average PC risk. Results of selenium for PC prevention in men at an elevated risk due to HGPIN, however, have not been previously reported.

Materials and Methods

Patient selection and clinical methods

We opened this study (ClinicalTrials.gov Identifier: NCT 00030901) February 1, 2000, and closed it to new registration in November 2006. It was coordinated by the Southwest Oncology Group (SWOG), with participation by the Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, and, under the Veterans Affairs (VA) Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) program, several VA hospitals that had also participated in the Prostate Cancer Prevention Trial (PCPT).

All patients gave oral and written informed consent in accordance with institutional and federal guidelines. The protocol was approved by the Institutional Review Boards at participating institutions, and was monitored by the Data and Safety Monitoring Committee of SWOG. The following eligibility criteria were required: 40 years of age or older; digital rectal examination; biopsy- confirmed diagnosis of HGPIN with no evidence of cancer; upper limit of prostate-specific antigen (PSA) of 10 ng/mL (as measured locally); American Urological Association (AUA) symptom score of less than 20 (41), signifying no debilitating urinary problems; ambulatory and able to carry out work of a light or sedentary nature. The following conditions were exclusion criteria: Diagnosis of any cancer, other than non-melanoma skin cancer, within 5 years prior to trial registration; taking selenium supplements containing more than 50 mcg/day within 30 days prior to registration; taking finasteride or other 5-alpha reductase inhibitors.

The diagnostic biopsy identifying HGPIN was to be confirmed by central pathology review. The biopsy could provide no evidence of cancer. This study was being developed in 1999, when cancer was commonly missed on the single sextant biopsy then in vogue (43, 44). Therefore, study registration required a first biopsy showing HGPIN and no cancer followed by a second sextant-or-greater, transrectal ultrasound (TRUS)-guided biopsy revealing no cancer; the second biopsy was not required to confirm HGPIN. Subjects could be randomized after no evidence of PC was found in the second biopsy (38). Between 1999 and 2002, the increasing use of an initial prostate biopsy of 10-or-more core samples led us to amend the protocol in 2002, allowing men with an initial biopsy of 10-or-more core samples that revealed HGPIN and no cancer and performed six or fewer months prior to registration to be eligible for our trial without a second biopsy; these patients could be randomized after central pathology review confirming the HGPIN diagnosis and absence of cancer.

After registration and central pathology review, subjects were randomized in a double-blind fashion to placebo or 200 mcg/day of selenium, with daily treatment scheduled for three years or until a PC diagnosis (Supplementary Fig. 1). They were seen in clinic at baseline and every six months thereafter. Blood samples were collected for PSA testing and for future biological and nutritional studies. A digital rectal examination was conducted, and subjects were queried about symptoms, adverse events, and any cancer diagnoses. Adherence to treatment was evaluated by manual pill counts. Patients were also contacted by telephone three months after randomization and three months after each clinic visit, with queries about PC, symptoms, and adverse events. Tissue blocks and corresponding pathology reports for all prostate procedures were to be submitted to the central study pathologist for review. The central pathologist was blinded to study assignment. Patients were also asked to provide consent for ancillary tissue specimen studies, although this consent was not mandatory.

The protocol recommended TRUS-guided biopsy if a baseline PSA of < 4 ng/ml increased by more than 1 ng/ml within a year, if a baseline PSA of 4–10 ng/ml increased by more than 25%, or if a digital rectal examination revealed any abnormality. Participating urologists were at liberty to recommend biopsy as they saw fit.

An end-of-study sextant-or-greater TRUS-guided prostate biopsy, within a window of plus or minus 90 days, was planned for patients not diagnosed with PC during the three-year course of the trial, for patients who received a negative interim biopsy, and for patients removed from study supplement early for any reason other than PC.

Subjects were stratified with dynamic balancing (45) for age (40–60 versus 61 or older), race (African-American versus other), pre-study PSA (< 4 ng/ml versus 4–10 ng/ml), and vitamin E supplementation (yes versus no). In addition, after the protocol was changed in November 2002, subjects were stratified on the number of cores in the initial biopsy (< 10 cores versus 10 or more cores).

