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Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P, Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men.

Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.

BACKGROUND: Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. OBJECTIVE: To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n = 150) or undetectable (n = 327) based on post-RP PSA nadir ≥0.1 ng/ml. OUTCOME MEASUREMENTS AND STATISITICAL ANALYSIS: Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. RESULTS AND LIMITATIONS: The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p = 0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p = 0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p = 0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p < 0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p = 0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. CONCLUSIONS: Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. PATIENT SUMMARY: Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

222 Background: AA men often present with more aggressive prostate cancer and are less likely to receive treatment, negatively affecting quality-of-life and overall survival (OS). Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Data from the PROCEED registry showed that OS for AA pts treated with SIP-T was 9.3 mo longer than OS for Caucasian pts. In a prior subgroup analysis of Phase III data, AA pts realized a 30.7-mo difference in OS with SIP-T vs. placebo (PBO). We calculated the NNTB to further interpret the OS benefit in AA pts. Methods: Data were pooled from 3 Phase III mCRPC SIP-T trials (D9901, D9902A, and IMPACT). The absolute risk reduction (ARR) is calculated from Kaplan-Meier estimates at 12-, 24-, and 36-mo for all SIP-T subjects, and an AA cohort, receiving ≥1 infusion. NNTB, the inverse of the ARR, represents the number of pts needed to be treated with SIP-T to prevent 1 additional death compared to PBO. All NNTB values are rounded up. Results: Of the 737 pooled mCRPC pts enrolled, 488 men were randomized to SIP-T (n=33 AA), and 249 to PBO. Baseline clinical characteristics between the SIP-T and PBO groups were well balanced; however, compared to overall SIP-T and PBO, AA SIP-T pts were more likely to have received prior chemotherapy, lower hemoglobin, and better performance status. The NNTB at 12-mo was the same (13) for both the pooled SIP-T and AA treated cohort. At 24-mo, the NNTB values were 10 for pooled and 5 for AA. At 36-mo, an NNTB of 8 (pooled) and 3 (AA) SIP-T treatments prevented 1 additional death (Table). Conclusions: This NNTB analysis shows a favorable survival benefit for AA men treated with SIP-T and all treated SIP-T subjects. NNTB values declined over 3-years, suggesting durability of clinical benefit with SIP-T, and that it may address a known survival disparity in AA with prostate cancer. Studies with larger sample sizes may confirm if AA pts derive a greater OS benefit from SIP-T. Clinical trial information: NCT00065442. [Table: see text]

BACKGROUND Prostate cancer is a complex multi-allelic disease and the most common malignancy in men. The incidence of prostate cancer in African American men is more than twice as high as that of any other race. Despite the high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. Although genomic copy number variations (CNVs) have been detected in prostate tumors, this is the first study describing germline CNVs in African American hereditary prostate cancer families. METHODS Ten high-risk African American families with three or more affected individuals and with an early age of onset were recruited. From these families, 37 individuals, including 23 affected males, and 14 unaffected males, were selected for CNV analysis. Array comparative genomic hybridization was used to characterize germline CNVs unique to African American men with hereditary prostate cancer. RESULTS Through common aberration analysis in affected family members; novel CNVs were identified at chromosomes 1p36.13 and 16q23.3. Differential analysis comparing affected and unaffected family members identified 9.4 kb duplication on chromosome 14q32.33 which segregate with prostate cancer patients in these high-risk families. CONCLUSIONS The duplication at 14q32.33 encompasses IGHG3 gene which has been shown to have both significant gains in copy number as well as overexpression in prostate tumors in African Americans. These CNVs may represent a component of genetic predisposition which contributes to the high prevalence and mortality of prostate cancer in African American men. Prostate 73: 614–623, 2013. © 2012 Wiley Periodicals, Inc.

BACKGROUND In the United States, incidence of prostate cancer in African American men is more than twice than that of any other race. Thus far, numerous disease susceptibility loci have been identified for this cancer but definite locus-specific information is not yet established due to the tremendous amount of genetic and disease heterogeneity; additionally, despite high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. METHODS In order to identify the susceptible locus (loci) for prostate cancer in African Americans, we have performed linkage analyses on members of 15 large high-risk families. Specifically, these families were recruited from Louisiana and represent a uniquely admixed African American population exclusive to Southern Louisiana. In addition to geographical constraints, these families were clinically homogeneous creating a well-characterized collection of large pedigrees. The families were genotyped with Illumina Infinium II SNP HumanLinkage-12 panel and extensive demographic and clinical information was documented from the hospital pathological reports and family interviews. RESULTS We identified two novel regions, 12q24 and 2p16, with suggestive evidence of linkage under the dominant model of inheritance. CONCLUSIONS This is the first time that chromosome 12q24 (HLOD = 2.21) and 2p16 (HLOD = 1.97) has been shown to be associated with prostate cancer in high-risk African American families. These results provide insight to prostate cancer in an exceptional, well-characterized African American population, and illustrate the significance of utilizing large unique, but homogenous pedigrees. Prostate 72:938–947, 2012. © 2011 Wiley Periodicals, Inc.

Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) compared to European American men (EAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes. Methods: We obtained deidentified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n=313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status, was applied to the prospective cohort for race prediction. Hallmarks of cancer, immune modulators, AR activity, and prognostic gene signatures available in the GRID were used to gain a molecular perspective on PCa racial disparities. Results: The race model was independently validated in the subset of men with known race and had an AUC of 0.98 for differentiating AAM from EAM. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM, and 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively, compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, NF-KB mediated tumor necrosis factor (TNF) activity, and interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair glycolysis scores compared to EAM. Conclusion: Known and predicted AAM were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair, and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities. Citation Format: Walter Rayford, Jennifer Jordan, Mandeep Takhar, Mohammed Alshalalfa, Darlene Dai, Nicholas Erho, Mark D. Greenberger, Elai Davicioni. Genomic variations associated with prostate cancer in large cohort of African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B098.

Objective: Prostate cancer (PCa) patients often must decide between several treatment modalities considered equally efficacious, but associated with different benefits and side-effects. For some, the decision-making process can be difficult, but little is known about patient characteristics and cognitive processes that might influence the difficulty of such decisions. This study investigated the roles of dispositional optimism and self-efficacy in PCa treatment decision-making difficulty and satisfaction. Methods: One hundred and twenty-five patients with clinically localized PCa completed a mail-in paper-and-pencil survey after they had made their treatment decision, but prior to treatment. Results: After adjusting for covariates, optimism and treatment decision-making self-efficacy were associated with less difficulty and greater satisfaction with the treatment decision-making process. Effects of optimism on difficulty and satisfaction were partially mediated by self-efficacy for making the treatment decision. Conclusions: Men with PCa and who are low in optimism may be at greater risk for treatment decision-making difficulty and lack of treatment decision-making satisfaction, in part, because they have lower confidence in their ability to make the decision compared with those who are more optimistic. As self-efficacy perceptions are modifiable, consideration should be given to including self-efficacy enhancing components as part of PCa treatment decision-making interventions. Copyright © 2008 John Wiley & Sons, Ltd.

Prostate cancer is the most common cancer in men in the United States. This is a complex disease with high heterogeneity and the exact causes are unknown in population-specific samples. Family history is a primary risk factor irrespective of race. Identifying prostate cancer families with multiple affected cancer cases is challenging. Herein we document recruitment techniques and present prostate cancer clinical factors described in a cohort of African Americans and Caucasians with or without a strong family history. A total of 521 prostate cancer patients (241 African Americans and 280 Caucasians) were identified using a novel cooperative methodology involving a combination of treating physicians and tumor registries. Higher prostate-specific antigen (PSA, P=0.0269) was found in familial cases as compared to sporadic cases in African-American men. In addition, PSA values for familial cases were higher (P=0.0093) in African-American as compared to Caucasian men. No differences were detected in Gleason score values in either race, regardless of family history. These findings remained the same after adjustment was made for age at diagnosis. In conclusion, methodologies for cohort acquisition, and clinical characteristics, are described for men with and without a family history of prostate cancer using both Caucasian and African-American populations.

s b l A enign prostatic hyperplasia (BPH) is the most common condition affecting men of all ethicities who are older than 50 years of age.1 The revalence of BPH increases with age, affecting ore than 50% of men aged 60 years and 90% of hose aged 80 years.2,3 The underlying prostatic yperplasia results in an increase in prostate volme (PV), which can be associated with obstrucive and irritative lower urinary tract symptoms LUTS). Evidence from a large number of epidemilogic studies and placebo arms of clinical trials as demonstrated that BPH is a progressive disease n many men, characterized by increasing prostatic nlargement, worsening symptoms, and a heightned risk of acute urinary retention (AUR) and equiring BPH-related surgical intervention.4 The greater prevalence of prostate cancer in cerain ethnic groups such as African-American men as received worthy attention; however, increasing vidence has shown that the prevalence and natual history of BPH may differ in this ethnic group. he aim of this review was to examine the studies

Free prostate specific antigen, complexed PSA and human glandular kallikrein 2 have independently been tested against the gold standard of total PSA for prostate cancer screening in largely white populations. With the incidence of prostate cancer much higher in black men, we sought to evaluate these markers simultaneously in a predominantly black population.A total of 138 men, of whom 108 were black, underwent ultrasound guided biopsy of the prostate for tPSA levels greater than 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn before biopsy and analyzed for tPSA, fPSA, cPSA and hK2 concentrations using standard methods (hK2 assay is for research use only, not for use in diagnostic procedures). The areas under the receiver operator characteristic curves were determined for each marker as well as biomarker combinations. Additionally, each parameter's specificity, positive and negative predictive values, and theoretical screening efficiency were assessed at or above the 95% sensitivity level.A total of 43 (31.1%) men had prostate cancer by biopsy. While the AUC for %fPSA was statistically the highest (0.822, p0.001), cPSA offered the highest specificity (31.6%) and positive predictive power (31.7%) of any of the tested biomarkers at comparable sensitivity (greater than 95%). The calculated efficiency of cPSA (51.4%) was also higher than the other markers. Nearly 20% of biopsies would be avoided using cPSA vs standard tPSA screening methods.Comparing the major PSA isoforms and hK2, cPSA alone appears to offer superior diagnostic discrimination for cancer detection in a predominantly black population.

