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Martin G Sanda

Publications and source records attributed to Martin G Sanda.

32 records · Page 2Linked to original sources

Long-term results of three-dimensional conformal adjuvant and salvage radiotherapy after radical prostatectomy.

OBJECTIVES: To evaluate the efficacy and toxicity of three-dimensional conformal radiotherapy (3D-CRT) in the adjuvant and salvage setting after radical prostatectomy (RP). METHODS: From 1986 to 1997, 38 patients received adjuvant 3D-CRT, with a median time from RP to 3D-CRT of 2.8 months, and 57 patients were treated with salvage RT for a rising prostate-specific antigen with a median time to 3D-CRT of 27.7 months. The median radiation dose was 64.8 Gy. The median follow-up from completion of RT was 7.0 years (range 1.0 to 14.2). RESULTS: Overall, the 8-year actuarial rate of biochemical disease-free survival was 40% in all patients. The 8-year biochemical disease-free survival rate was 45% (standard error [SE] 8%) and 30% (SE 7%) for the adjuvant and salvage group, respectively, from RT completion. When measured from the date of RP, the 5 and 8-year biochemical disease-free survival rate for salvage radiotherapy was 58% and 37%, respectively. The corresponding results for adjuvant RT were similar at 53% and 45%. On multivariate analysis, the Gleason score was the only prognostic factor predictive of prostate-specific antigen failure in the salvage group. No prognostic factor was significant in the adjuvant group. The prevalence of major complications after 3D-CRT was low using physician-reported data. CONCLUSIONS: Long-term biochemical control can be achieved in both adjuvant and salvage settings. For patients receiving salvage RT, a Gleason score greater than 7 was predictive of prostate-specific antigen failure. Prospective trials are needed to improve further on these results.

Actuarial Analysis↗

Determinants of long-term sexual health outcome after radical prostatectomy measured by a validated instrument.

PURPOSE: We combined the strengths of previous patient reported studies (that is use of a validated instrument) with the assets of previous single surgeon, physician reported series (that is prospective collection of operative data) by performing a multiple surgeon study to identify demographic and operative determinants of post-prostatectomy sexual health related quality of life outcomes. MATERIALS AND METHODS: Sexual outcome was measured after prostatectomy in 671 prostate cancer cases with a followup of 4 to 52 months treated by any of 7 urologists at a high volume medical center and 112 age matched controls by cross-sectional health related quality of life assessment using the Expanded Prostate Cancer Index Composite validated questionnaire. Multivariable ANCOVA was done to identify the baseline determinants affecting post-prostatectomy sexual health outcomes among 17 clinical and demographic factors. RESULTS: Factors independently associated with better sexual health outcome in patients included younger age (p <0.0001), nerve sparing technique (p <0.0001), time since prostatectomy (p = 0.0001), smaller prostate size (p = 0.003), higher education level (p = 0.02), and higher household income (p = 0.02). Orgasm was achieved at a higher rate than erection. In controls only age (p = 0.0004) and having a partner (p = 0.04) were significantly associated with sexual health. CONCLUSIONS: Larger prostate size adversely affected sexual health outcome after radical prostatectomy independent of all other measured factors. Patient sexual outcome did not differ significantly among surgeons who performed a broad range of such procedures yearly, suggesting that surgical expertise cannot be measured simply by the number of such operations that a surgeon performs. Stratifying patient reported sexual function by the principal determinants of age, nerve sparing and prostate size provides a basis for counseling patients.

Aged↗

Antigen-specific tumor vaccine efficacy in vivo against prostate cancer with low class I MHC requires competent class II MHC.

