Understanding racial differences in disease presentation and response to therapy is necessary for the effective treatment and control of prostate cancer. In this study, the authors examined the influence of race on biochemical disease-free survival (BDFS) among men who received prostate brachytherapy.
In total, 2301 men were identified who had a minimum follow-up of 24 months and had received low-dose-rate brachytherapy for prostate cancer at the Mount Sinai Medical Center from June 1990 to October 2008. Patient factors, with specific emphasis on patient race, were analyzed with respect to freedom from biochemical failure (FFbF). Kaplan-Meier analyses, life-tables, and log-rank tests were used to identify variables that were predictive of 10-year FFbF.
In this series, a total of 2268 patients included 81% Caucasians, 12% African Americans, 6% Hispanics, and 1% Asians. The 10-year actuarial FFbF rate was 70% for AA men and 84% for all others (P = .002). Between Caucasian men and AA men, the 10-year FFbF rate was 83% versus 70%, respectively (P = .001).There was no significant difference in 10-year FFbF between Caucasian men and Hispanic men (83% vs 86%, respectively; P = .6). The 10-year FFbF rate for Hispanic men and AA men was 86% versus 70%, respectively (P = .062). A greater percentage of AA men presented with higher prostate-specific antigen levels (PSA) (>10 ng/mL; 44% vs 21%; P < .001) and, thus, with higher risk disease (24% vs 15%; P < .001) compared with Caucasian men. Among the men with low-risk disease, the 10-year FFbF rate was 90% for Caucasian men and 76% for AA men (P = .041). The 10-year BDFS rate for patients who received brachytherapy alone was 86% for Caucasian men and 61% for AA men (P = .001); however, this difference was not observed when brachytherapy was combined with androgen-deprivation therapy(ADT) with or without supplemental external-beam radiotherapy (EBRT). Multivariate analysis revealed that PSA (P = .024), Gleason score (P < .001), the biologic effective dose (P < .001), EBRT (P = .002), ADT (P = .03), and AA race (P = .037) were significant predictors of 10-year FFbF. No significant differences was observed in overall survival, cause-specific survival, or distant metastasis-free survival between racial groups.
Globally, it is known that black men experience the highest incidence and mortality from prostate cancer.1 Several factors that contribute to this trend include inadequate access to health care, low socioeconomic factors, and race/ethnicity.2-4 Among these factors, race is the single most controversial and yet the least studied factor that impacts morbidity and mortality in men with prostate cancer. It has been demonstrated that African American (AA) experience prostate cancer at an earlier age compared with Caucasian men.5 Furthermore, AA men often present with higher tumor grade and disease stage at the time of diagnosis.5-8 Much work done regarding the effect of race on biochemical disease recurrence after treatment has focused on radical prostatectomy (RP) and, to a lesser extent, external-beam radiotherapy (EBRT).9-13 However, results from those studies have proven inconclusive because of conflicting data, likely caused by differences in selection criteria and an inadequate sample size in the AA population. A relatively large study on results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database and the Duke Prostate Center (DPC) database revealed that, despite favorable clinical or pathologic staging and low-risk disease at the time of diagnosis, AA men were at an increased risk of biochemical disease recurrence after RP.14 Whether race acts as an independent prognostic factor for biochemical disease recurrence in patients receiving radiotherapy is still under investigation. In this article, we examine the impact of race on biochemical disease-free survival (BDFS) in patients who received prostate brachytherapy.