The serum transferrin receptor (sTfR) is a sensitive indicator of iron-deficiency erythropoiesis that is not affected by inflammation. Concentrations of this molecule are inversely correlated with body-iron stores, and increased body-iron stores are associated with an increased risk of cancer of the liver and lungs. However, an association between iron status as assessed on the basis of sTfR and prostate cancer has not been previously investigated. We measured sTfR and serum ferritin by means of an enzyme immunoassay in 27 men with newly diagnosed, untreated prostate cancer and in 72 controls. Our study population ranged in age from 38 to 78 years. The mean serum ferritin concentration in men with prostate cancer was 44.8% lower than that in men without this tumor ( P.05). In contrast, the mean values of sTfR and sTfR/log serum ferritin were 32% and 60% higher, respectively, in men with prostate cancer than in those without this tumor ( P.05). Differences between groups persisted after we took into account inflammation (alpha 1-acid glycoprotein1 g/L, C-reactive protein10 mg/L; P.05). Among the entire study population and among men without inflammation, a higher percentage of subjects (29%-31%) than of controls (14%-22%) had sTfR values greater than 8 mg/L, suggestive of iron-deficiency erythropoiesis ( P.05). The odds ratios for men with prostate cancer to have sTfR values of less than 2.9 mg/L (suggestive of increased body-iron stores) was 0, compared with 1.745 to 3.65 for the same men to have sTfR values greater than 8 mg/L. sTfR was negatively correlated with log ferritin ( r = -.422, P.05) but did not correlate with tissue inflammation, tumor stage, or acute-phase proteins. It appears that prostate cancer is not associated with increased body-iron stores.

BACKGROUND Establishment of human prostate cancer cell lines is essential to advance our understanding of complex processes associated with the initiation and progression of the disease. In the present study, we report the establishment of a primary African-American prostate cancer cell line (E006AA) as well as its associated stromal cells (S006AA). METHODS E006AA cell line was established as a spontaneously immortalized cells from a patient with a clinically localized prostate cancer. Extensive characterization of the cells was accomplished using androgen-dependent growth and sensitivity assays, Western analyses, RT-PCR/real-time PCR, cytogenetic analyses, and tumorigenicity in nude mice. RESULTS E006AA cell line shows androgen-dependent growth, expresses PSA and the androgen receptor (AR) with 26 CAG repeats in exon 1 of AR. Cytogenetic analyses revealed a hypertriploid karyotype with additional numerical gains in chromosomes 5, 6, 8, 10, 17, 20, 21 and a marker chromosome of unknown origin as well as structural abnormalities in chromosomes 4, 5, 8, 9, 11–14, 18, and 20. This cell line is not tumorigenic in nude mice. S006AA cell line, isolated from the same tumor specimen, also expresses AR and shows the morphological characteristics of smooth muscle cells of prostatic stroma. CONCLUSIONS These cell lines are the first available primary epithelial and stromal cells derived from an African-American patient with organ-confined prostate cancer and in conjunction with other established cell lines, could provide an in vitro model system to investigate early transforming events in prostate cancer. © 2004 Wiley-Liss, Inc.

Objectives To determine the mean and median complexed prostate-specific antigen (cPSA) levels in a predominantly African-American population and to explore whether differences in cPSA exist between the races. Differences in total PSA (tPSA) levels between age-matched African-American and white men have been reported by several groups. Age-specific cPSA levels, however, have not been thoroughly evaluated and reported among African-American populations. Methods We prospectively evaluated the serum cPSA, tPSA, and percent cPSA levels by the Bayer Immuno 1 assay as a function of age among 1755 African-American and 630 white men in southern Louisiana presenting to a prostate cancer screening program. All men had a normal digital rectal examination or biopsy-proven benign pathologic findings. The intragroup and intergroup statistical analyses were carried out for each decade of age. Results The median cPSA level for African-American men aged 40 to 49, 50 to 59, and 60 to 69 years old was 0.45, 0.61, and 0.84 ng/mL, respectively. These did not differ significantly from those of age-matched white men. Also, no difference was found in the mean or median tPSA between the races. The percent cPSA values showed a trend for lower levels in African Americans. Conclusions These findings suggest that no significant difference exists between cPSA or tPSA levels in African-American and white men without prostate cancer. Genetic and epigenetic factors distinct to this region may account for this observation and thus need further evaluation.

Purpose: We evaluated the effects of the over expression of p27Kip1, a cyclin dependent kinase inhibitor and tumor suppressor protein, on the 786–0 human renal carcinoma cell line.Materials and Methods: The recombinant adenovirus Adp27Kip1 was evaluated for the induction of p27 protein expression in 786–0 renal carcinoma cells. Expression time and optimal vector concentration were determined. Growth curve studies, cell cycle analysis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling were done to determine the effects of p27Kip1 on the cell cycle. Cyclin dependent protein kinase (Cdk) inhibitor (CDKI) activity assays were done to determine the expression/activities of Cdks and Western blot analysis was performed to determine the presence of CDKIs and other cell cycle regulator proteins. Nude mouse xenografts were established to demonstrate the in vivo efficacy of Adp27Kip1.Results: p27Kip1 protein expression was detected within 12 hours after Adp27Kip1 infection...