BACKGROUND: Cancers can escape immune recognition by means of evading class I major histocompatibility complex (MHC) -mediated recognition by cytotoxic T lymphocytes. However, immunization strategies targeting defined tumor-associated antigens have not been extensively characterized in murine prostate cancer models. Therefore, we evaluated antigen-specific, antitumor immunity after antigen-encoding vaccinia immunization against mouse prostate cancer cells expressing a model tumor-associated antigen (beta-galactosidase) and exhibiting partially deficient class I MHC. METHODS AND RESULTS: Low class I MHC expression in beta-galactosidase-expressing D7RM-1 prostate cancer cells was shown by fluorescence activated cell sorting, and deficient class I MHC-mediated antigen presentation was shown in resistance of D7RM-1 to cytolysis by beta-galactosidase-specific cytotoxic T lymphocytes (CTL). Despite partially deficient class I MHC presenting function, immunization with vaccinia encoding beta-galactosidase conferred antigen-specific protection against D7RM-1 cancer. Antigen-specific immunity was recapitulated in beta(2)m knockout mice (with deficient class I MHC and CTL function), confirming that class I MHC antigen presentation was not required for immunity against tumor partially deficient in class I MHC. Conversely, antigen-specific antitumor immunity was abrogated in A(b)beta knockout mice (with deficient class II MHC and helper T cell function), demonstrating a requirement for functional class II MHC. Resistant tumors from the otherwise effectively immunized beta(2)m knockout mice (among which tumor progression had been reduced or delayed) showed reduced target antigen expression, corroborating antigen-specificity (and showing an alternative immune escape mechanism), whereas antigen expression (like tumor growth) was unaffected among A(b)beta knockout mice. CONCLUSION: Our results demonstrate that class I MHC-restricted antigen presentation and CTL activity is neither necessary nor sufficient for antigen-encoding vaccinia immunization to induce protective immunity against class I MHC-low tumors, whereas host class II MHC-mediated antigen presentation facilitates antigen-specific immunity against prostate cancer in vivo. Reduced expression of the target antigen developed rapidly in vivo as an immune escape mechanism for such cancers.

Animals↗

The polycomb group protein EZH2 is involved in progression of prostate cancer.

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.

Biomarkers, Tumor↗

alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer.

CONTEXT: Molecular profiling of prostate cancer has led to the identification of candidate biomarkers and regulatory genes. Discoveries from these genome-scale approaches may have applicability in the analysis of diagnostic prostate specimens. OBJECTIVES: To determine the expression and clinical utility of alpha-methylacyl coenzyme A racemase (AMACR), a gene identified as being overexpressed in prostate cancer by global profiling strategies. DESIGN: Four gene expression data sets from independent DNA microarray analyses were examined to identify genes expressed in prostate cancer (n = 128 specimens). A lead candidate gene, AMACR, was validated at the transcript level by reverse transcriptase polymerase chain reaction (RT-PCR) and at the protein level by immunoblot and immunohistochemical analysis. AMACR levels were examined using prostate cancer tissue microarrays in 342 samples representing different stages of prostate cancer progression. Protein expression was characterized as negative (score = 1), weak (2), moderate (3), or strong (4). Clinical utility of AMACR was evaluated using 94 prostate needle biopsy specimens. MAIN OUTCOME MEASURES: Messenger RNA transcript and protein levels of AMACR; sensitivity and specificity of AMACR as a tissue biomarker for prostate cancer in needle biopsy specimens. RESULTS: Three of 4 independent DNA microarray analyses (n = 128 specimens) revealed significant overexpression of AMACR in prostate cancer (P<.001). AMACR up-regulation in prostate cancer was confirmed by both RT-PCR and immunoblot analysis. Immunohistochemical analysis demonstrated an increased expression of AMACR in malignant prostate epithelia relative to benign epithelia. Tissue microarrays to assess AMACR expression in specimens consisting of benign prostate (n = 108 samples), atrophic prostate (n = 26), prostatic intraepithelial neoplasia (n = 75), localized prostate cancer (n = 116), and metastatic prostate cancer (n = 17) demonstrated mean AMACR protein staining intensity of 1.31 (95% confidence interval, 1.23-1.40), 2.33 (95% CI, 2.13-2.52), 2.67 (95% CI, 2.52-2.81), 3.20 (95% CI, 3.10-3.28), and 2.50 (95% CI, 2.20-2.80), respectively (P<.001). Pairwise comparisons demonstrated significant differences in staining intensity between clinically localized prostate cancer compared with benign prostate tissue, with mean expression scores of 3.2 and 1.3, respectively (mean difference, 1.9; 95% CI, 1.7-2.1; P<.001). Using moderate or strong staining intensity as positive (score = 3 or 4), evaluation of AMACR protein expression in 94 prostate needle biopsy specimens demonstrated 97% sensitivity and 100% specificity for detecting prostate cancer. CONCLUSIONS: AMACR was shown to be overexpressed in prostate cancer using independent experimental methods and prostate cancer specimens. AMACR may be useful in the interpretation of prostate needle biopsy specimens that are diagnostically challenging.

