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Objectives: Patients and referring physicians often ask about the significance of lymphovascular invasion (LVI) on pathology reports from radical prostatectomy specimens. However, limited data are available concerning the relationship between LVI and preoperative screening characteristics, pathologic tumor features, and patient prognosis., Methods: LVI was evaluated for its ability to predict elevated prostate-specific antigen velocity, adverse pathologic features, and biochemical progression in 1709 men who underwent radical prostatectomy for clinically localized disease., Results: LVI was present in 118 (7%) of the 1709 men. On univariate analysis, LVI was significantly associated with tumor grade, tumor volume, and other adverse pathologic features. Prostate-specific antigen velocity was not significantly associated with the presence of LVI. Biochemical progression occurred in 34% of those with LVI compared with 10% of those without LVI (P <0.0001). However, on multivariate analysis with other pathologic tumor features, LVI was not an independent predictor of progression., Conclusions: LVI is a relatively uncommon finding in radical prostatectomy specimens for clinically localized disease. Although LVI was seen primarily in large-volume, high-grade tumors, it was not an independent predictor of progression in the multivariate model.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Background: The distribution of prostate-specific antigen (PSA) values for men with or without prostate carcinoma are confounded because of verification bias. Correcting for verification bias, the means and variances of PSA values were estimated in specific clinical scenarios., Methods: Existing receiver operating characteristic (ROC) curves, adjusted for the presence of verification bias in a screening population, were used to estimate the mean and variance of PSA values for men with or without prostate carcinoma, stratified by age and the presence or absence of benign prostatic hyperplasia. Men with a suspicious digital rectal exam (nodular) were excluded from analysis., Results: Among men with cancer and the absence of benign prostatic hyperplasia, mean PSA values were 2.05 ng/mL and 2.66 ng/mL for younger (<60 yr) and older (> or =60 yrs) men, respectively. These estimates were 2.56 ng/mL and 3.90 ng/mL in the presence of benign prostatic hyperplasia for younger and older men, respectively. For men without prostate carcinoma, these values were 0.78 ng/mL and 1.23 ng/mL for younger and older men, respectively, among those without benign prostatic hyperplasia, and 0.97 ng/mL and 1.75 ng/mL for younger and older men, respectively, among those with benign prostatic hyperplasia., Conclusions: Accurate estimates of the mean and variance of PSA values for men with or without cancer may provide PSA thresholds for biopsy that are specific for age and prostate size as assessed by digital rectal exam. Therefore, the current threshold of 4.0 ng/mL should not be applied indiscriminately., (Copyright 2006 American Cancer Society.)

Prostate cancer screening is controversial, and major professional associations offer differing screening guidelines. The authors address 3 key issues about prostate cancer screening: 1) the prostate-specific antigen (PSA) criteria to recommend a prostate biopsy, 2) the appropriate age to start screening, and 3) the appropriate age to stop screening. The authors argue, on the basis of evidence published since 2000, that data supporting the efficacy of PSA screening are convincing. They recommend screening for risk assessment for average-risk men beginning at age 40 years, screening selected healthy men older than age 70 years, and lowering the PSA threshold for considering biopsy to 2.5 ng/mL for all men.

Purpose: We evaluated whether the proportion of patients with a postoperative PSA-DT less than 3 months, a surrogate for PCSM, decreased significantly during the PSA era., Materials and Methods: Between July 1988 and July 2002, 3,719 men with clinically localized prostate cancer treated with RP comprised the study cohort. A chi-square metric was used to compare the preoperative and postoperative characteristics, 5-year actual PSA failure rates, and PSA-DTs for patients treated during the 2 equally divided eras of the early PSA era, July 1988 to July 1995 and the late PSA era, August 1995 to July 2002., Results: Patients presenting in the more recent PSA era were of younger age (p < 0.0001), with earlier stage (p < 0.0001) and lower grade disease (p = 0.01). Similarly, patients had lower grade (p < 0.001), stage (p < 0.0001), and positive margin (p < 0.0001) and lymph node rates (p = 0.0002) at RP. The 5-year actual PSA failure rates decreased from 14.3% in the early PSA era to 2.5% in the later PSA era (p < 0.0001). There was a 37% reduction in the proportion of patients with a PSA-DT less than 3 months, corresponding to a decrease in absolute magnitude from 9% to 5.7% between the 2 eras. Absolute reductions of 3.1% and 9% were also noted for the proportion of PSA-DTs of 3 to 5.99 months and 6 to 11.99 months, respectively, whereas PSA-DTs of 12 months or greater increased by 15.3%., Conclusions: During the recent PSA era, postoperative PSA failure has significantly decreased and PSA-DTs have increased, suggesting that PCSM will continue to decrease.

