Ignacio F. San Francisco

Extended Prostate Needle Biopsy Improves Concordance Of Gleason Grading Between Prostate Needle Biopsy And Radical Prostatectomy

PURPOSE We examined the concordance of Gleason scores in prostate needle biopsy specimens and the corresponding radical retropubic prostatectomy specimens in a cohort of patients grouped according to the number of cores obtained during diagnostic needle biopsy. MATERIALS AND METHODS We reviewed clinical and pathological data on a cohort of 466 men diagnosed with localized prostate cancer by needle biopsies who underwent radical retropubic prostatectomy between January 1, 1990 and July 31, 2001. Two study groups were identified, including 126 patients diagnosed with prostate cancer by extended needle biopsies (10 or more cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer cores). Mean age was 60 years and median prostate specific antigen was 5.8 ng./ml. The median number of cores in the extended and nonextended biopsy groups was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy and prostatectomy specimens was compared and correlated with the number of cores on needle biopsy. RESULTS In the whole cohort 311 patients (67%) had identical Gleason scores on the needle biopsy and prostatectomy specimens, while 53 (11%) were over graded and 102 (22%) were under graded on needle biopsy. In patients who underwent extended needle biopsies the accuracy rate for Gleason scoring was 76% with 10% over and 14% under graded. The highest accuracy rates were in patients with 13, 14 and 16 cores (89%, 87% and 100%, respectively). No patients in the extended needle biopsy group had a discrepancy of more than 2 Gleason units in grade in the biopsy and surgical specimens. In those who underwent nonextended needle biopsies the accuracy rate for Gleason scoring was 63% with 12% over and 25% under graded. There were significantly different rates of accuracy (p = 0.008) and under grading (p = 0.01) in the 2 needle biopsy groups. Patients with a needle biopsy Gleason score of less than 7 had significantly higher concordance with the prostatectomy Gleason score when extended biopsies were done compared with nonextended biopsies (p = 0.001). CONCLUSIONS Prostate cancer grading by extended needle biopsy is a better predictor of the final Gleason score than nonextended needle biopsy, as determined by radical prostatectomy histological evaluation. Therefore, extended prostate needle biopsy provides better guidance to determine the appropriate treatment in patients with prostate cancer.

Risk Stratification and Validation of Prostate Specific Antigen Density as Independent Predictor of Progression in Men With Low Risk Prostate Cancer During Active Surveillance

PURPOSE We assessed risk stratification in patients with low grade prostate cancer managed by active surveillance using a 20-core saturation biopsy technique. MATERIALS AND METHODS A total of 135 consecutive patients with low risk prostate cancer were prospectively entered in an active surveillance program in a 10-year period. The study entrance requirement and progression definition followed Epstein criteria using only pathological parameters, ie fewer than 3 positive cores, Gleason score 6 or less and 50% or less of any single core involved. All patients were monitored by restaging 20-core saturation biopsy every 12 to 18 months. A total of 120 patients with at least 1 rebiopsy form the basis of this report. RESULTS Of the cohort 30% progressed during a median of 2.4 years. Three multivariate analyses were performed. The first analysis used variables only at diagnosis biopsy and revealed that prostate specific antigen density greater than 0.08 ng/ml/cc and prostate cancer family history were significant predictors of progression. When combined in a 3-level risk factor score, they were significant (p = 0.003). The second multivariate analysis considered changes in characteristics between diagnosis biopsy and first rebiopsy. Prostate specific antigen velocity along with prostate specific antigen density and family history highly predicted progression according to a 4-level risk factor score (p <0.0001). The third multivariate analysis validated the previously reported prostate specific antigen density cutoff of 0.08 ng/ml/cc at first rebiopsy as a significant predictor of subsequent progression (HR 3.16, 95% CI 1.12, 8.93; p = 0.03). CONCLUSIONS Risk factor stratification can be used to significantly predict the outcome in patients on active surveillance. Prostate specific antigen density 0.08 ng/ml/cc at first rebiopsy was validated as a significant predictor of subsequent progression.