Biomarkers, Tumor↗

Daily prostate targeting using implanted radiopaque markers.

PURPOSE: A system has been implemented for daily localization of the prostate through radiographic localization of implanted markers. This report summarizes an initial trial to establish the accuracy of patient setup via this system. METHODS AND MATERIALS: Before radiotherapy, three radiopaque markers are implanted in the prostate periphery. Reference positions are established from CT data. Before treatment, orthogonal radiographs are acquired. Projected marker positions are extracted semiautomatically from the radiographs and aligned to the reference positions. Computer-controlled couch adjustment is performed, followed by acquisition of a second pair of radiographs to verify prostate position. Ten patients (6 prone, 4 supine) participated in a trial of daily positioning. RESULTS: Three hundred seventy-four fractions were treated using this system. Treatment times were on the order of 30 minutes. Initial prostate position errors (sigma) ranged from 3.1 to 5.8 mm left-right, 4.0 to 10.1 mm anterior-posterior, and 2.6 to 9.0 mm inferior-superior in prone patients. Initial position was more reproducible in supine patients, with errors of 2.8 to 5.0 mm left-right, 1.9 to 3.0 mm anterior-posterior, and 2.6 to 5.3 mm inferior-superior. After prostate localization and adjustment, the position errors were reduced to 1.3 to 3.5 mm left-right, 1.7 to 4.2 mm anterior-posterior, and 1.6 to 4.0 mm inferior-superior in prone patients, and 1.2 to 1.8 mm left-right, 0.9 to 1.8 mm anterior-posterior, and 0.8 to 1.5 mm inferior-superior in supine patients. CONCLUSIONS: Daily targeting of the prostate has been shown to be technically feasible. The implemented system provides the ability to significantly reduce treatment margins for most patients with cancer confined to the prostate. The differences in final position accuracy between prone and supine patients suggest variations in intratreatment prostate movement related to mechanisms of patient positioning.

Dose Fractionation, Radiation↗

Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer.

PURPOSE: Health-related quality-of-life (HRQOL) concerns are pivotal in choosing prostate cancer therapy. However, concurrent HRQOL comparison between brachytherapy, external radiation, radical prostatectomy, and controls is hitherto lacking. HRQOL effects of hormonal adjuvants and of cancer control after therapy also lack prior characterization. PATIENTS AND METHODS: A cross-sectional survey was administered to patients who underwent brachytherapy, external-beam radiation, or radical prostatectomy during 4 years at an academic medical center and to age-matched controls. HRQOL among controls was compared with therapy groups. Comparison between therapy groups was performed using regression models to control covariates. HRQOL effects of cancer progression were evaluated. RESULTS: One thousand fourteen subjects participated. Compared with controls, each therapy group reported bothersome sexual dysfunction; radical prostatectomy was associated with adverse urinary HRQOL; external-beam radiation was associated with adverse bowel HRQOL; and brachytherapy was associated with adverse urinary, bowel, and sexual HRQOL (P < or =.0002 for each). Hormonal adjuvant symptoms were associated with significant impairment (P <.002). More than 1 year after therapy, several HRQOL outcomes were less favorable among subjects after brachytherapy than after external radiation or radical prostatectomy. Progression-free subjects reported better sexual and hormonal HRQOL than subjects with increasing prostate-specific antigen (P <.0001). CONCLUSION: Long-term HRQOL after prostate brachytherapy showed no benefit relative to radical prostatectomy or external-beam radiation and may be less favorable in some domains. Hormonal adjuvants can be associated with significant impairment. Progression-free survival is associated with HRQOL benefits. These findings facilitate patient counseling regarding HRQOL expectations and highlight the need for prospective studies sensitive to urinary irritative and hormonal concerns in addition to incontinence, sexual, and bowel HRQOL domains.