We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer [odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09-4.20, P=0.03] and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23-5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01-9.15) and OR=4.42 for two deletions (95%CI=1.32-14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02-2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.

Purpose: Since the introduction of PSA testing for CaP, there has been an increase in CaP detection. However, it is uncertain to what extent clinically insignificant tumors are being diagnosed and treated. In a large, community based population we determined the pathological characteristics of screening detected cancers., Materials and Methods: From 1989 to 2001, 35,661 men were enrolled in a longitudinal prostate cancer screening study. Data were available on 3,492 of the 3,568 men (98%) diagnosed with CaP during this study period. Radical prostatectomy was performed in 2,254 men (63%). Clinical stage, Gleason score and pathological analysis were recorded and analyzed in the context of preoperative PSA, digital rectal examination findings, PSA velocity and the year of cancer detection., Results: CaP was detected in 10% of men. Virtually all cases were clinically localized (99.8%) and approximately 70% treated with radical prostatectomy were pathologically organ confined disease. Fewer than 10% of tumors would be considered clinically insignificant based on 2 previously published pathological criteria., Conclusions: Compared to the high prevalence of CaP found in autopsy studies there is a lower detection rate using current screening protocols. Although the outcomes are unknown if these tumors had been left untreated, the majority met pathological criteria for significant cancer.

Objectives: Limited data are available concerning the extent to which the initial prostate-specific antigen (PSA) measurement in men younger than age 60 predicts for the risk of prostate cancer (CaP) and how this compares to other known risk factors., Methods: From 1991 to 2001, 13,943 men younger than 60 years old participated in a CaP screening study. Men aged 40 to 49 years were eligible for the study if they had a positive family history or African-American heritage, and men older than 50 years were screened without respect to risk factors. The CaP detection rate, PSA velocity, pathologic features, and treatment outcomes were evaluated as a function of the baseline PSA level., Results: The median PSA level was 0.7 ng/mL for men aged 40 to 49 years and 0.9 ng/mL for men aged 50 to 59. A baseline PSA level between the median and 2.5 ng/mL was associated with a 14.6-fold and 7.6-fold increased risk of CaP in men aged 40 to 49 and 50 to 59 years, respectively. A greater baseline PSA value was also associated with a significantly greater PSA velocity, more aggressive tumor features, a greater biochemical progression rate, and a trend toward a greater cancer-specific mortality rate., Conclusions: In men younger than 60, a baseline PSA value between the age-specific median and 2.5 ng/mL was a significant predictor of later CaP and was associated with a significantly greater PSA velocity. A young man's baseline PSA value was a stronger predictor of CaP than family history, race, or suspicious digital rectal examination findings. A greater baseline PSA level was associated with significantly more adverse pathologic features and biochemical progression.

Objectives: To describe the changes in pathologic outcomes and progression-free survival (PFS) rates after radical retropubic prostatectomy for clinically localized prostate cancer in men whose cancers were detected in a 12-year longitudinal prostate cancer screening study., Methods: Between 1989 and 2001, more than 36,000 men participated in a digital rectal examination-based and prostate-specific antigen (PSA)-based screening program. In 1995, the PSA cutoff for biopsy recommendation was lowered from 4.0 ng/mL to 2.6 ng/mL, and the biopsy protocol was changed from four to at least six-sector biopsies. From the screening study, 2952 men were diagnosed with cancer and 2241 of these men underwent radical retropubic prostatectomy. We analyzed the differences in clinical and pathologic stage and PFS after surgery, according to the greater PSA cutoff era (1989 to 1995) and lower PSA cutoff era (1996 to 2001)., Results: A significant downward clinical and pathological stage migration was found toward T1c and organ-confined disease, respectively, in men whose cancer was detected in the lower PSA cutoff era. Furthermore, men with cancer diagnosed in the lower PSA cutoff era had improved PFS rates 5 and 8 years after radical retropubic prostatectomy (P = 0.007). These changes occurred without a significant increase in the proportion of unimportant tumors (organ confined, smaller than 0.5 cm3 without a Gleason pattern of 4 or 5)., Conclusions: These findings support the enhanced detection of favorable cancer and improved PFS rates with lower PSA cutoffs and more intensive biopsy regimens, although the follow-up and lead-time and length-time biases, as well as improvements in surgical technique, might also have affected these results.