THE RELATIONSHIP OF PROSTATE GLAND VOLUME TO EXTENDED NEEDLE BIOPSY ON PROSTATE CANCER DETECTION

PURPOSE We investigated the relationship between prostate volume and cancer detection by needle biopsy, and determined the effect of an increased number of cores on the sampling error of needle biopsy on large prostate glands. MATERIALS AND METHODS The study cohort included 750 consecutive patients who underwent first time transrectal ultrasound guided prostate needle biopsy from January 1995 to August 2001. Prostate volumes were divided into quartiles (13 to 34, 34.1 to 45, 45.1 to 64 and 64.1 to 244 cc). Multivariate analysis controlling for age, prostate specific antigen (PSA) and biopsy indication was performed to determine the effect of the number of cores and prostate volume on prostate cancer detection. RESULTS Patients diagnosed with prostate cancer were older (p = 0.0035) and had higher PSA levels (p = 0.0002) than those with no cancer on biopsy. Decreasing cancer detection rates were seen with increasing prostate volume (p = 0.0074). The OR of detection for each additional core was 0.99 (95% CI 0.93, 1.06), suggesting that increasing the number of biopsy cores did not increase the rate of prostate cancer detection. Multivariate analysis revealed that patients with larger prostates had the same, or possibly lower, cancer detection rate as the number of biopsy cores was increased. Patients with larger prostates were older (p <0.0001), had higher PSA levels (p <0.0001) and were even more likely to have undergone biopsy for increased PSA rather than abnormal digital rectal examination alone (p <0.0001). CONCLUSIONS Our study suggests that the lower cancer detection rate for men with large prostates may be due to a decrease in the use of increased serum PSA for prostate cancer detection in larger prostates in addition to other factors such as sampling error. Increased serum PSA levels in cases of larger prostates, although a risk factor for prostate cancer warranting biopsy, may also be due to nonmalignant sources such as benign prostatic hyperplasia.

Expression of transforming growth factor‐beta 1 and growth in soft agar differentiate prostate carcinoma‐associated fibroblasts from normal prostate fibroblasts

Carcinoma‐associated fibroblasts (CAF) promote tumor progression of pre‐neoplastic epithelial cells. To investigate the basis of this phenomenon, we compared the properties of fibroblasts cultured from normal human prostate (NHPF) to prostate CAF. NHPF and CAF were assayed for growth potential, cell death and proliferative capacity by measuring population doubling time, cell cycle distribution and capability to form colonies in soft agar. Resistance to genotoxic (UV radiation: 0–50 J/cm2) and chemotoxic (0–200 nM Taxol) agents were compared between CAF and NHPF by measuring cell viability and cell cycle analysis. Transforming growth factor β1 (TGF‐β1) immunoreactivity was assessed in non‐malignant and malignant prostatic tissue. No detectable differences were found when comparing CAF and NHPF with respect to population doubling time, cell cycle distribution and response to genotoxic and chemotoxic agents. The mean number of colonies in soft agar was 120.5 for CAF vs. 18.2 for NHPF (p < 0.05). Because TGF‐β1 and matrix metalloproteinase (MMP)‐9 have been associated with growth of fibroblasts in soft agar and tumor promotion, we measured the expression of these factors in NHPF and CAF by ELISA. There was no difference in expression of MMP‐9; however, TGF‐β1 was expressed in higher concentrations in CAF than in NHPF (p < 0.0014). Furthermore, TGF‐β1 expression was higher in the carcinoma‐associated stroma of prostate cancer tissue than stroma of non‐malignant prostatic tissue. Increased capability of CAF as compared to NHPF to form colonies in soft agar may be due to a higher expression of TGF‐β1 and correlates with the ability of CAF to promote malignant progression of prostate epithelial cells.

Low age adjusted free testosterone levels correlate with poorly differentiated prostate cancer.

PURPOSE We determined the relationship between age adjusted free T, and stage, grade and the biochemical-free survival rate in patients with surgically treated prostate cancer. MATERIALS AND METHODS A retrospective cohort study was done between 1995 and 2001 in 333 patients treated for clinically localized prostate cancer with radical retropubic prostatectomy by a single surgeon at our institution. The study cohort consisted of 279 patients (84%) who had free T levels available. Free T was assessed by single cutoff value of 1.5 ng/dl or less, as suggested by the assay manufacturer, or by age adjusted free T. The relationship of low free T as a single cutoff value and age adjusted reference ranges with clinical and pathological measures of disease progression were assessed using the Fisher exact and Wilcoxon rank sum tests with the outcome assessed by the log rank test. RESULTS Using the assay manufacturer suggested single cutoff value of 1.5 ng/dl or less to define low free T 57% of patients with prostate cancer in the cohort were categorized as hypogonadal. However, using age adjusted free T reference ranges only 2.5% of patients with prostate cancer were categorized as hypogonadal, which is more logical and representative of clinically significant hypogonadism in the general population. Poorly differentiated prostate cancer was associated with low free T when measured by a single cutoff value of 1.5 ng/dl or less, or by age adjusted free T (p = 0.017 and 0.04, respectively). CONCLUSIONS Low age adjusted free T as well as single cutoff free T correlates with poorly differentiated prostate cancer in surgically treated patients.