Aged↗

Contemporary diagnosis and management of renal angiomyolipoma.

PURPOSE: We present a comprehensive resource that summarizes contemporary advances relevant to the clinical management of renal angiomyolipoma. MATERIALS AND METHODS: A MEDLINE search was done using the key words angiomyolipoma, hemangioma or lipoma and kidney neoplasm, and therapeutic embolization. References from these articles were reviewed to identify additional relevant source material. We identified 13 series published since 1986 comprising 336 patients as well as 24 reports of therapeutic embolization for angiomyolipoma, comprising 76 patients. To our knowledge we report the largest compilation series to date. RESULTS: Angiomyolipoma is generally benign, although an uncommon subtype (epithelioid angiomyolipoma) may behave more aggressively. Tuberous sclerosis associated angiomyolipoma tends to be larger, multiple and more likely to cause spontaneous hemorrhage than the sporadic entity. Tumors that hemorrhage tend to be larger. Computerized tomography or magnetic resonance is usually sufficient for diagnosis. Biopsy is rarely useful. Primary indications for intervention include symptoms such as pain or bleeding or suspicion of malignancy. Prophylactic intervention is justifiable for large tumors, in females of childbearing age or in patients in whom followup or access to emergency care may be inadequate. Recent advances that have affected management include improved understanding of tuberous sclerosis complex and angiomyolipoma genetics, the identification of molecular markers that facilitate histopathological diagnosis, and the refinement of embolization and partial nephrectomy techniques. CONCLUSIONS: Although some cases of angiomyolipoma may require complete nephrectomy, most can be managed by conservative nephron sparing approaches. Ongoing research into the molecular biology and clinical behavior of angiomyolipoma may improve our ability to manage these lesions.

Angiomyolipoma↗

Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy.

OBJECTIVES: Brachytherapy is increasingly used as a treatment for localized prostate cancer but information regarding long-term, postimplantation, patient-reported sexual health-related quality-of-life (HRQOL) is scant. Neoadjuvant hormonal therapy is commonly administered with brachytherapy, yet its potentially adverse effects on subsequent sexual health have not been described using a validated HRQOL instrument. We used a validated HRQOL survey to characterize the significance of neoadjuvant hormonal therapy and other baseline factors on postimplantation sexual function and impairment. METHODS: A cross-sectional survey using the expanded prostate cancer index composite HRQOL instrument was administered to all 114 localized prostate cancer patients who underwent ultrasound-guided, transperineal brachytherapy during a 4-year period and to 142 age-matched control men. Multivariable models measured the association of baseline factors and covariates with postimplantation sexual HRQOL. RESULTS: Older age (P = 0.01) and neoadjuvant hormonal therapy (P = 0.009) were independently associated with diminished sexual HRQOL after prostate brachytherapy. Among patients younger than 69 years old, 33% reported at least fair sexual function after brachytherapy alone compared with 19% of men after brachytherapy with neoadjuvant hormonal therapy. Of the age-matched control men younger than 69 years old, 78% reported at least fair sexual function. Among patients older than 69 years, 26% reported at least fair sexual function after brachytherapy alone compared with 5% after brachytherapy with neoadjuvant hormonal therapy, and 61% of age-matched controls reported at least fair sexual function. CONCLUSIONS: Patient age and neoadjuvant hormonal therapy are independent, significant determinants of sexual HRQOL after prostate brachytherapy. These factors should be taken into consideration when counseling patients with localized prostate cancer regarding the expected, postimplantation sexual HRQOL outcome.

Age Factors↗

Preoperative parameters for predicting early prostate cancer recurrence after radical prostatectomy.

