Pathophysiology of varicoceles in male infertility.

Varicoceles are found in 19 to 41% of infertile men, and is one treatable form of male infertility. The mechanism by which varicoceles cause the variable effect on male infertility and spermatogenesis is still unknown. Experimental animal models play a useful (but limited) role due to the sudden and variable iatrogenic nature of the varicoceles and the duration of the studies. Much of the human data are derived by the characterization of associated differences in measurable parameters between men with and without varicoceles. The role of hyperthermia, testicular blood flow and venous pressure changes, reflux of renal/adrenal products, hormonal dysfunction, autoimmunity, defects in acrosome reaction, and oxidative stress, in the pathophysiology of varicocele will be discussed.

Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma.

The transcription factor EGR1 is frequently overexpressed in human prostate cancer and regulates the expression of several genes important for tumor progression. In addition, mice lacking the Egr1 gene show a defect in prostate tumorigenesis. NAB2 is a novel corepressor molecule that modulates EGR1 activity and is induced by the same stimuli that induce EGR1. The human NAB2 gene has been localized to 12q13.3-14.1, within a chromosomal region that is thought to harbor a prostate tumor suppressor. We have examined the expression of NAB2 in human prostate carcinoma specimens. We show here that NAB2 protein expression is lost in a majority of primary prostate carcinoma specimens, including many samples that have high EGR1 levels. This loss occurs early in the tumorigenic process and is sustained, as it is seen in precursor prostatic intraepithelial neoplasia lesions as well as in metastases. Furthermore, loss of NAB2 did not correlate with the tumor grade or stage. Our findings suggest that high levels of EGR1 coupled with low levels of NAB2 can result in high, unrestrained EGR1 transcriptional activity in human prostate cancers.

Impaired prostate tumorigenesis in Egr1-deficient mice.

The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.

Impact of transrectal ultrasound guided prostate biopsy on quality of life: a prospective randomized trial comparing 6 versus 12 cores.

PURPOSE: Recent studies advocating an increase in the number of cores of sextant transrectal ultrasound guided biopsy of the prostate to improve the cancer detection rate often have not addressed the impact on quality of life. We performed a prospective randomized trial comparing 6 to 12 prostate biopsy cores to determine the impact on the cancer detection rate, pain and morbidity, and quality of life. We report the impact on health related and screening specific quality of life in men undergoing 6 versus 12 core transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: We prospectively randomized 244 men with a mean age plus or minus standard deviation of 65 +/- 8 years, serum total prostate specific antigen between 2.5 and 20.0 ng./ml., and/or digital rectal examination findings suspicious of cancer to undergo 6 or 12 core peripheral zone tissue biopsy. Of the men 71 (29%) were black. All patients completed a self-administered questionnaire before, and 2 questionnaires 2 and 4 weeks after the procedure. Health related quality of life was measured using 2 subscales (emotional well-being and role limitation due to physical health) of the short form 36-Item Health Survey. Screening specific quality of life was addressed by questions on the functional consequences of the procedure (return to daily activity, work-employment and sports-exercise). Health related and screening specific quality of life responses were compared in the groups. RESULTS: After controlling for cancer diagnosis, patient age, race, education, report of pain and baseline emotional well-being there was no significant difference in the mean change in emotional well-being scores at 2 and 4 weeks in the 6 and 12 core groups (p = 0.7 and 0.3, respectively). Similarly after controlling for these factors and baseline role limitation due to physical health there was no significant difference in the mean change in role limitation due to physical health scores at 2 and 4 weeks in the 2 groups (p = 0.3 and 0.5, respectively). There was no difference in the percent of men returning to routine daily activity (p = 0.6), work-employment (p = 0.5) or sports-exercise (p = 0.3) at 0 to 1, 2 to 3 and 4 to 7 days or longer than 1 week after the procedure in the groups. CONCLUSIONS: Doubling the sextant biopsy does not affect the quality of life in regard to emotional well-being, role limitation due to physical health, or return to routine daily activity, work-employment or sports-exercise.

A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection.

PURPOSE: Several studies suggest that sextant transrectal ultrasound guided biopsy of the prostate provides insufficient material to detect all clinically important prostate cancer, and obtaining more biopsy cores may improve the cancer detection rate. We performed a prospective randomized trial comparing 6 to 12 prostate biopsy cores to determine the impact on the cancer detection rate. MATERIALS AND METHODS: We prospectively randomized 244 men, including 71 (29%) black men, with a mean age plus or minus standard deviation of 65 +/- 8 years to undergo biopsy with 6 or 12 peripheral zone tissue cores. In our study subjects serum total prostate specific antigen (PSA) was between 2.5 and 20 ng./ml., and/or digital rectal examination was suspicious for cancer. All men completed a self-administered pre-biopsy and 2 post-biopsy questionnaires at 2 and 4 weeks. Cancer detection rates were compared in the groups and correlated with race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume and PSA density, as determined by the formula, total PSA/transrectal ultrasound volume. RESULTS: The cancer detection rate in the 6 and 12 core groups was almost identical (26% and 27%, p = 0.9). There was no significant difference in cancer detection in the 2 trial arms with respect to subject race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume or PSA density. However, our study did not have the statistical power to rule out small differences. CONCLUSIONS: The overall cancer detection rate is not materially increased by 12 core, peripheral zone biopsy in men in whom prostate cancer was mainly detected by screening.

