The evolution of chemotherapy for the treatment of prostate cancer.

Chemotherapy has been explored as a treatment option for metastatic prostate cancer since the early 1980s. Docetaxel, a taxane chemotherapeutic, was approved for the treatment of men with metastatic castration-resistant prostate cancer in 2004, and is now standard of care for late stage disease. Recent clinical studies demonstrated that patients with metastatic castration-sensitive disease, and possibly those with high-risk localized prostate cancer also benefit from docetaxel administration, expanding the role of chemotherapy in the prostate cancer treatment landscape. Another taxane, cabazitaxel, is approved for post-docetaxel metastatic castration-resistant prostate cancer. Taxanes and other chemotherapeutics, such as carboplatin, are now being tested in combination regimens. This review presents an outline of recent and ongoing clinical studies assessing docetaxel and its derivative cabazitaxel at different stages of the disease, and in various combinations with other agents. We summarize current knowledge on biomarkers predictive of response to chemotherapy, which may in future be used to guide individualized treatment decisions.

Periprostatic adipose inflammation is associated with high-grade prostate cancer.

BACKGROUND: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. METHODS: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. RESULTS: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05). CONCLUSION: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.

Updated postoperative nomogram incorporating the number of positive lymph nodes to predict disease recurrence following radical prostatectomy.

BACKGROUND: A significant number of patients with minimal lymph node disease at radical prostatectomy (RP) and pelvic lymph node dissection (PLND) have better than expected long-term outcomes. We explored whether stratification by number of positive nodes enhances our institutional prediction model for biochemical recurrence after RP. METHODS: A total of 7789 patients underwent RP and pelvic lymph node dissection from 1995 to 2012 at a tertiary referral center. We compared two recurrence prediction models: one incorporated lymph node invasion and the other tracked the number of positive nodes. Existing and updated models' discrimination was assessed using Harrell's c-index and calibration. The 10-fold cross-validation was performed to correct for model overfitting. RESULTS: Of the 491 patients (6.3%) harboring nodal disease, 387 (5.0%) had 1-2 positive nodes and 104 (1.3%) had ⩾3 positive nodes. Data on number of positive nodes did not improve the c-index for the cohort as a whole. When we assessed discrimination for node-positive patients only, c-index for the model with number of positive nodes was 0.01 (95% confidence interval 0.001-0.024) higher than the model with lymph node invasion. Illustrative examples were provided by reclassification tables using number of positive lymph nodes. For instance, 40 of 7789 patients would be reclassified with a cutoff point of 50% for biochemical recurrence at 1 year, and 36 of 7789 patients would be reclassified with a cutoff point of 40% for biochemical recurrence at 10 years. CONCLUSIONS: Stratification by number of positive lymph nodes provided additional discriminative ability for evaluating risk in node-positive patients. Pending external validation, this model could be used for patient counseling and clinical trial stratification in this subpopulation.

Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer. / Número de ganglios linfáticos metastásicos como determinante de los resultados de la prostatectomía radical de rescate en el cáncer de próstata de recidivante tras radioterapia.

BACKGROUND: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. MATERIAL AND METHODS: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. RESULTS: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively. CONCLUSIONS: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer.

The diffusion of minimally invasive radical prostatectomy in the United States: a case study of the introduction of new surgical devices.

BACKGROUND: The diffusion of minimally invasive radical prostatectomy (MIRP) in the United States may have led to adverse patient outcomes due to rapid surgeon adoption and collective inexperience. We hypothesized that throughout the early period of minimally invasive surgery, MIRP patients had inferior outcomes as compared with those who had open radical prostatectomy (ORP). METHODS: We used the Surveillance, Epidemiology and End RESULTS-Medicare dataset and identified men who had ORP and MIRP for prostate cancer from 2003-2009. Study endpoints were receipt of subsequent cancer treatment, and evidence of postoperative voiding dysfunction, erectile dysfunction (ED) and bladder outlet obstruction. We used proportional hazards regression to estimate the impact of surgical approach on each endpoint, and included an interaction term to test for modification of the effect of surgical approach by year of surgery. RESULTS: ORP (n=5362) and MIRP (n=1852) patients differed in their clinical and demographic characteristics. Controlling for patient characteristics and surgeon volume, there was no difference in subsequent cancer treatments (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76-1.05), although MIRP was associated with a higher risk of voiding dysfunction (HR 1.31, 95% CI 1.20-1.43) and ED (HR 1.43, 95% CI 1.31-1.56), but a lower risk of bladder outlet obstruction (HR 0.86, 95% CI 0.75-0.97). There was no interaction between approach and year for any outcome. When stratifying the analysis by year, MIRP consistently had higher rates of ED and voiding dysfunction with no substantial improvement over time. CONCLUSIONS: MIRP patients had adverse urinary and sexual outcomes throughout the diffusion of minimally invasive surgery. This may have been a result of the rapid adoption of robotic surgery with inadequate surgeon preparedness.