OBJECTIVES: To determine whether easily measurable prostate biopsy features could complement Gleason score, prostate-specific antigen (PSA), or clinical stage in predicting recurrence-free survival after prostatectomy. Information relating preoperative parameters to recurrence-free survival is needed to counsel patients with newly diagnosed prostate cancer regarding expectations for postprostatectomy cancer control. METHODS: The data of a cohort of 588 consecutive prostatectomy patients (median age 61 years, range 39 to 83) with ascertained preoperative data and up to 4 years of postprostatectomy follow-up were analyzed. Bivariate and multivariate Cox proportional hazards analysis evaluated preoperative factors (clinical stage, PSA, biopsy Gleason score, greatest percentage of a biopsy core involved by cancer [GPC], number of biopsy cores containing cancer, perineural invasion) to identify those relating significantly to recurrence-free survival. Functional forms of these factors were evaluated to optimize accuracy in predicting cancer control. RESULTS: The baseline parameters significantly affecting PSA-free survival included PSA level (P <0.01), biopsy Gleason score (P = 0.04), and GPC (P <0.01). Although clinical stage and perineural invasion had a marginal association with PSA-free survival as univariate factors, this association was not independently significant in multivariable analysis. The multivariate Cox model using PSA, Gleason score, and GPC was highly predictive of PSA free-survival (chi-square = 48.2, P = 0.0001). A set of plots representing these data can be used to identify the risk of early postoperative PSA recurrence on the basis of specific preoperative PSA, Gleason score, and GPC values. CONCLUSIONS: These findings provide a highly significant model and a simple tool for assisting preoperative patient counseling regarding predicted cancer control after radical prostatectomy.

Adult↗

Prostate cancer involving the bladder neck: recurrence-free survival and implications for AJCC staging modification. American Joint Committee on Cancer.

OBJECTIVES: In the American Joint Committee on Cancer (AJCC) TNM staging system, prostate cancer involving the bladder neck after radical prostatectomy is considered pT4 disease, suggesting a high risk of recurrence. The recurrence risk with pathologic invasion of the bladder neck, however, has not been definitively compared with that associated with extra-organ disease. We therefore compared the recurrence risk in cases with bladder neck involvement with that of cases with extraprostatic extension and/or seminal vesicle invasion. METHODS: The study cohort was composed of 1123 men with clinically localized prostate cancer treated with prostatectomy as monotherapy. The preoperative prostate-specific antigen (PSA) level, bladder neck involvement, margin positivity, Gleason score, and other pathologic categories were assessed as covariates contributing to the PSA-recurrence risk in univariate and multivariable models. RESULTS: Bladder neck involvement was found in 60 (5%) of 1123 cases. In univariate analysis, the bladder neck was the site-specific margin with the greatest PSA-recurrence risk of focal involvement (relative risk 1.52, 95% confidence interval [CI] 1.15 to 2.00, P = 0.0030). The PSA-recurrence relative risk with extraprostatic extension was 3.05 (95% CI 2.13 to 4.38, P <0.0001) and with seminal vesicle invasion was 8.59 (95% CI 5.76 to 12.82, P <0.0001). In the multivariable model, the PSA-recurrence risk with bladder neck involvement (relative risk 1.19, 95% CI 0.72 to 1.96, P = 0.5) was not a significant independent prognostic factor. Extraprostatic extension (relative risk 2.25, 95% CI 1.54 to 3.27, P <0.0001) and seminal vesicle invasion (relative risk 4.12, 95% CI 2.57 to 6.62, P <0.0001) were significant independent predictors of PSA recurrence. CONCLUSIONS: Any staging system should be evidence based. The current AJCC system for staging bladder neck involvement, however, is contrary to the available evidence. Reclassification of bladder neck involvement as part of the pT3 category should be considered.

Analysis of Variance↗

Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival.