Locally secreted growth factors and neuropeptides may play an important role in sustaining the growth of hormone-independent prostate cancer. Our previous studies have shown that calcitonin-like immunoreactive peptide (CTI) is secreted by primary prostate cells in culture, and its secretion from malignant prostate cells is significantly higher than benign cells. Exogenously added calcitonin (CT) induces DNA synthesis in serum-starved prostate cancer LNCaP and PC-3M cells. Present studies extended these findings by cloning cDNAs for CT and CT receptor (CT-R) from prostate cancer cells and studying the expression of CT and CT-R mRNA in prostate cancer cell lines and primary prostate tumor specimens. The results have shown that PC-3 cells expressed CT, and not CT-R, mRNA, whereas CT-R, but not CT, mRNA was expressed by LNCaP cells. Conditioned media from PC-3 cells induced DNA synthesis of LNCaP cells, and this mitogenic response was abolished by anti-CT serum. Highly aggressive PC-3M cells co-expressed CT and CT-R mRNAs. CT also induced a twofold increase in DNA synthesis of primary prostate cells and anti-CT serum caused a 56% decline. In-situ hybridization histochemistry of archival prostate specimens has selectively localized CT and CT-R mRNA in basal epithelium of benign and low grade PC specimens, and these mRNAs were not detected in either luminal epithelium or stroma. In contrast, CT and CT-R mRNA were detected throughout the luminal epithelium of moderate and high-grade PC specimens. Most epithelial cells of low and moderately differentiated tumors expressed either CT or CT-R mRNA, suggesting that CT may serve as a paracrine factor. In contrast, CT and CT-R mRNAs were co-expressed by most tumor cells in advanced PC specimens. The cells expressing CT-R mRNA in primary tumors also co-expressed PCNA. These results, when combined with mitogenic actions of CT on primary prostate cells as well as PC cell lines, strongly support the role for CT in sustaining the growth of cancer cells.

Purpose: Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with von Hippel-Lindau disease and hereditary papillary renal cancer.Materials and Methods: Patients with von Hippel-Lindau disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the large renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.Results: The 3 cm. surgical threshold was evaluated in 52 patients with von Hippel-Lindau disease (group 1) at a median followup of 60 months (range...

Purpose: In patients with von Hippel-Lindau disease multiple bilateral adrenal pheochromocytoma can develop, which has traditionally been treated with adrenalectomy. Partial adrenalectomy can preserve normal adrenal function and avoid the morbidity associated with medical adrenal replacement. We demonstrate whether adrenal function could be preserved by partial adrenalectomy in patients with von Hippel-Lindau disease.Materials and Methods: From 1995 to 1998, 13 consecutive von Hippel-Lindau disease patients with pheochromocytoma underwent 14 partial and 6 complete unilateral adrenalectomies. Function of residual normal adrenal and recurrence of adrenal pheochromocytoma were determined at followup.Results: Of the patients 2 had undergone unilateral adrenalectomy and 1 had undergone complete and partial adrenalectomy previously. Following surgery residual normal adrenal tissue consisted of 1 partial adrenal in 3 patients, bilateral partial adrenal in 5, partial and complete adrenal gland in 1, 1 com...

To evaluate the use of dual-phase three-dimensional magnetic resonance (MR) angiography in the preoperative staging of renal cancer.MR angiography was performed in 18 patients before performance of partial (n = 7), radical (n = 10), or laparoscopic (n = 1) nephrectomy to treat renal cancer. Dynamic, three-dimensional MR angiograms were obtained with gadoteridol enhancement, breath holding, and a three-dimensional spoiled gradient-echo sequence. Images were obtained at 15-second intervals to achieve opacification of arteries and veins. Source, maximum intensity projection, and multiplanar reconstruction images were evaluated. Imaging results were compared with surgical findings.Renal arterial phase MR angiograms depicted 30 of 31 (97%) surgically confirmed renal arteries, with one false-positive result (an artery that arose from an early-branching single main renal artery, interpreted as a separate accessory artery). Renal venous phase MR angiograms depicted all seven instances of renal vein involvement, including extension to the inferior vena cava in two patients. Collateral vessels around the tumor, including prominent gonadal veins in three patients, were demonstrated. Additional findings included adenopathy and adrenal and pulmonary metastases.Dual-phase MR angiography of the kidney may be a useful technique in depicting renal vessels before nephrectomy.

BACKGROUND Recent evidence suggests that muscarinic receptors induce mitogenesis in cells capable of undergoing cell proliferation. Human prostate gland is innervated by the autonomic nervous system and muscarinic receptors have been localized in the prostate gland. METHODS Effects of carbachol (a stable analog of acetyl choline) on DNA synthesis of LNCaP cells (a human prostate cancer cell line) and primary prostate cells was examined. The DNA synthesis in the cultured cells was assessed using techniques of 3H-thymidine incorporation and bromodeoxyuridine (BrdU) incorporation immunocytochemistry. RESULTS Carbachol induced a significant increase in BrdU- and 3H-thymidine incorporation of LNCaP cells. The effect of carbachol was completely reversed by atropine, a selective muscarinic antagonist. Subtypes of muscarinic receptors mediating carbachol-induced DNA synthesis were identified using selective receptor subtype antagonists. Pirenzepamine and gallamine did not affect carbachol action on LNCaP cells but diphenylpyralamine, an M3 receptor antagonist, completely blocked carbachol-induced DNA synthesis. Carbachol also stimulated DNA synthesis in primary prostate cells. Prostate carcinoma (PC)-derived primary prostate cells displayed a dramatically greater response to carbachol (a ten-fold increase in DNA synthesis) as compared to benign prostate hypertrophy (BPH)-derived cells (a two-fold increase in DNA synthesis). CONCLUSIONS M3 receptors stimulate the proliferation of LNCaP cells, BPH-derived and PC-derived primary prostate cells. A dramatically higher response to carbachol by PC-derived prostate cells suggests that M3 receptors may be up-regulated in PC. M3 receptors may play a significant role in PC tumor growth and androgen-independent tumor progression. Prostate 30:160–166, 1997. © 1997 Wiley-Liss, Inc.