MATERIALS AND METHODS
In total, 2301 patients who had a minimum follow-up of 24 months and received low-dose-rate brachytherapy for prostate cancer at the Mount Sinai Medical Center from June 1990 to October 2008 were identified from our database. Patient and treatment data were provided by a prospectively collected database of 3000 men. Patients had received brachytherapy with or without EBRT and/or androgen-depravation therapy (ADT). Patients who had radiologic or pathologic evidence of metastatic disease before treatment were not included in this study. Thirty-three with unknown or unspecified ethnicity were excluded from the data. The remaining 2268 patients were subgrouped according to race/ethnicity as Caucasian, AA, Hispanic, or Asian. All patients were evaluated initially by a thorough history and physical examination (including digital rectal examination [DRE]) followed by routine laboratory studies, including pelvic computed tomography scans, bone scans, serum prostate-specific antigen (PSA) levels, and Gleason score determined by needle biopsy and reviewed at the Mount Sinai Medical Center. All patients were staged according to the 1992 American Joint Committee on Cancer staging system.15 Patients were stratified further into low, intermediate and high risk groups according to the recent National Comprehensive Cancer Network (NCCN) guidelines as follows: Patients who had T1 to T2a tumors, and a Gleason score <7, and a PSA level <10 ng/mL were classified as low risk; patients who had T2b to T2c tumors, and/or a Gleason score of 7, and/or a PSA level between 10 ng/mL and 20 ng/mL were classified as intermediate risk; and patients who had >T3 tumors, or a Gleason score between 8 and 10, or a PSA level >20 ng/mL were classified as high risk.16
Different radiotherapy combinations are used to treat difference stages of disease. Seed implantation monotherapy is used for low-risk prostate disease, whereas combination therapy, which typically includes brachytherapy seed implantation and/or EBRT with or without ADT, is reserved for intermediate-risk to high-risk disease.
Brachytherapy Seed Implantation
All patients were seeded using the real-time transrectal ultrasound-guided technique that was developed at Mount Sinai in 1990. Iodine-125 (125I) seeds were received by patients with low-risk disease (prescription dose, 160 grays [Gy]; calculated using the AAPM TG-43 dosimetry parameters), and palladium-103 (103Pd) seeds were received by patients with intermediate-risk and high-risk disease. Patients who had positive results on seminal vesicle biopsy received supplemental EBRT, as described below.
Combination therapy began in 1994 with the EBRT delivered using a 3-dimensional conformal techniques and 16-megavolt (MV) photons. The rectal, prostate, and seminal vesicle margins were 1.0 cm, 1.5 cm, and 1.5 cm, respectively. The dose was prescribed to the isodose line covering the planned target volume and was delivered using 1.8-Gy fractions (25 days). In 2003, image-guided radiotherapy was implemented using gold fiducial markers, and the position of the prostate was checked before each treatment using portal imaging with anteroposterior and lateral films. Sixteen-MV photons were used, and the margins were reduced to 8 mm for the rectum and to 1 cm for all other margins. In 2005, patients were treated on a stereotactic radiosurgery machine with a 10 × 10 cm field size using 6-MV photons with image guidance provided by oblique kilovolt x-rays before each treatment. Margins were reduced only in the area of the rectum to 6 mm. Patients with intermediate-risk and high-risk status received treatment using the same technique. For 103Pd monotherapy, the prescription dose was increased from 115 Gy to 124 Gy in 1998; and, for partial 103Pd (combination) therapy, the dose was increased from 85 Gy to 100 Gy.
ADT consisted of a gonadotropin-releasing hormone agonist (leuprolide acetate or goserelin acetate) with or without antiandrogen (flutamide or bicalutamide). ADT typically was given 3 months preimplantation and an additional 2 or 3 months after seed implantation.17 However, when ADT was used as part of trimodality therapy (ie, combined brachytherapy, EBRT, and ADT), hormone therapy was continued for an additional 6 months after implantation, resulting in a total median ADT duration of 9 months (range, 6-28 months).18
Follow-Up and Treatment Endpoints
All patients were followed at least every 6 months, at which time a complete evaluation, including DRE and serial PSA values, were determined and recorded. A Phoenix failure (PSA nadir plus 2 ng/mL) or a rising PSA after patients achieved their PSA nadir was an indication for further workup, including a bone scan and prostate biopsy. Treatment outcomes often correlate with biochemical control rates; thus, Phoenix failure was used to define biochemical failure, and freedom from biochemical failure (FFbF) was used as a surrogate for disease-free survival.19
Differences in the distribution of demographic, clinical, pathologic, and risk stratification between the various racial groups were evaluated using the Pearson chi-square test and analyses of variance. The FFbF rate was determined on the basis of time to Phoenix failure using the life-table method and Kaplan-Meier analysis. Cox regression analysis and log-rank tests were used to evaluate the influence of race, age, clinical stage, PSA, Gleason score, biologic effective dose (BED), EBRT, and ADT on biochemical disease recurrence. P values < .05 were considered as statistically significant. The analysis was done using the IBM SPSS statistical software (version 19; SPSS, Inc., Chicago, Ill).