Coupling array technology to laser capture microdissection (LCM) has the potential to yield gene expression profiles of specific cell populations within tissue. However, remaining problems with linear amplification preclude accurate expression profiling when using the low nanogram amounts of RNA recovered after LCM of human tissue. We describe a novel robust method to reliably amplify RNA after LCM, allowing direct probing of 12K gene arrays. The fidelity of amplification was demonstrated by comparing the ability of amplified RNA (aRNA) versus that of native RNA to identify differentially expressed genes between two different cell lines, demonstrating a 99.3% concordance between observations. Array findings were validated by quantitative polymerase chain reaction analysis of a randomly selected subset of 32 genes. Using LCM to recover normal (N=5 subjects) or cancer (N=3) cell populations from intact human prostate tissue, three differentially expressed genes were identified. Independent investigators have previously identified differential expression of two of these three genes, hepsin and beta-microseminoprotein, in prostate cancer. Taken together, the current study demonstrates that accurate gene expression profiling can readily be performed on specific cell populations present within complex tissue. It also demonstrates that this approach efficiently identifies biologically relevant genes.

Purpose: Since the United States Food and Drug Administration approved the prostate specific antigen (PSA) blood test as an aid to early prostate cancer detection, using a cutoff of 4.0 ng/ml in 1994, this cutoff has been widely adopted to recommend prostate biopsy. There has been recent investigation into lowering the PSA prompt for biopsy, especially in men younger than 60 years. We determined how a lower cutoff would perform in men older than 60 years., Materials and Methods: From a prostate cancer screening study we studied 782 consecutive men who underwent prostate biopsy for PSA greater than 2.5 ng/ml or suspicious digital rectal examination. Biopsy results were evaluated as a function of patient age., Results: Clinical and pathological characteristics of cancers detected in the PSA range 2.6 to 4.0 ng/ml were similar regardless of patient age. Overall PSA between 2.6 and 4.0 ng/ml was associated with a cancer detection rate of 16.2% using a sextant biopsy technique. PSA velocity was similar in men with prostate cancer in all age groups., Conclusions: More than 15% of men with PSA 2.6 to 4.0 ng/ml who are 40 years or older have prostate cancer detected with sextant needle biopsies. PSA velocity, tumor stage, Gleason grade and tumor volume were similar in all age groups.

Purpose: We evaluated men treated with salvage radiation therapy for increasing serum prostate specific antigen (PSA) following radical retropubic prostatectomy (RRP)., Materials and Methods: We retrospectively reviewed the records of 3,478 consecutive men who underwent radical retropubic prostatectomy (RRP) between 1983 and 2003, as performed by a single surgeon. A total of 307 men received salvage radiation therapy for persistently increased or increasing PSA after RRP. We compared perioperative and peri-radiotherapy clinicopathological parameters in men who achieved an undetectable PSA level after radiation therapy (responders) vs those who did not (nonresponders). We then evaluated the durability of the PSA response., Results: Median time from RRP to PSA progression was 23 months (range 1 to 129). Median followup from RRP was 104 months (range 7 to 225). Median followup from salvage radiotherapy was 56 months (range 0 to 188). Of 223 men with sufficient followup information 162 (73%) subsequently had undetectable PSA (less than 0.3 ng/ml) in response to salvage radiation therapy. There was no significant difference between responders and nonresponders in the distribution of clinical and pathological tumor stages, age at RRP, surgical margin status, and the interval between RRP and salvage radiation therapy. A Gleason score of 8 to 10 was more prevalent in nonresponders than responders (28% vs 13%). Median PSA at salvage radiation therapy was 1.2 ng/ml in nonresponders vs 0.7 ng/ml in responders. Actuarial 5 and 10-year progression-free (PSA less than 0.3 ng/ml) survival probabilities in all 223 men following salvage radiation therapy were 40% (95% CI 32 to 48) and 25% (95% CI 15 to 36), respectively. Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in responders only were 55% (95% CI 45 to 64) and 35% (95% CI 21 to 49), respectively. Only seminal vesicle invasion was significantly associated with progression-free survival following radiation therapy on multivariate analysis., Conclusions: An undetectable PSA level following salvage radiation therapy is more frequently achieved in men with lower pre-radiation serum PSA and those without seminal vesicle or lymph node involvement. Overall approximately a fourth of men with PSA evidence of cancer progression following RRP had a durable response 10 years after the initiation of salvage radiation therapy in the protocols used in this patient cohort.