Loss of p27Kip1, a cyclin-dependent kinase inhibitor, is observed in aggressive prostate cancers. We demonstrated that intratumoral injections of recombinant adenovirus overexpressing p27Kip1 (Adp27) reduced the growth of prostate cancer xenografts in nude mice. Presently, we studied the mechanism(s) of cell death induced by Adp27 in prostate cancer cell line PC-3. Cells were infected with Adp27 and compared with those infected by empty virus or were non-infected. Cell cycle and typical markers of apoptosis were analyzed by flow cytometry in the presence of the following reagents: cycloheximide, pan-caspase inhibitor ZVAD-fmk, neutralizing anti-TNFR1, and anti-TNFR2. Overexpression of p27Kip1 protein and cell cycle arrest were noted within 24 h after Adp27-infection. Sub-G1 fraction, chromatin margination, and phosphatidylserine exposure were evident by the third day of treatment. Cycloheximide elevated sub-G1 fraction in Adp27-infected cells by threefold, while ZVAD-fmk reduced sub-G1 to control levels. Caspase-dependent apoptosis occurred in a third of the population, while two-thirds were ZVAD-fmk insensitive but TUNEL-positive. Flow cytometry showed increased expression of TNFR1 and TNFR2 in Adp27-infected cells. Neutralizing anti-TNFR1 decreased TUNEL-positive score, while anti-TNFR2 did not affect p27Kip1-induced apoptosis. This is the first report showing that p27Kip1 induces caspase-dependent and -independent stages of cell death that may involve TNF-signaling through TNFR1.

BACKGROUND: Nonmedical factors may modify the biological risk of prostate cancer (PCa) and contribute to the differential use of early detection; curative care; and, ultimately, greater racial disparities in PCa mortality. In this study, the authors examined patients' usual source of care, continuity of care, and mistrust of physicians and their association with racial differences in PCa screening. METHODS: Study nurses conducted in-home interviews of 1031 African-American men and Caucasian-American men aged ≥50 years in North Carolina and Louisiana within weeks of their PCa diagnosis. Medical records were abstracted, and the data were used to conduct bivariate and multivariate analyses. RESULTS: Compared with African Americans, Caucasian Americans exhibited higher physician trust scores and a greater likelihood of reporting a physician office as their usual source of care, seeing the same physician at regular medical encounters, and historically using any PCa screening. Seeing the same physician for regular care was associated with greater trust and screening use. Men who reported their usual source of care as a physician office, hospital clinic, or Veterans Administration facility were more likely to report prior PCa screening than other men. In multivariate regression analysis, seeing the same provider remained associated with prior screening use, whereas both race and trust lost their association with prior screening. CONCLUSIONS: The current results indicated that systems factors, including those that differ among different sources of care and those associated with the continuity of care, may provide tangible targets to address disparities in the use of PCa early detection, may attenuate racial differences in PCa screening use, and may contribute to reduced racial disparities in PCa mortality. Cancer 2009. Published 2009 by the American Cancer Society.

Disparities based on race and ethnicity still exist in the US healthcare system. Such disparities are reflected in the diagnosis and treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) among African Americans and Latinos. The prevalence of risk factors for BPH and LUTS and symptom progression are higher in these populations, but treatment is less common. African American men and Latinos frequently have other serious comorbidities, such as cardiovascular disease, diabetes mellitus, and metabolic syndrome. Health plan constraints and variabilities, race/ethnicity, socioeconomic status, language, healthcare-seeking behaviors, and cultural beliefs and practices influence the treatment of BPH and LUTS, oftentimes resulting in unequal access to care or inferior quality of care. The provision of nondiscriminatory treatment poses a challenge to clinicians that can partially be addressed by improving the cultural competence of practitioners in minority communities. An awareness of the customs and healing traditions of African Americans and Latinos may also facilitate culturally appropriate care and improve outcomes, and the participation of clinicians in continuing education/professional development programs to increase knowledge about minority health issues is recommended. Conversely, improving the health literacy of African American and Latino patients with BPH and LUTS can help avoid ineffective nontraditional methods of treatment.