Midurethral sling is the dominant procedure for female stress urinary incontinence: analysis of case logs from certifying American Urologists.

OBJECTIVE: To investigate contemporary trends in the use of midurethral sling procedures for the surgical correction of female stress urinary incontinence over the past decade. METHODS: Annualized case log data for female incontinence surgeries from certifying and recertifying urologists were obtained from the American Board of Urology. Descriptive analysis of the number and type of cases per year was performed. Associations between surgeon characteristics and the use of female incontinence procedures were evaluated. RESULTS: A total of 6355 nonpediatric urologists applied for certification or recertification between 2003 and 2012. Two-thirds (4185) reported performing any procedures for female incontinence. Procedures sharply increased from 4632 in 2003 to 7548 in 2004, then remained relatively stable between 2005 and 2012 (range, 8014-10,238 cases). Traditional procedures decreased from 17% of female incontinence procedures in 2003 to 5% in 2004 to <1% since 2010 (P <.0005). Midurethral sling procedures have risen sharply from 3210 procedures in 2003 to 7200 in 2012 (P <.0005). Endoscopic injection treatments have remained stable. CONCLUSION: Midurethral slings have been widely adopted by urologists over the last decade. Increase in sling usage coincided with a drastic decline in traditional repairs, implying that the newer midurethral slings were replacing these traditional procedures for the treatment of female incontinence. In addition, the fact that the use of periurethral injections did not change significantly during this time period indicates that increased sling usage is responsible for most of the decline in traditional repairs.

Near infrared photonic finger imager for prostate cancer screening.

A portable rectal near infrared (NIR) scanning polarization imaging unit with an optical fiber-based rectal probe, designated as a Photonic Finger (PF), was designed, developed, built and tested. PF was used to image and locate the three dimensional (3D) positions of abnormal prostate tissue embedded inside normal prostate tissue. An inverse image reconstruction algorithm, namely Optical Tomography using Independent Component Analysis (OPTICA) was developed to unmix the signal from targets (cancerous tissue) embedded in a turbid media (normal tissue) in the backscattering imaging geometry. The Photonic Finger combined with OPTICA was ex vivo tested to characterize different target(s) inside different tissue medium, including cancerous prostate tissue embedded inside large pieces of normal tissue. This new developed instrument, Photonic Finger, may provide an alternative imaging technique, which is accurate, of high spatial resolution and non-or-less invasive for prostate cancers screening.

Racial variation in prostate specific antigen in a large cohort of men without prostate cancer.

Several studies have reported racial variation in serum prostate specific antigen (PSA) levels. Many of these studies, however, have included a significant number of men without a documented digital rectal examination (DRE) result or without prostate biopsies if abnormalities in PSA or DRE were detected. Thus, it is not clear that men with prostate cancer have been excluded in these analyses. In this report, data from 9,162 men (3,786 African-American men and 5,376 white men) are reviewed. All men had both serum PSA and DRE testing. Every man in this study had either a documented normal DRE and PSA (< 4 ng/mL) (3,422 African-American men and 4,795 white men) or a negative prostate biopsy (364 African-American men and 581 white men). Data were analyzed in age-matched decades. African-American men and white men had no difference in serum PSA levels between 30 and 39 years of age. At 40-49, 50-59, 60-69 and 70-79 years of age, African-American men had a statistically higher serum PSA level than white men. From these data, we conclude that racial variation in serum PSA is present in all decades above 40 years of age. Our data are unique in that this cohort included a substantial number of men between 30 and 39 years of age. In this group of young men, no racial differences in serum PSA were detected. These studies indicate, for the first time, that the onset of racial variation in PSA occurs after the fourth decade of life.