Objectives: To compare the pathologic outcomes and prostate-specific antigen (PSA) progression rates of patients who underwent radical prostatectomy because of prostate cancers and whose cancer was detected at a PSA level of 2.6 to 4.0 ng/mL versus those with cancer detected after the PSA level rose to greater than 4.0 ng/mL. Some studies have suggested that clinically significant prostate cancer is detected more frequently in an organ-confined stage with a PSA level between 2.6 and 4.0 ng/mL than with a PSA level greater than 4 ng/mL. However, it is uncertain whether this will affect clinical outcomes., Methods: From 1991 to 2001, 20,788 men enrolled in a prostate cancer screening study had an initial PSA level of less than 2.6 ng/mL. Of these patients, 523 had a PSA level that rose to greater than 2.5 ng/mL and had prostate cancer detected. Of the 297 patients who subsequently underwent radical prostatectomy, 223 had a preoperative PSA level of 2.6 to 4.0 ng/mL and 74 had a preoperative PSA level greater than 4.0 ng/mL. The median follow-up was 4 years. The pathologic stage, mean tumor volume, Gleason score, possibly insignificant cancer rate, possibly rapidly progressive cancer rate, and PSA progression rate were compared between the two groups., Results: The patients with a preoperative PSA level between 2.6 and 4.0 ng/mL had more favorable pathologic outcomes in terms of cancer volume, pathologic stage, and possibly rapidly progressive cancer rate. The possibly insignificant cancer rates were not different between the groups. A trend was noted for patients with a preoperative PSA level between 2.6 and 4.0 ng/mL to have a lower PSA progression rate., Conclusions: Biopsy in men with PSA levels between 2.6 and 4.0 ng/mL may detect clinically significant prostate cancer more frequently at an organ-confined stage, with a lower PSA progression rate. Additional study in a larger population with longer follow-up is needed to confirm this trend.

Purpose: We evaluated whether men at risk for significant versus clinically insignificant prostate-specific antigen (PSA) failure after radical prostatectomy could be identified using information available at diagnosis., Patients and Methods: A prospective prostate cancer screening study that enrolled, diagnosed, and treated 1,011 men with radical prostatectomy at Barnes-Jewish Hospital (St Louis, MO) from January 1, 1989, to June 1, 2002, for localized prostate cancer formed the study cohort. Preoperative predictors of a postoperative PSA doubling time (DT) of less than 3 months and more than 12 months or no PSA failure were identified using logistic regression., Results: A preoperative PSA velocity more than 2.0 ng/mL/yr (P = .001) and biopsy Gleason score 7 (P = .006) or 8 to 10 (P = .003) were significantly associated with having a postoperative PSA DT less than 3 months. A PSA level less than 10 ng/mL (P = .005), a nonpalpable cancer (P = .001) with a Gleason score < or = 6 (P = .0002), and a preoperative PSA increase that did not exceed 0.5 ng/mL/yr (P = .03) were significantly associated with a postoperative PSA DT of at least 12 months or no PSA failure. Most men with these preoperative characteristics and a postoperative PSA DT of 12 months or more had a persistent postoperative PSA level of at least 0.2 ng/mL that did not exceed 0.25 ng/mL after a median follow-up of 3.6 years., Conclusion: A postoperative PSA DT less than 3 months is associated with a preoperative PSA velocity more than 2.0 ng/mL/yr and high-grade disease. Select men with a postoperative PSA DT more than 12 months may not require salvage radiation therapy.

Purpose: Almost 75% of men with a prostate specific antigen (PSA) of 2.6 to 4.0 ng/ml have no evidence of prostate cancer on biopsy. Deciding whether and when to repeat the biopsy is challenging. We determined if patient specific variables might identify men at increased risk for the subsequent detection of prostate cancer., Materials and Methods: We analyzed the records of 24,893 men from a community based prostate cancer screening study. Our study group consisted of 1,202 men with PSA 2.6 to 4.0 ng/ml and a previously negative prostate biopsy. Patient specific variables were analyzed for their value in predicting a future diagnosis of prostate cancer., Results: Of 1,011 men with adequate followup 136 (13.5%) were subsequently diagnosed with prostate cancer. Mean followup +/- SD in men without prostate cancer was 72 +/- 36 months. Prostate cancer was subsequently diagnosed in 35% of men with high grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy (p <0.0001), in 18% with abnormal or suspicious digital rectal examination (DRE) (p = 0.02) and 16% with an annual PSA velocity of 0 ng/ml (p = 0.002). Multivariate analysis identified HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, family history of prostate cancer and annual PSA velocity 0 ng/ml as predictors of prostate cancer., Conclusions: Men with a PSA of 2.6 to 4.0 ng/ml and negative biopsy should be advised to undergo repeat biopsy if they have HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, a family history of prostate cancer or a PSA velocity of 0 ng/ml or greater.

