Faculty Bibliography

PURPOSE: Prostate specific antigen is the most widely used oncological biomarker in medicine today. Before its implementation as an early diagnostic marker, urologists were limited to prostatic acid phosphatase, digital rectal examination and transrectal ultrasound for the detection of prostate cancer. We review the history of the discovery of prostate specific antigen as a biomarker for the early detection of adenocarcinoma of the prostate. MATERIALS AND METHODS: We performed a structured literature review, searching PubMed for papers on the subject of prostate specific antigen limited to humans between the years 1970 to 2005. We found a total of 8,365 articles. RESULTS: While the use of prostate specific antigen in evaluating newly diagnosed prostate disease, and followup of men after treatment for prostate disease is accepted practice, prostate specific antigen screening for prostate cancer remains controversial. CONCLUSIONS: In the next decade the results of randomized trials of screening may answer some of the questions posed at the beginning of the prostate specific antigen era. To what extent does prostate specific antigen screening affect prostate cancer mortality and at what cost?

CONTEXT: Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. OBJECTIVE: To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. INTERVENTION: Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. RESULTS: Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. CONCLUSIONS: These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304

There are numerous molecular modifications known to occur in cancer. New nucleic acid-based biomarkers provide a unique approach to patient management in urologic oncology. Malignant transformation of a normal cell requires a series of epigenetic and genetic changes or 'hits.' Epigenetics produced by deoxyribonucleic acid methylation, adding a methyl group to the fifth position of cytosine within CpG dinucleotides, are important players in deoxyribonucleic acid repair, genome instability, and regulation of chromatin structure. Genetic alterations in cancer can include mutations, chromosome deletions, insertions, amplifications, and translocations. In addition, the modifications of telomeres are critical to the maintenance of chromatin structure, transcription, and cell function in cancer. We review only nucleic acid-based molecular biomarkers in urologic oncology that can assist the clinician in establishing the diagnosis of disease, or that can predict the behavior of the disease or the patient's survival

PURPOSE: Recent studies have suggested that the cut point for recommending prostate biopsy among men with a normal digital rectal examination should be greater than 2.5 ng/ml as opposed to the more traditional greater than 4.0 ng/ml. We compared outcomes between men with clinical stage T1c disease undergoing radical prostatectomy who had a low vs slightly increased prostate specific antigen. MATERIALS AND METHODS: The study population consisted of 2,896 men treated with radical prostatectomy between 1985 and 2004 at a tertiary care referral center with clinical stage T1c disease and a pre-biopsy prostate specific antigen between 2.6 and 6.0 ng/ml. Using multivariate analysis we evaluated the association between pre-biopsy prostate specific antigen 2.6 to 4.0 ng/ml (784) vs 4.1 to 6.0 ng/ml (2,112), and pathological outcomes and biochemical progression. RESULTS: After adjusting for multiple clinical and pathological characteristics, lower preoperative serum prostate specific antigen values were associated with decreased odds of Gleason score 7 or greater in the surgical specimen (p = 0.004), positive surgical margins (p = 0.02) and extraprostatic extension (p = 0.001). There was no significant association between these preoperative prostate specific antigen groups and odds of seminal vesicle invasion (p = 0.47) or lymph node metastasis (p = 0.90). Among the 1,534 men with followup information available there was a trend for increased risk of biochemical progression associated with a higher preoperative prostate specific antigen, although this trend did not reach statistical significance (relative risk 1.48, 95% CI 0.69-3.19, p = 0.31). CONCLUSIONS: In the current study of men with clinical stage T1c treated with radical prostatectomy a lower preoperative prostate specific antigen was associated with significantly more favorable pathological findings. Whether this degree of improved outcomes justifies the limitations associated with decreasing the prostate specific antigen cut point (eg increased biopsies performed and diagnosis of insignificant cancers) remains to be determined

PURPOSE: Bleeding after surgery is a rare but potentially life threatening complication. We reviewed operative and postoperative clinical features in patients who required surgical exploration secondary to hemorrhage following laparoscopic renal procedures. MATERIALS AND METHODS: We retrospectively reviewed the records of patients undergoing laparoscopic renal surgery between January 1996 and September 2004. Nine of 1,123 patients (0.8%) underwent early exploration for bleeding within 5 days of surgery. RESULTS: Two groups were identified. Group 1 consisted of 4 patients who underwent early exploration at less than 10 hours after surgery and had arterial bleeding. Group 2 consisted of 5 patients who underwent exploration a mean 38 hours after surgery and in whom no bleeding source was identified. Group 1 patients had pronounced hypotension with systolic blood pressure 70 to 79 mmHg and hematocrit decreases (mean 10.5%) in a short time course before repeat exploration (mean 4.5 hours). Arterial bleeding was identified in the hilum and adrenal bed. Group 2 patients demonstrated a decrease in hematocrit from an initial mean of 28.3% to 22.5% with tachycardia and mild hypotension (systolic blood pressure 90 to 99 mmHg). On exploration group 2 patients had diffuse oozing. Mean hospital stay in group 1 was 8 days (range 4 to 9) vs 12 (range 6 to 24) in group 2. CONCLUSIONS: Early hemodynamic instability after laparoscopic renal surgery is likely to indicate a discrete arterial bleeding source from the hilum or adrenal bed, requiring surgical control. In patients who underwent exploration after a delayed bleeding presentation no discrete source was found intraoperatively. Therefore, it is unclear whether these patients benefited from surgical exploration