Huntingtin-interacting protein 1 (HIP1) is a cofactor in clathrin-mediated vesicle trafficking. It was first implicated in cancer biology as part of a chromosomal translocation in leukemia. Here we report that HIP1 is expressed in prostate and colon tumor cells, but not in corresponding benign epithelia. The relationship between HIP1 expression in primary prostate cancer and clinical outcomes was evaluated with tissue microarrays. HIP1 expression was significantly associated with prostate cancer progression and metastasis. Conversely, primary prostate cancers lacking HIP1 expression consistently showed no progression after radical prostatectomy. In addition, the expression of HIP1 was elevated in prostate tumors from the transgenic mouse model of prostate cancer (TRAMP). At the molecular level, expression of a dominant negative mutant of HIP1 led to caspase-9-dependent apoptosis, suggesting that HIP1 is a cellular survival factor. Thus, HIP1 may play a role in tumorigenesis by allowing the survival of precancerous or cancerous cells. HIP1 might accomplish this via regulation of clathrin-mediated trafficking, a fundamental cellular pathway that has not previously been associated with tumorigenesis. HIP1 represents a putative prognostic factor for prostate cancer and a potential therapy target in prostate as well as colon cancers.

Animals↗

Contemporary preoperative parameters predict cancer-free survival after radical prostatectomy: a tool to facilitate treatment decisions.

Prostate specific antigen (PSA) screening has heralded stage migration in prostate cancer toward cancers that may be readily eliminated by primary intervention. We sought to identify contemporary, preprostatectomy measures of cancer severity useful and significant for predicting postprostatectomy, recurrence-free survival. The association of baseline variables clinical variables (age, clinical stage, serum PSA, and race) and prostate biopsy parameters (Gleason score, presence of perineural invasion, number of biopsy cores with cancer, and the greatest percentage of a biopsy core occupied by cancer--GPC) with recurrence-free survival was evaluated by multivariate Cox proportional hazards regression among consecutive patients that underwent radical prostatectomy as primary therapy between 1994 and 2002. Tables were generated depicting expected 5-year recurrence-free survival after prostatectomy. From 1414 patients, 183 developed biochemical recurrence, 8 died from prostate cancer, and 31 died of all causes. Multivariable Cox regression found that clinical stage, PSA, Gleason score, and the greatest percentage of a biopsy core involved by cancer (GPC), were each significant determinants of post-prostatectomy, PSA recurrence-free survival (P < 0.05 for each). Gleason score and GPC were also significantly associated with clinical recurrence-free survival and cancer death, whereas other biopsy parameters and PSA were not. The amount of cancer in a biopsy core is a significant predictor of recurrence-free survival after prostatectomy, and is a simple clinical measure that complements baseline PSA, and Gleason score in predicting outcome. Tabulated 5-year PSA-free survival outcomes, stratified by these preoperative parameters, provide a basis for preoperative counseling of patients regarding postprostatectomy cancer control expectations.

Adenocarcinoma↗

Postprostatectomy cancer-free survival of African Americans is similar to non-African Americans after adjustment for baseline cancer severity.

African American men with localized prostate cancer are less likely than White men to receive a radical prostatectomy. This disparity may exist because African American men have prostate cancers that are more biologically aggressive. We investigated if similar stage cancers of African American men and White men show differences in cancer control after radical prostatectomy. Men with localized prostate cancer who underwent radical prostatectomy during a 6-yr period were stratified by race, and time to prostate-specific antigen recurrence was measured. We used Chi-square and t-tests to compare baseline clinical and pathological factors based on race. Cox proportional hazards model was used to determine effects of race on cancer control while controlling for baseline measures of cancer severity. There were 1,228 cases evaluated. At baseline, African American men were treated at a significantly younger age than White men (P = 0.0027) but showed no significant difference in prostate-specific antigen PSA, Gleason score, pathology stage, maximum tumor dimension, and surgical margin status. Multivariable Cox proportional hazards analysis controlling for cancer severity at prostatectomy revealed that cancer-free survival was not worse among African Americans compared to other subjects (P = 0.16). The responsiveness of prostate cancers among African American men to radical prostatectomy was similar to White men of similar stage and grade. Early detection in African American men may facilitate diagnosis of cancer amenable to prostatectomy. Studies are needed to evaluate the possible interaction of prostate cancer stage and grade shift in African American men and the disease free survival in this population.

Black or African American↗