Purpose: Current guidelines of the American Cancer Society and the National Comprehensive Cancer Network recommend offering annual prostate cancer screening with prostate specific antigen (PSA) and digital rectal examination (DRE) beginning at age 50 (age 45 in high risk men). There are limited data concerning outcomes if all men followed screening guidelines. We report early outcome data on men who entered a prostate cancer screening study, complied with the screening guidelines and were subsequently diagnosed with prostate cancer., Materials and Methods: We reviewed records of men 45 to 59 years old at study entry with a PSA less than 2.6 ng/ml and benign DRE who underwent annual DRE and PSA testing in a screening study between 1991 and 2001. Of 10,174 men with these characteristics, 232 (2.3%) were subsequently diagnosed with prostate cancer. We evaluated PSA, Gleason score, clinical and pathological tumor stage, and treatment outcomes in these men., Results: Median PSA at diagnosis was 3.1 ng/ml (range 0.4 to 9.6). Gleason scores ranged from 4 to 9. All patients had clinically localized disease. Management included predominantly radical prostatectomy (87%) and radiation therapy (10%). Of cancers in which tumor volume was assessed 13% were considered possibly harmless tumors by previously published criteria and 2% were considered possibly rapidly progressive tumors by criteria we set in this study., Conclusions: Prostate cancer screening using some current guidelines results in the detection of cancers that are organ confined in 79% of patients, possibly harmless in less than 15% and possibly rapidly progressive in 2%.

Objectives: To examine biochemical progression-free survival (PFS) rates as a function of preoperative prostate-specific antigen (PSA) in patients with clinical Stage T1c prostate cancer treated with radical prostatectomy. Controversy exists about whether performing prostate biopsies for PSA levels in the 2.6 to 4.0 ng/mL range provides a PFS advantage compared with detection at higher PSA ranges., Methods: A total of 2804 men with clinical Stage T1c prostate cancer were treated with radical retropubic prostatectomy and monitored prospectively. The study parameters included preoperative PSA level, pathologic tumor stage, and Gleason grade. Patients were grouped into four clinically relevant strata according to their preoperative PSA level: 2.6 to 4.0, 4.1 to 7.0, 7.1 to 10.0, and greater than 10 ng/mL. The primary outcome was the 10-year actuarial biochemical PFS estimate generated using the Kaplan-Meier method. We compared the strata using the log-rank test. Cancer progression rates were compared using the Cochran Armitage test for trend. The chi-square test was used to compare the pathologic parameters among the PSA strata., Results: Of the men with a preoperative PSA level of 2.6 to 4.0, 4.1 to 7.0, 7.1 to 10.0, and greater than 10.0 ng/mL, 81%, 74%, 72%, and 60%, respectively, had organ-confined disease (P = 0.001) and 23%, 28%, 35%, and 47%, respectively, had a pathologic Gleason grade of 7 or greater (P = 0.001). The corresponding 10-year PFS estimates were 88%, 80%, 76%, and 61% (P = 0.0001, for trend)., Conclusions: Among men with clinical Stage T1c prostate cancer, those with a PSA level of 2.6 to 4.0 ng/mL had the greatest rate of organ-confined disease, lowest pathologic Gleason grade, and greatest 10-year PFS rate.

Purpose: We compared biochemical progression rates measured by increasing prostate specific antigen (PSA) levels using a standard definition of biochemical recurrence among patients with screen detected prostate cancer treated with radical prostatectomy (RP) or radiotherapy (RT)., Materials and Methods: A total of 1,939 patients diagnosed with clinically localized prostate cancer in a community based screening study from 1989 to 1998, followed through 2001, were treated with RP or RT and agreed to enroll in a followup study. This prospective cohort study (median followup 62 months, range 0.2 to 141) used adjusted Cox proportional hazards models to examine time to progression. Selection bias was addressed with propensity scores. Biochemical evidence of cancer progression was defined as PSA greater than 0.2 ng/ml in patients who underwent RP and 3 consecutive PSA increases as recommended by the American Society for Therapeutic Radiology and Oncology criteria for radiotherapy., Results: Of the patients 17% had evidence of cancer progression. The percentage with progression-free survival at 5 and 9 years for RP was 84% and 76%, respectively, and for RT 80% and 70%, respectively. Cox proportional hazards models produced a hazard ratio of 1.63 (95% CI, 1.12, 2.38) for RT compared with RP, adjusting for clinical stage, Gleason grade, preoperative PSA, biopsy age, treatment year and propensity for treatment type., Conclusions: With intermediate term followup, patients treated with RT were more likely to have cancer progression than with RP adjusting for demographics, clinical factors, selection bias and treatment year.