The demographic distribution of clinical characteristics of the study groups is presented in Table 1. Of the 2268 men who were included in this series, 1831 men (81%) were Caucasian, 270 men (12%) were AA, 141 men (6%) were Hispanic, and 26 men (1%) were Asian. Age at presentation, initial PSA value, and clinical stage differed significantly among racial groups. Consistent with previous reports,5-8, 14, 20, 21 AA men presented at an earlier age compared with Caucasian men (<60 years; 30% vs 22%; P = .021) and more often had PSA levels >10 ng/mL compared with Caucasian men (44% vs 21%; P < .001). In addition, more Caucasian men presented with PSA levels <4 ng/mL (11%) compared with AA men (3%). Ninety-six percent of Asians in the study population presented with an initial PSA level <10 ng/mL. Hispanic men had the lowest percentage of patients with T1 to T2a tumors (54%) and the highest percentage with T2b to T2c tumors compared with all the other ethnicities at the time of diagnosis (43%; P = .005for both). There was no statistical difference in Gleason scores between study groups.
Table 1. Demographic Distribution of Study Variables
Statistical differences between groups were assessed with the Pearson chi-square test.
Initial PSA, ng/mL
Clinical tumor classification
Median follow-up, mo
The 10-year actuarial FFbF rate was 70% for AA men and 84% for all others (Caucasians and Hispanics; P = .002), as indicated in Table 2. When Caucasian men were compared with AA men, the 10-year actuarial FFbF rate was 83% and 70%, respectively (P = .001). Kaplan-Meier survival plots also revealed a difference in 10-year BDFS between Caucasian men and AA men (Fig. 1A) (P < .001), but not between Caucasian men and Hispanic men (Fig. 1B) (P = .94). There was an observable difference in BDFS between AA men and Hispanic men (Fig. 1C) (P = .062); however, this difference almost achieved statistical significance. The 10-year overall survival (OS) rate was 80.5%, 79.5%, and 69.5% for AA men, Caucasian men, and Hispanic men, respectively. The 10-year cause-specific survival (CSS) rate between racial groups was 96% for AA men, 98% for Caucasian men, and 100% for Hispanic men. There was no statistically significant difference in OS or CSS between racial groups (P = .56 and P = .67, respectively) (Fig. 2A,B). An analysis of 10-year distant metastasis-free survival (DMFS) also indicated that there was no significant difference between AA men (93%), Caucasian men (95%), and Hispanic men (96%; P = .49) (Fig. 2C).
Table 2. Ten-Year Actuarial Freedom From Biochemical Failure Rate Between Races/Ethnicities
Abbreviations: FFbF, freedom from biochemical failure.
The number of patients censored at 10 years.
Significance was determined with the log-rank (Mantel-Cox) test.
Table 3 indicates that more Caucasian men presented with low-risk disease that AA men (49% vs 36%; P < .001), whereas more AA men presented with high-risk disease (24% vs 15%; P < .001). Consequently, more AA men received trimodality therapy compared with Caucasian men (41% vs 27%; P < .001). A comparison of the 10-year actuarial FFbF rate between Caucasian men and AA men according to risk group revealed that men with low-risk disease had rates of 90% versus 76%, respectively (P = .041), and men with intermediate-risk disease had rates of 81% versus 73%, respectively (P = .069) (Table 4).There was no significant difference in the 10-year FFbF rate for men with high-risk disease. Among the patient characteristics that determine risk, only Gleason score (P = .002) and clinical tumor classification (P = .001) contributed significantly to the observed difference in FFbF between Caucasian men and AA men (Table 5). Among patients who experienced biochemical failure within 10 years, a greater percentage of AA men than Caucasian men had Gleason scores <7 (62% vs 48%; P < .001) and had clinical T1 to T2a tumors (53% vs 46%; P < .001) (Table 5).
Table 3. Distribution According to Risk Group and Treatment Type
Significance was determined by using the log-rank (Mantel-Cox) test.
Initial PSA, ng/mL
Clinical tumor classification
An analysis of treatment type and risk group in our study population indicated that most men in the low-risk group received seed implantation only with or without ADT (97.5%), whereas most patients in the high-risk group (81.3%) received trimodality therapy (Table 6). We compared 10-year BDFS rates between Caucasian men and AA men according to treatment type (Table 7). It is noteworthy that there was a highly significant difference in the 10-year BDFS rate between Caucasian men and AA men who received seed implantation only (86% vs 61%, respectively; P = .001) (Fig. 3A). However, this difference was not observed when seed implantation was combined with either ADT, or EBRT, or both (Fig. 3B-D).