Percentage of free PSA in black versus white men for detection and staging of prostate cancer: a prospective multicenter clinical trial.

OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks. METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used. RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens. CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.

Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores.

PURPOSE: An increasing number of studies suggest that 6-sector transrectal ultrasound guided biopsy of the prostate provides insufficient material to detect all clinically important prostate cancers and more cores may improve detection rates. We performed a prospective, randomized study to determine the effect of increasing the number of cores from 6 to 12 on pain and other morbidity associated with the biopsy procedure. MATERIALS AND METHODS: A total of 160 men (44 black, 28%) with a mean age plus or minus standard deviation of 65+/-8 years who had serum prostate specific antigen between 2.5 and 20.0 ng./ml. and/or digital rectal examination findings suspicious for cancer were prospectively randomized to undergo 6 or 12-core biopsy. Patients completed a self-administered questionnaire addressing pain and other morbidity before, and immediately and 2 and 4 weeks after biopsy. RESULTS: There was no difference between groups in mean pain scale with time for abdominal and rectal pain. For probe insertion, needle insertion and overall pain there was a significant increase in pain recalled at 2 which persisted at 4 weeks compared to immediately after biopsy. However, there was no difference for these 3 post-biopsy pain measures between the 6 and 12-core groups. In the 12-core group there was a statistically significant increase in hematochezia and hematospermia (24% versus 10%, p = 0.04 and 89% versus 71%, p = 0.01, respectively) but no significant difference between groups reporting morbidity as a moderate or major problem. There was no significant change in International Prostate Symptom Score, fever or hospitalization in the 12-core group. CONCLUSIONS: The 12-core prostate biopsy procedure is generally well tolerated and can be safely performed with no significant difference in pain or morbidity compared to the 6-core procedure.

Retrograde endopyelotomy in association with active distal ureteral dilation: a contraindication for the use of the 7F ureteral "tail" stent.

Since its introduction in 1997, the 7F "Tail" stent has been used after a variety of endourologic procedures. We describe 2 patients who underwent retrograde endopyelotomy with distal ureteral dilation; in both patients, after placement of a 7F "Tail" stent, a clinically significant urinoma developed. We believe that in the setting of extensive distal ureteral manipulation or distal active ureteral dilation to greater than 10F, placement of a "Tail" stent is contraindicated.

Clinical and pathologic tumor characteristics of prostate cancer as a function of the number of biopsy cores: a retrospective study.

OBJECTIVES: Many men with negative prostate biopsies and persistently elevated serum total prostate-specific antigen (tPSA) values will have cancer detected on a repeated biopsy. An important issue is whether the cancer would have been detected on the initial biopsy had more biopsy samples been obtained. The objective of our study was to retrospectively characterize the clinical and pathologic tumor features associated with men who underwent sextant core biopsies compared with men who needed more than six core biopsies during one or more biopsy sessions to detect prostate cancer. Transrectal ultrasound (TRUS)-estimated prostatic volume was evaluated to determine whether the number of biopsy cores needed for prostate cancer detection was influenced by gland size. METHODS: We retrospectively evaluated the number of biopsy core samples obtained in 185 men (mean age 63+/-6 years) enrolled in our PSA-based screening study for prostate cancer who were found to have prostate cancer and elected radical prostatectomy as treatment. Correlation coefficients were calculated and univariate analyses were performed to evaluate clinical (age, tPSA, TRUS volume, PSA density) and pathologic (Gleason score, pathologic weight, organ confinement, "possibly harmless" cancer) characteristics associated with men who required more biopsy cores to detect the cancer. RESULTS: Of the 185 men, 103 (56%) had 6 or fewer total biopsy cores taken and 82 (44%) had more than 6 cores (44 [24%] of 185 had 7 to 12 cores and 38 [20%] of 185 had 13 or more cores). There was a positive correlation between age, serum tPSA, TRUS-determined prostate volume, and pathologic specimen weight and an increasing number of total cores (all P values < 0.05). The number of biopsy cores was not associated with PSA density, Gleason score, cancer volume, organ confinement, or "possibly harmless" cancers (all P values > 0.05). Men with a TRUS volume 30 cc or less (46%) required a mean of 8 total cores to detect the cancer compared with a mean of 11 cores (P = 0.003) in men with a TRUS volume greater than 30 cc (54%). A greater percentage of men with a TRUS prostate volume greater than 30 cc compared with men whose volume was 30 cc or less would have had their cancer missed with only a six-core biopsy (64% versus 46%, P = 0.01). CONCLUSIONS: Sextant core biopsies may be inadequate to detect prostate cancer in some men. These data support the performance of more than six core biopsies to detect clinical prostate cancer. A prospective trial using TRUS-determined prostate volume to determine the number of cores to take is needed to accurately assess this issue.