Prostate specific antigen (PSA) is frequently used for prostate cancer (PCa) screening, but serum levels are also increased by prostate inflammation. Elevations in serum levels of alpha1-antitrypsin (ATT), a marker of inflammation, in cancer patients are well documented. However, an association between PSA and ATT has never been investigated. The authors, therefore, measured serum acute phase proteins (APPs) ATT, alpha1-acid glycoprotein, C-reactive protein, and alpha1-antichymotrypsin in 174 men without and 34 with newly diagnosed untreated PCa (38-80 years old). As expected, men with PCa had higher mean PSA levels than those without PCa (P0.00001). Men with PCa and those without PCa but with PSA2 ng/mL (n = 68) had significantly higher ATT concentrations than those without these conditions (n = 106) (mean +/- SEM g/L): 1.94+/-0.083, 1.92+/-0.066, 1.25+/-0.043, respectively; p0.005). Interestingly, African-American men without PCa (n=111) had higher ATT levels than Caucasian men (n=63) (1.565+/-0.045 g/l versus 1.395+/-0.056 g/l; p0.005); and differences persisted in men with PSA2 ng/ml (2.094+/-0.07 g/l versus 1.593 for all0.095 g/l; p0.0002). There were no differences among groups in the levels of other APP. ATT showed the strongest correlation with PSA (r = 0.346 to 0.395; p0.001) than any other APP (ror =0.245). Our data suggest that men with PCa have higher ATT levels than those without PCa; and African-American men without PCa have higher ATT levels than Caucasian men. The possible implications of elevated ATT levels in African-American men on the risk of PCa are discussed.

Aim: To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation, migration and invasion, as well as its effect on the expression of urokinase plasmonogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells. In addition, we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily. Methods: We employed Western blot analysis, phospho-specific antibodies, cell proliferation assay, reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells. Results: Saposin C, in a cell type-specific manner, upregulates uPA/uPAR and immediate early gene c-Jun expression, stimulates cell proliferation, migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells. Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies. Conclusion: Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells. These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer. (Asian J Androl 2005 Jun; 7: 147–158)

To examine age, racial, and regional differences in serum PSA levels among men in Louisiana.From January 1, 2001 through December 31, 2001, there were 10,012 serum PSA tests performed at Louisiana Health Care Services Division (HCSD) hospitals. Manual and electronic data mining were performed to select the earliest PSA value in those men who had multiple determinations. This PSA data file was then linked with those of the Louisiana Tumor Registry and from HCSD pathology laboratories, all matched cases were removed. Men younger than 40 years and older than 79 years were excluded from this study. The final data file contained 7,258 men, of whom 4,244 were African-Americans and 3,014 were Caucasians. Comparisons of median and geometric mean serum PSA level were made between and among races for each age-decade as well as among the hospitals to assess for racial and regional differences.Median PSA levels were statistically significantly higher in African-American men than in Caucasian men for each age group (por = 0.0002). The median PSA (ng/ml) for African-American men was 0.7, 0.9, 1.3, and 2.3 for age-decades 40-49, 50-59, 60-69, and 70-79, respectively, whereas for Caucasian men the median PSA levels were 0.8, 1.2, and 1.6 for age-decades 50-59, 60-69, and 70-79, respectively. Nonparametric analysis of variance did not demonstrate a regional pattern of PSA values among the hospitals.In a first statewide analysis of age and racial differences of serum PSA levels, African-American men without prostate cancer had significantly higher serum PSA levels than their age-matched Caucasian male counterparts. Additionally, there were no regional patterns of PSA values among the racial groups.

Purpose: Artificial intelligence based pattern recognition algorithms have been developed and successfully used to analyze complex serum proteomic data streams generated by surface enhanced, laser desorption ionization time-of-flight mass spectroscopy. In the current study we used a high performance, hybrid quadrupole time-of-flight mass spectrometer to generate discriminatory serum proteomic profiles to determine if this technology could be used to determine the need for prostate biopsy in men with elevated prostate specific antigen (PSA). Materials and Methods: Serum samples were collected from 154 men with serum PSA 2.5 to 15.0 ng/ml and/or abnormal digital rectal examination prior to transrectal ultrasound guided biopsy. Serum samples were applied to WCX2 (weak cation exchange protein chip) Protein Arrays (Ciphergen Biosystems, Fremont, California) by a Biomek 2000 robotic liquid handler (Beckman-Coulter, Chaska, Minnesota) and low molecular weight (less than 20 kDa) proteomic patterns were generated with an API QSTAR Pulsar i LC/MS/MS System (Applied Biosystems, Framingham, Massachusetts). High resolution mass spectra were analyzed with a pattern recognition bioinformatics tool, that is Proteome Quest beta version 1.0 (Correlogic Systems, Inc., Bethesda, Maryland), in an attempt to identify and discover key discriminating ion signatures. Serum samples from 63 men (2 or more negative prostate biopsies in 23, 1 negative biopsy in 10 and biopsy detected prostate cancer [CaP] in 30) were used to train the diagnostic algorithm. The remaining 91 samples, including 28 of prostate cancer and 63 of 1 or more negative biopsies, were analyzed in blinded fashion. Results: The most discriminatory model was found using the WCX2 chip. Testing the remaining 91 men with this model yielded 100% sensitivity and 67% specificity. In other words, if the proteomic pattern had been used to determine the need for prostate biopsy in this cohort of men with PSA between 2.5 and 15.0 ng/ml, 67% (42 of 63) with negative biopsies would have avoided unnecessary biopsy, while no cancers would have been missed. Conclusions: Our data demonstrate that high resolution mass spectroscopy can generate serum proteomic patterns that discriminate men with elevated PSA due to benign processes from men with CaP even when PSA is within the diagnostic gray zone. We are currently expanding the testing set to determine the reliability of this new technology to decrease unnecessary prostate biopsies without compromising the detection of curable CaP.