Table 6. Analysis of Treatment Type According to Risk Group
Significance was determined by using the log-rank (Mantel-Cox) test.
Implantation and ADT
Implantation and EBRT
Implantation, EBRT, and ADT
We previously demonstrated that there is a positive correlation between the biologic effective dose (BED) of seed implants and FFbF. A higher BED was associated with lower rates of biochemical failure and positive biopsies.22 Table 8 indicates that, among the patients who received a BED ≤200, more AA men than Caucasian men experienced biochemical failure in the low-risk group (9.5% vs 5.8%; P = .29) and the intermediate-risk group (18.5% vs 7.4%; P = .019). Consequently, there was an observed difference in the 10-year FFbF rate between Caucasian men and AA men who received a BED ≤200 compared with those who received a BED >200 for low-risk disease (P = .063) and intermediate-risk disease (P = .036). This result suggests that AA men with low-risk to intermediate-risk disease may require higher radiation doses to improve biochemical disease control. There was no significant difference in the biochemical failure rate between Caucasian and AA men with high-risk disease, likely because most patients in this risk group received trimodality therapy, thus masking the BED effect. Cox regression analysis revealed that, after correcting for initial PSA (P = .024),Gleason score (P < .001), BED (P < .001), EBRT (P = .002), and ADT (P = .03), AA race (Exp[B]; odds ratio), 0.68; 95% confidence interval, 0.47-0.98; P = .037) still remained a negative predictor of FFbF (Table 9).
Table 8. Biochemical Failure Rate Between Races According to the Biologic Equivalent Dose Within Risk Groups
The influence of genetic predisposition, such as race/ethnicity, on prostate cancer in men before and after treatment has been under intense scrutiny over the past 2 decades. However, whether race acts as an independent prognostic factor for BDFS after radiotherapy remains largely unclear. Consistent with previous reports,5-8, 14, 20, 21 our study indicated that AA men present at an earlier age and with higher initial PSA levels compared with their Caucasian counterparts. However, in our study population, there was no significant difference in Gleason score or clinical stage between Caucasian men and AA men at the time of diagnosis. Furthermore, AA men presented with higher risk disease compared with Caucasian men (24% and 15%, respectively). Because risk is determined by PSA, Gleason score, and tumor classification, it appears that the major contributing factor for this difference is a higher initial PSA level among AA men.
In our study population, we observed that AA men had a significantly lower 10-year BDFS rate compared with Caucasian men (70% and 83%, respectively). We also observed higher initial PSA levels (>20 ng/mL) in our Hispanic population compared with Caucasians (16% and 5%, respectively). This is consistent with the results from a study by Rosser et al,9 who reported that 22% of Hispanics presented with a PSA level >20 ng/mL compared with only 11% among Caucasians. However, contrary to the data reported by Rosser et al indicating a marginally lower 5-year BDFS rate among Hispanic men compared with Caucasian men (65% and 52%, respectively; P = .077), our current results indicated no significant difference in the 10-year BDFS rate between Caucasian men and Hispanic men.
To further explore the preponderance of lower 10-year BDFS among AA men, we subdivided Caucasian men and AA men according to risk groups based on the new NCCN guidelines for risk group classification16 and analyzed the 10-year actuarial FFbF. We observed that, within the low-risk category, AA men demonstrated a significantly lower 10-year FFbF rate compared with Caucasian men (70% and 90%, respectively). Although our demographic data indicated that more AA men presented with higher risk disease as a result of higher initial PSA levels, there was no difference in the 10-year FFbF rate between Caucasian men and AA men with intermediate-risk and high-risk disease. It is noteworthy that, among the factors identified in univariate analysis that determined risk (PSA, Gleason score, and tumor classification), initial PSA was the only variable that did not have a significant impact on 10-year FFbF. Because of the finding that, unlike PSA, Gleason score and tumor classification often correlate with disease progression and severity, we hypothesize that, based on our results, there may be differences in tumor characteristics and disease progression in AA men with prostate cancer.