Robot-Assisted Partial Nephrectomy: Early Unclamping Technique

Robot-assisted partial nephrectomy (RAPN) is emerging as a viable minimally invasive surgical technique for small renal tumors. The warm ischemia time (WIT) during laparoscopic partial nephrectomy has been reduced using an early unclamping (EU) technique. We present our technique of EU technique in RAPN. From November 2009 to June 2010, 12 consecutive RAPNs were performed by a single surgeon (A.W.) using EU technique. The median operative time was 227 minutes (176-315); median WIT, 16 minutes (11-25). Median estimated blood loss was 150 mL (50-500) and length of stay 2 days. There were no intraoperative or postoperative complications. RAPN using EU technique is a safe and feasible option in experienced hands, allowing for a shorter WIT without increasing blood loss. This approach requires a highly skilled bedside assistant who is imminently familiar with the robotic system and advanced laparoscopic techniques.

Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance

To determine whether total testosterone and free testosterone levels predict disease reclassification in a cohort of men with prostate cancer (PCa) on active surveillance (AS).

Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results

This report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa). A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution. The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively. Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS. Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa. Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4. All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4). Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years. Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men.

Androgen receptor in human endothelial cells

Androgen receptor (AR) is a ligand-inducible transcription factor, and a member of the steroid-thyroid-retinoid receptor superfamily, that mediates the biological effects of androgens in a wide range of physiological and pathological processes. AR expression was identified in vascular cells nearly 20 years ago, and recent research has shown that AR mediates a variety of actions of androgens in endothelial and vascular smooth muscle cells. In this mini-review, we review evidence indicating the importance of AR in human endothelial cell (HUVEC) homeostatic and pathogenic processes. Although a role for AR in the modulation of HUVEC biology is evident, the molecular mechanisms by which AR regulates HUVEC homeostasis and disease processes are not fully understood. Understanding these mechanisms could provide critical insights into the processes of pathogenesis of diseases ranging from cardiovascular disease to cancer that are major causes of human morbidity and mortality.

Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms

BackgroundSex-related differences in the role of androgen have been reported in cardiovascular diseases and angiogenesis. Moreover, androgen receptor (AR) has been causally involved in the homeostasis of human prostate endothelial cells. However, levels of expression, functionality and biological role of AR in male- and female-derived human endothelial cells (ECs) remain poorly characterized. The objectives of this work were (1) to characterize the functional expression of AR in male- and female-derived human umbilical vein endothelial cell (HUVEC), and (2) to specifically analyze the biological effects of DHT, and the role of AR on these effects, in male-derived HUVECs (mHUVECs).ResultsImmunohistochemical analyses of tissue microarrays from benign human tissues confirmed expression of AR in ECs from several androgen-regulated and non-androgen-regulated human organs. Functional expression of AR was validated in vitro in male- and female-derived HUVECs using quantitative RT-PCR, immunoblotting and AR-mediated transcriptional activity assays. Our results indicated that functional expression of AR in male- and female-derived HUVECs was heterogeneous, but not sex dependent. In parallel, we analyzed in depth the biological effects of DHT, and the role of AR on these effects, on proliferation, survival and tube formation capacity in mHUVECs. Our results indicated that DHT did not affect mHUVEC survival; however, DHT stimulated mHUVEC proliferation and suppressed mHUVEC tube formation capacity. While the effect of DHT on proliferation was mediated through AR, the effect of DHT on tube formation did not depend on the presence of a functional AR, but rather depended on the ability of mHUVECs to further metabolize DHT.Conclusions(1) Heterogeneous expression of AR in male- and female-derived HUVEC could define the presence of functionally different subpopulations of ECs that may be affected differentially by androgens, which could explain, at least in part, the pleiotropic effects of androgen on vascular biology, and (2) DHT, and metabolites of DHT, generally thought to represent progressively more hydrophilic products along the path to elimination, may have differential roles in modulating the biology of human ECs through AR-dependent and AR-independent mechanisms, respectively.