Elevated body iron stores (serum ferritin >300 microg/L, transferrin saturation TS >50%) are associated with increased risk of liver and lung cancers. To determine whether such association also exists for prostate cancer (PC), we measured serum ferritin, serum iron, total iron-binding capacity (TIBC), and TS in serum samples from 34 men with newly diagnosed, untreated PC and 84 healthy men, ranging in age from 49-78 years. In contrast with other malignancies, men with PC had significantly lower mean concentrations of serum ferritin (156 microg/L) and TS (24.35%) than those without PC (ferritin, 245 microg/L; TS, 31.98%) (p300 microg/L) and TS (50%) (p

Recent studies have reported enhanced prostate cancer detection in Caucasians with serum human glandular kallikrein 2 (hK2) in combination with total- (tPSA) and free-prostate-specific antigen (fPSA). The purpose of this study is to validate these findings in an African-American patient cohort. A total of 137 African-American men were found by routine screening to have tPSA levels above 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn prior to biopsy of the prostate and Hybritech PSA, FPSA and hK2 (for research use only, not for use in diagnostic procedures) concentrations were determined on Beckman Coulter's Access immunoanalyzer. These independent variables and the ratios of percent fPSA (%fPSA), hK2/tPSA, hK2/fPSA, and hK2*tPSA/fPSA were compared between cancer and non-cancer groups. In all, 49 of 137 men had prostate cancer. hK2 and its calculated ratios outperformed tPSA on receiver operator characteristic (ROC) analysis, but %fPSA had statistically the highest area under the curve (AUC) at 0.801. When restricting the analysis to only the tPSA range of 4.0-10 ng/ml, hK2/fPSA yielded the highest AUC (0.721). The ratio of hK2/fPSA was also found to increase the positive predictive value (PPV) of the %fPSA ranges less than 10 and 10-25%. %fPSA offered the best performance and highest specificity in prostate cancer detection in African-American males over the entire range of tPSA. hK2/fPSA may offer modest improvement in the tPSA range of 4.0-10 ng/ml. Furthermore, hK2/fPSA can enhance the PPV of low %fPSA values. Therefore, the use of multiple biomarkers may ultimately increase the specificity of prostate cancer screening in African-American men.

Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with “aggressive” clinicopathological features, was associated with an elevated risk of recurrence ( P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence ( P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

Objectives Complexed prostate-specific antigen (cPSA) has been shown to improve the differentiation of benign and malignant disease compared with total PSA (tPSA) in studies evaluating predominantly white populations of men. We sought to evaluate the diagnostic performance of cPSA relative to tPSA in a population of African-American men. Methods Consecutive African-American men scheduled for prostate biopsy were enrolled prospectively at the Louisiana State University Medical Center, New Orleans. Serum was collected before the biopsy procedure and tested with the Immuno 1 tPSA and cPSA methods. Receiver operating characteristic curve analysis was performed and the area under the curve was calculated for tPSA and cPSA. Results A total of 156 patients were evaluated, 51 (32.7%) of whom were diagnosed with prostate cancer. The median PSA value for men with prostate cancer was 4.96 ng/mL and for those with benign disease was 3.93 ng/mL. The receiver operating characteristic analysis indicated that the area under the curve for cPSA (0.679) was statistically greater than that achieved for tPSA (0.642, P = 0.004). Using cutoff values for cPSA of 2.3 ng/mL and for tPSA of 2.85 ng/mL provided a specificity of 31.4% and 26.7%, respectively, at a sensitivity for prostate cancer detection of 95%. This was not statistically significant ( P = 0.18). Conclusions cPSA offers modest improvement in prostate cancer detection compared with tPSA in African-American men, but not at the clinically relevant 95% sensitivity level. Additional work is needed to improve prostate cancer detection in this high-risk cohort of patients.

In all, 22 African-American males undergoing radical prostatectomy for prostate adenocarcinoma had serum drawn for tPSA, cPSA, and total protein concentrations prior to, during, and after operation to determine the respective elimination rates. African-American cPSA was found to fit best a simple first-order exponential elimination kinetic, with a half-life of 44.6 h. fPSA followed a two-compartment elimination with an alpha-phase elimination of 0.50 h and a beta-phase half-life of 4.2 h. Our results suggest higher rates of elimination for both cPSA and fPSA in an African-American male population with respect to Caucasians and may account for differences in PSA values between races.