The recent treatment guidelines for patients with low-risk prostate cancer who have a life expectancy >10 years recommend either RP, or definitive radiotherapy (EBRT or brachytherapy), or active surveillance. Accordingly, most of our low-risk patients received brachytherapy seed implants alone (72%) or seed implants plus ADT (25.5%). It is striking that the most significant difference we observed in BDFS (86% in Caucasian men and 61% in AA men) occurred in the treatment group that received seed implants only, and >95% of those men were in the low-risk category. However, when ADT or EBRT was added to seed implantation, there was no longer any significant difference in the rate of biochemical disease recurrence between racial groups. Consistent with previous reports indicating that the BED is correlated with FFbF,18, 22 we observed increased biochemical disease recurrence among patients who received a BED ≤200 compared with those who received a BED >200. This difference was more robust in AA men compared with Caucasian men, suggesting that AA men may require higher radiation doses to improve BDFS. Furthermore, our multivariate Cox regression analysis identified AA race as an independent negative predictor of FFbF. It is noteworthy that the observed difference in biochemical disease recurrence among the racial groups did not correlate directly with clinical endpoints like OS, CSS, or DMFS rates. This is consistent with work done by Kupelian et al,23 who investigated the impact of biochemical failure on OS rates during the first 10 years after definitive radiotherapy for localized prostate cancer. Those authors concluded that biochemical failure after definitive radiotherapy for localized prostate cancer is not associated with increased mortality within 10 years after initial therapy. Furthermore, Radiation Therapy Oncology Group (RTOG) phase 3 randomized trials by Roach et al24 assessed the impact of race on survival in 2012 men who received EBRT with or without ADT for localized prostate cancer. Results from that study indicated that black race was associated with lower OS and disease-specific survival; however, after adjusting for risk group and treatment type, race no longer was associated with outcome. It would be interesting to determine whether the increased biochemical disease recurrence rate among AA men may lead to more frequent salvage therapy in this patient population.
There is conflicting evidence pertaining to a greater risk of biochemical disease recurrence among AA men after RP. Nielsen et al13 investigated whether black race was associated with poorer oncologic outcomes in a study population that consisted of 4962 Caucasian men and 326 AA men who underwent RP between 1988 and 2004 at the Johns Hopkins Hospital. Those authors reported that AA men were likely to present with adverse preoperative clinical features at a younger age and had a higher biochemical recurrence rate; however, in a multivariate analysis, black race was not an independent predictor of biochemical recurrence or adverse pathologic outcome. Conversely, Hamilton et al10 evaluated racial differences in pathologic features, time to disease recurrence, and PSA doubling time among 953 Caucasian men and 659 black men in the SEARCH database who underwent RP between 1988 and 2006. Those investigators reported that, despite earlier clinical stage at presentation and similar pathologic characteristics, black men were at a slightly increased risk of biochemical disease recurrence. Furthermore, Moreira et al14 evaluated whether race modified the accuracy of nomograms to predict biochemical disease recurrence after RP among 1721 patients and 4511 patients from the SEARCH and DPC databases, respectively. They reported that, in both cohorts, AA men were more likely to experience biochemical disease recurrence compared with Caucasian men.
Several studies that evaluated racial differences in biochemical disease recurrence among patients who received radiotherapy also demonstrated equivocal results. Rosser et al9 retrospectively analyzed the clinical characteristics and outcomes of 964 patients from various racial groups that received EBRT for localized or locally advanced prostate cancer, including 810 Caucasian men and 86 AA men. Those authors observed that, when patients were stratified according to known prognostic factors, the outcome for both AA men and Caucasian men was comparable. Another series by Sohayda et al25 analyzed outcomes after prostatectomy or radiotherapy for localized prostate cancer with respect to race in 2219 men between 1986 to 1998 (14% AA and 86% Caucasian). They demonstrated a statistically insignificant trend toward higher biochemical failure in AA men. Conversely, Thompson et al5 evaluated outcomes of men with metastatic prostate disease in the context of a randomized phase 3 trial (Southwest Oncology Group Study 8894) that compared orchiectomy with or without flutamide in 288 AA men and 975 Caucasian men who had metastatic prostate cancer. Those results indicated that AA men were more likely to have extensive disease; and, even after adjusting for initial quality-of-life assessment and pretreatment factors, AA men had a statistically significantly worse prognosis than Caucasian men. Because these studies included patients with different selection criteria, disease stages, and varied treatment modalities, a comparison of treatment-dependent biochemical disease recurrence among these study populations should be interpreted with caution. In 2002, Lee et al26 conducted a study design very much identical to that presented by our group in the current report. They compared PSA relapse-free survival (PSA-RFS) between 246 AA men and 835 Caucasian men who received brachytherapy with or without EBRT and/or ADT for clinically localized prostate cancer. In their study, they concluded that race was not a predictor of 5-year PSA-RFS among patients who were with or without ADT within the low-risk, intermediate-risk, and high-risk groups. However, a caveat to their study is that, unlike other types of malignancy, prostate cancer has a relatively slower rate of disease progression; therefore, a 5-year follow-up may be insufficient to adequately demonstrate a racial effect on biochemical disease recurrence. Their data also indicated that more AA men than Caucasian men received ADT (41.5% vs 27.2%; P = .01). This is consistent with results from our study indicating that the addition of ADT (or EBRT) to brachytherapy eliminated the observed difference in biochemical disease recurrence (Fig. 3B), arguing in favor of more aggressive treatment for AA men.