The target sample size of 466 randomized patients, 233 per arm, was designed to provide 90% power, based on the following assumptions:

  1. A three-year period prevalence of PC among men with HGPIN of 50% in the placebo group;
  2. A 33% reduction in three year period prevalence of PC in the selenium arm (versus placebo);
  3. One-sided alpha level of 0.025 (to address the one-sided hypothesis that selenium would reduce the risk of PC); this alpha was halved from 0.05 to be comparable to the more acceptable convention of a two-sided alpha of 0.05;
  4. Eighty percent of randomized patients with biopsy-confirmed three-year PC status.

Statistical methods

The primary treatment comparison was to compare the proportion of men diagnosed with PC within three years ± 90 days of randomization in the selenium arm versus this proportion in the placebo arm. The denominator was men with a known three-year endpoint status; men with missing/unknown status were excluded. The chi-square was used to evaluate the statistical significance of the difference between the proportions. Cumulative incidence plots for time to PC were derived for the placebo arm and the selenium arm; patients not developing PC were censored at the earliest of the following dates: Last contact, three years plus 90 days post-randomization, or at death if it occurred prior to a diagnosis of PC.

Results

We registered 619 men, of whom 167 were ineligible and 452 were randomly assigned to selenium (227 men) or placebo (225 men; Fig. 1). Twenty-nine randomized patients (15, selenium; 14, placebo) were later found to have been ineligible (11 by central pathology review, 18 for other reasons; Fig. 1), in all cases because of pre-randomization status. Therefore, the final cohorts of randomly assigned men were 212 to selenium and 211 to placebo. No patients were declared ineligible on the basis of a condition that developed or emerged after randomization.

Figure 1
CONSORT diagram.

Table 1 summarizes the baseline status of patients with regard to stratification and other factors. Selenium and placebo patients were well balanced with respect to age, race, ethnicity, pre-study PSA category, vitamin E supplements, and number of cores in the initial biopsy. They also were well balanced in body mass index, baseline blood selenium, performance status, and number of cores revealing HGPIN.

Table 1
Patient Characteristics (eligible, randomized patients)

Adherence to treatment was strong. Over 90% of selenium and placebo subjects who had not yet died or been diagnosed with PC were on study treatment for at least one year, and nearly 80% were on for three years (Table 2A). Adherence was very similar in the selenium and placebo arms. Plasma selenium levels (ascertained in random subsets of patients randomized to each arm) are summarized in Table 2B. The impact of selenium supplementation on plasma selenium levels is evident across all time points in the selenium arm. The data also suggest a slight rise in plasma selenium levels in the placebo arm, possibly due to some placebo subjects taking non-study supplements containing selenium.

Table 2
Compliance with study treatment

Of the eligible randomized patients, 36.3% (77/212) of selenium and 36.5% (77/211) of placebo patients did not have their three-year PC status confirmed (i.e., no interim cancer or end-of-study biopsy; Table 3). Small numbers of participants—similar numbers in each arm—died, had a primary cancer other than prostate cancer, or had an intercurrent illness. In a small, similar number of cases in each arm, a subject's physician recommended against the end-of-study biopsy, and 21 selenium and 18 placebo patients declined the end-of-study biopsy.

Table 3
Study endpoints (by treatment assignment)

Our primary analysis involved the 135 men (63.7%) of the selenium arm and 134 men (63.5%) of the placebo arm with an endpoint status known through an interim biopsy or a biopsy taken at ± 90 days of the end of study (Table 3). Among these patients, prostate cancer was diagnosed in 48 (35.6%) on selenium versus 49 (36.6%) on placebo (P = 0.73, adjusted for stratification factors; P = 0.86, unadjusted). The numbers of PC diagnoses after an interim biopsy were similar in the selenium and placebo arms, as were the numbers of PC diagnoses after an end-of-study biopsy. End-of-study biopsies were negative in 64.4% of selenium and 63.4% of placebo subjects with a known endpoint status. A previous negative interim biopsy occurred in 12 selenium patients and 23 placebo patients who were still alive, had no interim PC, and therefore were expected to have, but did not have, an end-of-study biopsy. An analysis that widened the window of the end-of-study biopsy to ± 180 days, and thus increased the proportion of biopsy-confirmed endpoints to 68% of selenium and 72% of placebo patients, also found highly similar prostate cancer rates in the two arms (P = 0.90, adjusted for stratification factors; P = 0.96, unadjusted).