Renal cell carcinoma detected in a cadaveric donor after orthotopic liver and contralateral renal transplantation in two recipients: four-year follow-up.

BACKGROUND: Although rare, renal cell carcinoma has been found during renal recovery for cadaveric organ transplantation. Previously, we reported this incidence to be 0.9%. In one cadaveric donor, the liver and left kidney had been transplanted before the discovery of renal cell carcinoma (T1) in the right kidney. METHODS: We retrospectively reviewed the medical records of two patients who had received cadaveric allografts from a donor with a known renal cell carcinoma. RESULTS: Both patients have been followed for 4 years with blood chemistries and chest x-ray every 3 months for year 1, every 4 months for years 2 and 3, and every 6 months thereafter. They also underwent allograft ultrasound every 6 months and an annual CT scan of the abdomen. Both patients have shown no evidence of metastatic disease throughout their follow-up. DISCUSSION: In the rare instance that a patient receives an organ from a cadaveric donor with a known renal cell carcinoma, it is mandatory to follow these patients closely observing for both allograft recurrence and metastatic disease.

Tensile strength of cadaveric fascia lata compared to small intestinal submucosa using suture pull through analysis.

PURPOSE: The modified pubovaginal sling has become popular as first line treatment for stress urinary incontinence. With the increasing use of cadaveric fascia as a sling material, widespread shortages are prevalent, hence limiting its availability. The increased morbidity with the use of synthetic sling materials and autologous fascia has stimulated investigation of other sling materials. We evaluated the tensile strength of 4 suture types, and compared tensile strength of cadaveric fascia lata to porcine small intestinal submucosa using suture pull through analysis to assess their efficacy and durability for use in anti-incontinence procedures. MATERIALS AND METHODS: Suture breaking load was determined using 2 and 1-zero polypropylene suture, and 2 and 1-zero polyglactin suture. Freeze dried gamma irradiated human fascia lata and freeze-dried small intestinal submucosa were evaluated. Suture was fixed to sling material using the cross fold technique. Mean suture breakage and suture pull through were determined using a tensionometer by measuring the load applied to the sling/suture system. Statistical analysis was performed. RESULTS: Mean suture breakage load was greatest with 1-zero polyglactin (8.10 pounds) and least with 2-zero polypropylene (3.68 pounds). Mean suture breakage strength was similar for 1-zero polypropylene and 2-zero polyglactin at 5.26 and 5.40 pounds, respectively. Mean suture pull through load using 1-zero polypropylene suture and the cross fold technique was 5.64 pounds for cadaveric fascia and 2.74 pounds for small intestinal submucosa (p <0.0001). Maximum load was limited by the suture strength when using cadaveric fascia, whereas, maximum load was limited in small intestinal submucosa by its inherent tensile strength. However, using a new technique for suture fixation to the small intestinal submucosa, we were able to increase significantly mean suture pull through load to 3.36 pounds (p = 0.008). Additionally, with this new technique small intestinal submucosa allowed gross stretching before suture pull through that was not seen with cadaveric fascia. CONCLUSIONS: Despite the current standard use of 1-zero polypropylene suture for pubovaginal sling fixation, our data suggest that 1-zero polyglactin suture is the strongest, and its use with pubovaginal sling fixation warrants further investigation. Using the cross fold technique and 1-zero polypropylene suture, tensile strength was greatest with cadaveric fascia compared to small intestinal submucosa. Although small intestinal submucosa was not as strong as cadaveric fascia, our persuasive preliminary data suggest that further investigation is warranted in the use of small intestinal submucosa and other suture fixation techniques, and its observed stretch capacity. Hence, with further studies small intestinal submucosa may remain a viable option for pubovaginal sling material.

Suppression of primary tumor growth and the progression to metastasis with p53 adenovirus in human prostate cancer.