BACKGROUND Adp27Kip1, a recombinant adenovirus, was evaluated for expression of p27, a cyclin-dependent kinase inhibitor (CDKI) and tumor suppressor protein, in human prostate carcinoma cells. Effects of p27Kip1 on cell cycle and apoptosis were analyzed. METHODS We evaluated the effects of overexpression of p27Kip1 in the human prostate carcinoma cell lines LNCaP, DU-145, and PC-3 in vitro and in vivo. Growth curve studies, cell cycle analysis, terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL), and annexin V–fluorescein isothiocyanate apoptosis analyses were conducted to determine effects of p27Kip1 on cell cycle. CDKI activity assays and Westerns blots were conducted to determine presence/activities of CDKIs. RESULTS Adp27Kip1-induced protein levels increased in a dose-dependent manner; p27Kip1 protein was detected within 6 hr of infection with Adp27Kip1 and remained stable for at least 48 hr. The activities of Cdk2, Cdk4, and Cdc2 kinases were inhibited 24 hr after infection with Adp27Kip1. Bromodeoxyuridine incorporation demonstrated a dose-dependent decrease in S-phase cells 24 hr postinfection. TUNEL analysis revealed an induction of apoptosis (10 pfu/cell) within 48 hr of infection in all cell lines. Growth curve analyses demonstrated that Adp27Kip1 infection inhibited proliferation of all cell lines tested and decreased cell numbers for Adp27Kip1-infected LNCaP and PC-3 cells by 96 hr. Cell cycle analysis of DNA content demonstrated an accumulation of cells in G0/G1-phase 24–120 hr after Adp27Kip1-infection. In vivo studies demonstrated a reduction in LNCaP xenograft tumor growth rates in mice injected with Adp27Kip1. CONCLUSION Exogenous p27Kip1 overexpression results in cell cycle regulation in the human prostate carcinoma cell lines tested, representing the first use of this vector on prostate cancer cell lines in vitro and in vivo. Moreover, p27Kip1 expression is associated with an increase in early apoptosis, which represents a recently discovered function for this protein. It also represents the first time this association has been observed in prostate carcinoma cell lines. This study provides support for the further development of Adp27Kip1 as a potential therapeutic vector in the treatment of adenocarcinoma of the prostate. Prostate 53: 77–87, 2002. © 2002 Wiley-Liss, Inc.

In primary hyperaldosteronism, discriminating bilateral adrenal hyperplasia (BAH) from an aldosterone-producing adenoma (APA) is important because adrenalectomy, which is usually curative in APA, is seldom effective in BAH. We analyzed the results from our most recent 7-yr series to evaluate the predictive value of preoperative noninvasive tests compared with adrenal vein sampling (AVS). Forty-eight patients with hypertensive hyperaldosteronism underwent bedside testing, computed tomography (CT) imaging, and AVS. Those in whom the results of AVS indicated APA underwent adrenalectomy. Twelve (30%) and 14 (34%) of 41 patients with APA had paradoxical falls with ambulation in plasma aldosterone concentration (PAC) and 18-hydroxycorticosterone (18-OH-B), respectively. Twenty-nine (70%) and 26 (65%) APA patients had a rise in PAC and 18-OH-B, respectively, as did all 8 BAH patients. Significant identifiers of BAH were supine PAC values less than 15 ng/dL (P: = 0.04), an increase greater than 60% (P: = 0.02) in PAC with ambulation, and supine 18-OH-B values less than 60 ng/dL (P: = 0.04). CT imaging alone was not predictive for BAH or APA. In our population, patients with a positive bedside test result (e.g. a fall in PAC and/or 18-OH-B) and a unilateral adrenal nodule on CT (10 of 41 patients) could have proceeded directly to adrenalectomy for APA. However, a positive bedside test result with a negative CT or a negative bedside test result regardless of CT findings required AVS to confirm the diagnosis and site of disease.

Our recent study has shown that a calcitonin (CT)-like immunoreactive substance(s) is secreted by cultured prostate cells, and secretion of this material is significantly higher in malignant than in benign prostate cells. To test the hypothesis that prostatic CT may serve as a paracrine/neuroendocrine factor, the present study investigated for the presence of CT receptors in the prostate gland. Signal transduction mechanisms activated by CT were examined, and the study also tested its effects on prostate cell proliferation, as assessed by [3H]thymidine incorporation. The results show that high affinity binding sites for [125I]salmon CT were present in plasma membrane fractions of human prostate tissue specimens and the prostate cancer LnCaP cell line. The maximal binding for CT receptors was 564 +/- 163 fmol/mg protein, and the apparent dissociation constant (Kd) was 2.89 +/- 0.58 nM. CT induced a dose-dependent increase in cAMP generation in LnCaP cells. The effect of CT on cytoplasmic Ca2+ transients of LnCaP cells was examined by videofluoromicroscopy. CT (100 nM) induced a rapid and sharp increase in cytoplasmic Ca2+ concentrations in LnCaP cells. The CT-induced increase in cytoplasmic Ca2+ transients appeared to be biphasic (spike and plateau), and this increase was 4- to 10-fold during the initial phase. The profile of this response is characteristic of the activated Ca2+/phospholipid second messenger system. CT also caused a dose-dependent increase in [3H]thymidine incorporation by LnCaP cells. These results suggest that a locally secreted CT-like peptide(s) induces mitogenic responses in prostate cancer cells. This action seems to be mediated through activation of signaling mechanisms, leading to the accumulation of two different second messengers, cAMP and calcium. Activation of dual second messenger systems by CT receptors suggests that the peptide hormone may play an important role in rapidly growing cell populations during the process of tumor formation.