We also analyzed the cumulative incidence of PC by treatment arm over the three-year treatment period (Fig. 2), finding that the cumulative incidence curves of the two arms are extremely similar, with no evidence of diverging trends (P = 0.98). This analysis approximates an intent-to-treat analysis in that it includes all randomized men (and assuming that those not known to have PC and with no end-of-study biopsy to be negative for PC); it also evaluates whether the time to a PC diagnosis differed between the two treatment groups. The preponderance of patients diagnosed with PC—70.8% (selenium) and 75.5% (placebo)—were diagnosed with a Gleason sum score of 6 or less (Fig. 3). A Gleason score of 7 was diagnosed in 25% of selenium and 20.4% of placebo patients with PC. Among the 12 selenium patients with a Gleason score of 7, 10 had pattern 3+4, whereas 2 had pattern 4+3; among the 10 placebo patients with a Gleason score of 7, 7 had pattern 3+4, and 3 had pattern 4+3. Only 3 patients overall had a Gleason score of 8 or higher. None of these differences between the selenium and placebo arms is statistically significant.

Figure 2
Cumulative incidence of prostate cancer by study arm.
Figure 3
Gleason score of diagnosed prostate cancers (by study arm).

We assessed the association between baseline serum selenium concentration and PC risk for randomized patients with a known endpoint in each treatment arm (Table 4). The probability of a PC diagnosis [relative risk (RR)], stratified by baseline selenium concentration, is reflected in column 5 of Table 4. Although the confidence intervals (CIs) are wide because of the modest sample sizes, there is no clear dose-response trend between the baseline selenium strata and the impact of selenium supplementation on a PC diagnosis. With adjustment for stratification factors and baseline selenium quartiles, there is no appreciable or statistically significant association between selenium treatment and a PC diagnosis (P = 0.73). Subset analyses did show, however, a nonsignificantly reduced PC risk (RR = 0.82; 95% CI, 0.40–1.69) in selenium versus placebo patients in the lowest quartile of baseline selenium level (< 106 ng/ml).

Table 4
Baseline plasma selenium and the effect of treatment on prostate cancer diagnosis among those evaluable for study outcome

Adverse events were graded by clinicians using the National Cancer Institute Common Toxicity Criteria (CTC) version 2.X. There were 21 grade-2 events in the selenium arm and 13 in the placebo arm (detailed data not shown). There was only one grade-3 event, which was dermatologic, in the selenium arm, and there were three grade-3 events—one cardiovascular, one gastrointestinal, and one renal/bladder— in the placebo arm.

Discussion

This trial focused on men potentially at an elevated risk of PC based on biopsy-identified HGPIN. The study extends SELECT, which randomized average-risk subjects to selenomethionine and/or vitamin E (alpha-tocopherol; ref. 39) and showed that neither agent had any effect in preventing PC. Fleshner et al. (46) also found no effect on the progression of HGPIN to PC in a trial of a putative prevention cocktail containing vitamin E, selenium, and soy in HGPIN patients.

These results differ strikingly from those of the NPC, in which selenium supplementation was associated with a 50% decrease in PC incidence (35, 36). The effect of selenium supplementation on PC risk appeared early enough in the NPC trial to suggest that a three-year treatment period in the present trial would be adequate to reveal a protective effect. The benefit of selenium supplementation in the NPC trial was confined to subjects in the lowest two tertiles of baseline plasma selenium. In general, the NPC participants had much lower baseline blood selenium levels (mean 114 ng/ml; refs. 35, 36) than did the HGPIN patients in the present trial (over 135 ng/ml). There was no protective effect of selenium among NPC participants with baseline selenium levels comparable to those of generally replete subjects in the present trial (36). The levels in our study, as in SELECT, were well above even the mean of 123 ng/ml estimated for the U.S. population (47). Selenium was not protective, however, even in HGPIN patients in the lowest baseline selenium quartile (an upper boundary of 106 ng/ml), although the risk was nonsignificantly reduced in this group. Although selenium had no effect in the second quartile, the levels in this quartile ranged from 106 to 132 ng/ml, which substantially overlaps the highest tertile of the NPC study. The NPC study tested selenized yeast, whereas selenomethionine was tested in our present study and SELECT; nonetheless, if there was a protective organoselenium compound other than selenomethionine in this yeast, it remains to be identified (37).