PURPOSE: Numerous advances have been made in gene therapy approaches for the treatment of solid tumors, including prostate cancer. While treatment of the primary tumor has been well investigated, little information is available regarding gene therapy techniques which might impact on the progression to metastatic disease. We investigate the ability of p53 adenovirus to suppress not only primary tumor growth, but also the progression to metastatic disease. Mutation of the p53 tumor suppressor gene has been associated with the progression of prostate cancer. In this study, we utilized a metastatic model for human prostate cancer to determine if introduction of the wild-type p53 gene using an adenoviral vector (rAd-p53) impacted on primary tumor growth as well as the progression to metastatic disease. MATERIALS AND METHODS: For our studies, we used the human prostate cancer cell line PC-3, which has a homozygous loss of p53 expression. Expression of exogenous p53 as well as p21 induction at various time points after infection with rAd-p53 was determined in vitro. In vivo studies were performed in nude mice following orthotopic (intraprostatic) injection of PC-3 cells. Primary tumor growth as well as the progression to metastatic disease was assessed following rAd-p53 treatment. RESULTS: In vitro studies demonstrated high levels of p53 gene expression as well as the induction of p21 gene expression. Infection of PC-3 cells with rAd-p53 resulted in marked growth inhibition, as well as wide-spread fragmentation of nuclei and secretion of nuclear matrix proteins into the culture medium consistent with the process of apoptosis. In vivo studies demonstrated that a single injection of rAd-p53 into an established orthotopic prostate tumor resulted not only in primary tumor growth suppression (treated = 97.5 +/- 25.3 mm.3 versus control = 393.4 +/- 67.2 mm.3; p = 0.0002) but also reduced the frequency of progression to metastatic disease (treated = 8 of 19 versus control = 18 of 19; p = 0.001). CONCLUSION: These experiments demonstrate that a single injection of rAd-p53 into an established orthotopic prostate tumor results not only in suppression of primary tumor growth, but also in a reduction of the frequency of progression to metastatic disease. These results suggest that a rAd-p53 gene therapy strategy may be useful in the treatment of human prostate cancer.

Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point.

PURPOSE: The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting. PATIENTS AND METHODS: Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m(2), administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival. RESULTS: Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months. CONCLUSION: The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.

Disease recurrence in black and white men undergoing radical prostatectomy for clinical stage T1-T2 prostate cancer.

PURPOSE: The reported incidence and mortality of prostate cancer are higher among black than white men. Reasons for the disproportionate racial incidence of this disease are not known but most surveys suggest that increased mortality among black men is due to more advanced tumor stage at diagnosis. To determine if racial differences exist in men with similar stage disease we compared disease recurrence in black and white men who underwent radical prostatectomy for clinical stage T1-T2 prostate cancer. MATERIALS AND METHODS: We reviewed the records of all 257 white and 218 black men undergoing radical prostatectomy for clinical stage T1-T2 prostate cancer at the Louisiana State University Medical Center-Shreveport and the Overton-Brooks Veterans Affairs Medical Center between January 1990 and November 1998. Age, race, serum prostate specific antigen (PSA), ultrasound measured prostate volume, PSA density (PSA divided by prostate volume), histological features of the prostate biopsy, clinical stage, pathological stage, histological features of the radical prostatectomy specimen and disease recurrence were reviewed. RESULTS: Black men had significantly higher mean serum PSA and PSA density than white men (2-sided p = 0.005 and 0.03, respectively). There were no statistically significant differences by race in terms of patient age, prostate volume, clinical stage, biopsy Gleason score, pathological stage, positive pelvic lymph nodes, positive surgical margins or PSA recurrence rates. CONCLUSIONS: Black men with clinical stage T1-T2 prostate cancer who underwent radical prostatectomy had significantly higher serum PSA and PSA density than similarly treated white men. However, race appears to have no independent impact on pathological findings or disease recurrence in men with clinically localized prostate cancer treated with radical prostatectomy when the effects of differences in serum PSA are controlled.

Undifferentiated sex cord/stromal testis tumor.

Completely undifferentiated sex cord/stromal tumors of the testis are rare after puberty. We describe such a tumor in an 18-year-old man presenting with a right testis mass.

Serum testosterone levels in African-American and white men undergoing prostate biopsy.