Results from our study suggest that racial differences in genetic and/or physiologic factors may play a role in prostate cancer disease characteristics, progression, and treatment response. It has been demonstrated that several genes involved in the androgen pathway exhibit racial variations. AA men reportedly have a higher density of androgen receptor protein expression in tissues from clinically localized prostate cancer.27 Other studies have indicated that AA men have distinct polymorphisms in the androgen receptor classified as a greater percentage of short CAG repeats, which may be associated with increased androgen sensitivity at any given testosterone hormone level.28, 29 Furthermore, other groups have demonstrated racial differences in the gene cytochrome P450, family 3, subfamily A polypeptide 4 (CYP3A4), which is responsible for testosterone metabolism, and those differences reportedly lead to slower metabolism of testosterone in AA men, resulting in a more sustained androgen signal.30 A study by Paris et al31 demonstrated that, among black men with prostate cancer, 46% were homozygous for the CYP3A4 gene variant compared with only 28% of healthy black men (P < .005). Furthermore, those with the variant allele tended toward higher grade and disease stage, although the difference was not statistically significant. Zeigler-Johnson et al32 also reported that the presence of both the CYP3A4 variant allele and the CYP3A5 variant allele was associated with a higher probability of prostate cancer in AA men but not in Caucasian men. Powell et al reported an association between the CYP3A4 gene variant and disease-free survival among Caucasian men and AA men.33 More recently Roach et al34 determined whether racial variations in the CYP3A4 gene were correlated with the survival of men treated for localized prostate cancer with EBRT with or without ADT using patients from the RTOG 9202 phase 3 randomized trial. Indeed, those authors observed a strong association between race and the CYP3A4 polymorphisms, with 75% of Caucasian men possessing the wild-type allele compared with only 25% of AA men (P < .0001). However, after adjusting for risk group and treatment type, Roach et al reported that CYP3A4 was no longer associated with OS or biochemical disease progression. A limitation to their study was that, because of inadequate tissue samples, the data were underpowered to detect differences in biochemical progression as a result of the CYP3A4 gene polymorphism. In addition, the selection criteria for the RTOG 9202 trial were limited to patients with locally advanced prostate cancer, most of whom received combination therapy because of higher risk disease. Consequently, the results obtained based on this select patient population were in keeping with our findings, which indicated that there was no difference in biochemical disease recurrence between racial groups in the intermediate-risk/high-risk disease category that received combination therapy.
In conclusion, AA men in our patient population presented with more intermediate-risk and high-risk prostate cancer, mainly because of higher initial PSA levels. We observed a difference in biochemical disease recurrence between AA men and Caucasian men, particularly among those who were treated for low-risk prostate cancer. Furthermore, AA race appeared to be an independent negative predictor of FFbF. Finally, among patients who received brachytherapy alone, AA men experienced an increased incidence of biochemical disease recurrence. However, AA men who received more aggressive treatment options achieved BDFS rates comparable to those of Caucasian men. Our findings suggest that AA men are predisposed to a significantly greater risk of biochemical failure, thus warranting more aggressive therapy to achieve effective local control and to decrease their rate of biochemical disease recurrence.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Nelson Stone has ownership of Prologics, LLC, and is a consultant for Nihon-Mediphysics. Richard Stock has received payment as a lecturer for BARD and for Diversified Conference Management Inc.