A key limitation of the NPC results—a substantial number of patients with elevated PSA tests were not biopsied—has been reported (36). More critical, subjects on selenium were less likely than subjects on placebo to have a biopsy following an elevated PSA test (36). The NPC investigators attempted to adjust for this difference between the arms statistically, and the association between selenium supplementation and decreased risk persisted in spite of the adjustment (36). Nonetheless, the association between selenium supplementation and PC in NPC was a secondary trial endpoint that could have resulted from confounding due to an unmeasured or imperfectly measured factor or to statistical error inherent in secondary analyses; it could have been a chance occurrence.

Our present study focused strictly on PC and was not powered or otherwise designed to evaluate other chronic disease endpoints such as diabetes. The NPC study found that selenium was associated with a statistically significantly higher rate of diabetes than was placebo. In SELECT, a slight, statistically nonsignificant excess of diabetes was observed in patients who received selenium alone (versus placebo) although the excess was much smaller than that in NPC. Additional analyses of the SELECT data are ongoing.

Although family history of PC is linked to PC risk, the present study was not powered to control for family history. We relied on randomization to balance a number of potential confounding factors between the selenium and placebo arms, and the congruence of our present results with those of SELECT (39) and Fleshner et al. (46) strongly suggests that they were not confounded by family history.

In the present study, 29 men proposed by the clinical sites to be eligible for enrollment and randomization were deemed ineligible by centralized pathology review of their biopsy samples or other reasons following their randomization. However, no subject was ruled ineligible on the basis of a condition that developed after randomization, and excluding these ineligible subjects likely did not lead to a study bias.

This study's 36% period prevalence of PC in three years suggests that its HGPIN patients were at a higher PC risk than were men recruited to other PC prevention trials. Men in the PCPT were believed to be at a low risk with no known HGPIN and a PSA level of ≤ 3.0 ng/ml at study entry (2), and 24% (placebo) were diagnosed with PC within the approximately 7 year study period. In the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (PSA eligibility 2.5–10.0 ng/ml), 25% of men were diagnosed with PC within the four years of the trial (3). Although secondary analyses of variables—including the number of biopsy cores positive for HGPIN, baseline micronutrient status, body mass index, and potential germline and somatic molecular biomarkers (48)—that may have predicted progression of HGPIN to invasive disease are beyond the scope of this report, we plan to conduct such analyses within the present trial's population for a future report.

We minimized the enrollment of men with PC (accompanying HGPIN) that was missed at the baseline biopsy. At the beginning of the study, subjects whose initial biopsy showed HGPIN and no cancer were required to undergo a second, negative biopsy of six or more cores before they could be randomized. After November 2002, subjects whose initial biopsy of 10 or more cores showed HGPIN and no cancer were not required to be re-biopsied. The rationale for this change was that 10-or-more core biopsies were coming into use in 2002 and substantially lowered the probability that PC would be missed on a single biopsy. It is likely that a few small cancers were missed at study entry, both before and after 2002, but it is unlikely that they hampered the trial's ability to assess selenium for PC prevention.

PC that developed in the present trial was in large part low grade, with Gleason score 6 or lower in 70.8% of graded cancers in the selenium arm and in 75.5 % in the placebo arm. In the placebo arm of the 7-year PCPT, 78% of graded cancers were Gleason score 6 or lower. In the placebo arm of REDUCE, about 73% of PC were Gleason score 6 or lower (3). In SELECT, 53% of diagnosed PCs were Gleason score 6 or lower, likely reflecting the fact that biopsies in SELECT were not mandated but were triggered by clinical criteria. These collective findings suggest that the presence of HGPIN does not signal an increased risk of high-grade or aggressive disease.