OBJECTIVES: Because androgen levels are known to influence prostate growth, we performed a prospective analysis of serum testosterone levels in all African-American and white men who underwent transrectal ultrasound-guided prostate biopsies to evaluate an abnormal digital rectal examination (DRE) and/or serum prostate-specific antigen (PSA) level greater than 4 ng/mL. METHODS: From June 1996 through July 1998, we evaluated 453 men (189 African-American and 264 white men) who underwent prostate needle biopsy because of an abnormal DRE or serum PSA greater than 4 ng/mL, or both. All men had morning serum testosterone levels determined just before undergoing prostate needle biopsy. Serum testosterone levels were compared on the basis of the prostate biopsy result (positive or negative for prostate cancer) and by race. RESULTS: A total of 453 men underwent prostate biopsy and had morning serum testosterone levels available for comparison. Of the 264 white men who underwent biopsy, 88 (33%) were found to have prostate cancer compared with 67 (35%) of 189 African-American men who underwent biopsy. In the white men without cancer, the mean serum testosterone level was 380. 19 ng/dL; those with prostate cancer had a mean serum testosterone level of 419.52 ng/dL. The mean serum testosterone level in African-American men without cancer was 424.30 ng/dL; it was 386.55 ng/dL in those with prostate cancer. There was no statistical difference in serum testosterone levels based on biopsy result or race. CONCLUSIONS: Although several studies have suggested that African-American men have higher serum testosterone levels than white men, these differences were noted only in men 40 years of age or younger. As was noted in our study, after age 40, African-American and white men have comparable serum testosterone levels. In addition, although prostate growth is androgen dependent, we found no difference in serum testosterone levels in men with and without prostate cancer.

Amphiregulin is coordinately expressed with heparin-binding epidermal growth factor-like growth factor in the interstitial smooth muscle of the human prostate.

Peptide growth factors have been proposed as mediators of smooth muscle-epithelial cell interactions in the human prostate; however, the identity of these molecules has not been established. In this study, we compared expression levels of messenger RNAs (mRNAs) encoding the epidermal growth factor (EGF) receptor-related receptor tyrosine kinases (ErbB1 through 4), the six EGF receptor ligands, EGF, transforming growth factor (TGF)-alpha, amphiregulin (ARG), HB-EGF, betacellulin, and epiregulin, and the related molecule heregulin-alpha, in a series of 10 prostate tissue specimens. Only EGF showed a disease-specific association, with increased mRNA levels in four of five PCa specimens in comparison to matched normal tissue from the same subject. In contrast, ARG and HB-EGF mRNAs showed a coordinate pattern of expression in 7/10 specimens that was distinct from all other growth factor or receptor genes examined and from mRNAs for prostate specific antigen, the androgen receptor and GAPDH, a house-keeping enzyme. Analysis of an additional series of benign prostatic hyperplasia and prostate cancer specimens from 60 individuals confirmed that ARG and HB-EGF mRNA levels varied in a highly coordinate manner (r = 0.93; P < 0.0001) but showed no association with disease. ARG was immunolocalized largely to interstitial smooth muscle cells (SMC), previously identified as the site of synthesis of HB-EGF in the prostate, while the cognate ARG and HB-EGF receptor, ErbB1, was localized exclusively to ductal epithelial cells and carcinoma cells. Although ARG was a relatively poor mitogen for Balb/c3T3 cells in comparison to HB-EGF, it was similar in potency to HB-EGF in stimulating human prostate epithelial cell growth, suggesting that prostate epithelia may be a physiologic target for ARG in vivo. Expression of both ARG and HB-EGF mRNAs was induced in cultured prostate SMC by fibroblast growth factor-2, a human prostate SMC mitogen linked to prostate disease. These findings indicate that ARG and HB-EGF are likely to be key mediators of directional signaling between SMC and epithelial cells in the human prostate and appear to be coordinately regulated.

Race is not an independent predictor of positive surgical margins after radical prostatectomy.

OBJECTIVES: To determine whether race is an independent predictor of positive surgical margins in patients who undergo radical prostatectomy. METHODS: Radical prostatectomies were performed on 750 patients at five Veterans Affairs hospitals: Shreveport, Louisiana (n = 451), Houston, Texas (n = 92), Jackson, Mississippi (n = 83), New Orleans, Louisiana (n = 69), and Little Rock, Arkansas (n = 55). All men who did not receive neoadjuvant hormonal therapy and for whom complete follow-up data were available were included in the analysis (of 607, 260 were African-American and 347 were white). Multiple logistic regression analysis was used to determine the significance of race as an independent predictor of surgical margin status after radical prostatectomy for clinically localized prostate cancer. RESULTS: After controlling for clinical stage, Gleason grade, and preoperative prostate-specific antigen (PSA), multivariable logistic regression analysis revealed that race was not an independent predictor of positive surgical margins (P = 0.9). Of the variables evaluated, both preoperative PSA (P = 0.0005) and biopsy Gleason grade (P = 0.047) were significant predictors of an increased risk of a positive surgical margin. CONCLUSIONS: Positive surgical margins are a widely accepted surrogate marker of increased biologic potential in patients with prostate cancer. In our study population, race was not an independent predictor of surgical margin status. Coupled with observations that survival is not related to race, this finding suggests that the biology of prostate cancer in African-American and white men is similar and that observed racial differences more likely are due to ethnic factors that influence tumorigenicity.

Development of a nomogram that predicts the probability of a positive prostate biopsy in men with an abnormal digital rectal examination and a prostate-specific antigen between 0 and 4 ng/mL.

OBJECTIVES: Early detection of prostate cancer traditionally involves both digital rectal examination (DRE) and serum prostate-specific antigen (PSA) determination in an informed patient population. Abnormalities in either of these studies typically lead to additional evaluations, including prostate biopsy. In this study, we analyzed the operational characteristics of serum PSA between 0 and 4 ng/mL as an initial test for prostate cancer. METHODS: From January 1990 through May 1997, transrectal biopsies were obtained from 700 men with a serum PSA level less than 4.0 ng/mL but DRE suspicious for cancer. Patient age, race, and serum PSA level were reviewed for this study. RESULTS: Of the 700 men studied, 445 were white (64%) and 255 were African American (36%). In multivariate analysis of prebiopsy risk factors (age, race, serum PSA), serum PSA was the only independent predictor of a positive prostate biopsy. A nomogram was created that determines the worst-case probability of a positive prostate biopsy in men with PSA between 0 and 4 ng/mL and a DRE suspicious for cancer. The predictions from the nomogram appeared accurate and discriminating, with a bias-corrected area under the receiver operating characteristic curve (i.e., comparison of the predicted probability with the actual outcome) of 0.75. CONCLUSIONS: Although early detection of prostate cancer has traditionally used both PSA measurement and DRE, PSA testing alone could be more easily implemented and may encourage some men to seek consultation who might not otherwise have done so. By providing a nomogram which provides a worse-case scenario (assuming a positive DRE) of the probability of a positive biopsy, the patient and clinician can make an informed decision as to whether additional evaluation is warranted.

Cloning and characterization of the prostate-specific membrane antigen promoter.

Prostate-specific membrane antigen (PSMA) is a protein that is expressed predominantly in normal prostate epithelial cells and in most adenocarcinomas of the prostate (Cap) and in virtually all Cap metastases. In this article we describe the cloning of a 2-kb human genomic DNA fragment containing the 5' upstream untranslated region of the PSMA gene and present evidence that it provides promoter activity. When the DNA fragment was cloned into transient expression vectors to examine promoter activity, the vectors were functional in promoting expression in several prostate and nonprostate cell lines in transient transfection assays. A 614-bp fragment derived from the 3' end of the 2-kb fragment may represent the minimal PSMA promoter as determined by deletion mutagenesis. The 2-kb fragment compared with the 614-bp fragment provided higher expression levels when using prostate-derived cell lines (DU 145 and LNCaP). The increased transcription using the 2-kb fragment was not as great in non-prostate cell lines. Little or no transcription over basal levels was seen with a 232-bp promoter fragment. When the concentration of dihydrotestosterone was depleted or supplemented in the growth medium, no significant effect was seen on PSMA-promoted transient expression in LNCaP cells, a prostate cell line. J. Cell. Biochem. 74:395-405, 1999. Published 1999 Wiley-Liss, Inc.