Although the endpoint for over 60% of men in the present trial was definitively assessed per protocol (by biopsy within 90 days of ending the three-year duration of study), this percentage was not as high as we had intended. The percentage of endpoint assessments, however, was virtually identical for selenium and placebo participants and is in line with the rates of endpoint assessment in the PCPT (60%, finasteride arm, and 63%, placebo arm; ref. 2) and in the four-year REDUCE (58% protocol-directed biopsy rate at 25–48 months, although 82% had at least one biopsy, and 80% had a protocol-directed biopsy at 19–24 months; ref. 3). Men who had a negative interim biopsy but no end-of-study biopsy were not counted as having complied with the end-of-study biopsy requirement. Counting these 35 interim-biopsy patients and assuming that a three-year biopsy also would have been negative raises the biopsy-defined endpoint rates to 69% for selenium and 74% for placebo patients. An alternate analysis expanded the end-of-study window to ± 180 days and provided further evidence that PC risk was similar in the selenium and placebo arms.

Recruitment to cancer therapy trials or to prevention trials in non-IEN people (like PCPT and SELECT) is generally easier than is recruitment to trials designed for IEN patients, and our HGPIN trial was no exception to the rule. Major hindrances to IEN-patient recruitment include the fact that IEN patients generally are not seen in cooperative cancer treatment (primarily) groups or tertiary academic referral centers and that IEN trials involve complexities (e.g., in sampling and monitoring) not common to prevention trials in generally healthy volunteers. Recruitment during our first one to two years was very slow. We successfully addressed this problem in several ways, including doubling the initial enrollment payment from 500 to 1000 dollars and adding more recruitment sites. We have previously reported the obstacles to recruitment and our solutions to them in completing accrual to the present trial in ref. 43, where we would refer readers interested in further information on this critical issue of clinical cancer prevention.

Despite advances in PC therapy, it still imposes significant human costs and complications for men diagnosed with PC (49). Ambiguities in the management of men with low-grade, low-volume PC and over-screening for PC persist (50, 51). PC prevention would lessen the need for patients to undergo treatment and would bear on the debate over the value of aggressive screening and therapy for low-grade, low-volume PC (52). An increased preventive focus on HGPIN as a marker of an increased PC risk, as shown in the present trial, is warranted. Selenium (200 mcg/day) in the form of selenomethionine is clearly ineffective for reducing PC risk in selenium-replete men with HGPIN. However, men with HGPIN might well be treated with agents, such as 5-alpha reductase inhibitors or other molecular-targeted agents, that would not be acceptable for those at average or low risk. The present trial's suggestion of a selenium benefit in selenium-deficient men, which is consistent with earlier NPC findings, and selenium pharmacogenetics (53) may identify men who would benefit from selenium, suggesting an approach for future study of selenium. As the largest randomized controlled trial of a preventive agent in HGPIN patients, the present study extends the findings of the massive SELECT in showing that selenium does not prevent prostate cancer in selenium-replete men, which is an important contribution to the public health.

Supplementary Material

Acknowledgments

We gratefully acknowledge the efforts of the investigators participating in this trial, the patients who are represented in our analysis, and the Associate Chair for the Cancer Control & Prevention Committees of the Southwest Oncology Group (SWOG), Dr. Frank Meyskens

Grant Support: This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA35178, CA04919, CA35192, CA105409, CA86780, CA20319, CA95860, CA42777, CA58686, CA11083, CA35261, CA46282, CA35119, CA45377, CA35431, CA45450, CA27057, CA67663, CA128567, CA13612, CA74647, CA45807, CA58348, CA67575, CA63844, CA58882, CA46368, CA45560, CA63850, CA35262, CA16385, CA76132, CA68183, CACA04919, CA76447, CA58686, CA27057, CA58416, CA46113, CA68183, CA2106, CA21115, CA59518.

Footnotes

Disclosure of Potential Conflicts of Interest: Other Commercial Research Support: JM Gaziano (Wyeth: vitamin pills & packaging). Honoraria from Speakers Bureau: WR Lee (Minor < $10,000: Sanofi-Aventis). The following authors report no potential conflicts of interest: JR Marshall, C Tangen, B Ely, D Jarrard, W Sakr, IM Thompson, H Parnes, DS Alberts, SM Lippman, L Minasian, DL Berry, MJ Ray, E Klein, ED Crawford, D Wood, W Davis.

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