Purpose: Seminal vesicle invasion (SVI) in a radical prostatectomy (RRP) specimen is associated with a guarded prognosis. We evaluated patients with SVI treated in the pre-prostate specific antigen (PSA) (1983 to 1991) and PSA (1992 to 2003) eras., Materials and Methods: Of patients with prostate cancer treated with RRP from January 1983 through March 2002, 220 with SVI were evaluated, including 67 in the pre-PSA era and 153 in the PSA era. Postoperative PSA greater than 0.2 ng/ml was considered biochemical evidence of cancer progression. Survival rates were compared using Kaplan-Meier estimates to calculate progression-free, cancer specific and all cause survival. Multivariate Cox proportional hazard models were used to correlate variables with disease progression., Results: The incidence of SVI in the PSA era was lower than in the pre-PSA era (6.0% vs 10.2%, p = 0.001). To date 124 patients (56%) have had evidence of cancer progression. The 4 and 7-year progression-free, cancer specific and all cause survival rates were significantly higher in men with SVI in the PSA era (p = 0.02). PSA at diagnosis, cancerous surgical margins and higher Gleason score were significantly associated with progression. Neither adjuvant nor salvage radiotherapy appeared to confer a significant progression-free survival benefit., Conclusions: The incidence of SVI has decreased in the PSA era. Progression-free, cancer specific and all cause survival rates following RRP in patients with SVI have improved in the PSA era. This may reflect earlier detection in this pathological tumor stage and more favorable prognostic factors associated with PSA screening. Adjuvant radiotherapy does not appear to confer any therapeutic benefit. Salvage radiotherapy can lead to durable PSA regressions in a small percent of men, although no long-term survival advantage can be proved.

Purpose: The American Urological Association and American Cancer Society advocate annual screening with serum prostate specific antigen (PSA) and digital rectal examination starting at age 50 years in the general population and earlier in men at high risk. Some groups have suggested that screening at 2 or 4-year intervals may be sufficient in men with initial PSA 2 ng/ml or less. We reviewed the records of men enrolled in a PSA and digital rectal examination based prostate cancer screening study to determine the extent to which the diagnosis of cancer would have been delayed using a 2 or 4-year screening interval., Materials and Methods: We evaluated 18,140 volunteers in a prostate cancer screening study in whom PSA was less than 2 ng/ml at initial screening and who were screened at 6-month to 1-year intervals for up to 8 years. We evaluated the cancers detected in these intervals to determine the possible delay in cancer diagnosis that would occur using prolonged screening intervals. We report the overall cancer detection rate, clinical and pathological tumor stage, and Gleason grade of the cancers detected., Results: Excluding 70 men in whom prostate cancer was detected at initial evaluation 2.0% had prostate cancer detected during the next 8 years (mean 21.6 cancers per 6 months, median 20, range 12 to 33). Using a hypothetical 2-year screening interval cancer detection 62% would have been delayed by 4 to 20 months. Using a hypothetical 4-year screening interval cancer detection would have been delayed in 77% of men by 4 to 44 months. Of the tumors detected 100% were clinically localized, 77% were pathologically organ confined and 29% had a Gleason score of 7 or greater., Conclusions: The 2 or 4-year PSA screening interval in men with initial serum PSA less than 2 ng/ml would result in substantial delays in prostate cancer detection. To our knowledge the extent to which these delays would affect treatment outcomes is undetermined.

Objectives: To assess the current incidence of prostate carcinoma detection in serial biopsies in a prostate-specific antigen-based screening population after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia (HG-PIN) in needle biopsy tissue., Methods: We retrospectively identified 190 men with a diagnosis of isolated HG-PIN in needle biopsy tissue. Most men (86%) were diagnosed from 1996 to 2000. Logistic regression analysis was used to predict the presence of carcinoma in these 190 men and in a control group of 1677 men with only benign prostatic tissue in needle biopsy tissue., Results: The cumulative risk of detection of carcinoma on serial sextant follow-up biopsies was 30.5% for those with isolated HG-PIN compared with 26.2% for the control group (P = 0.2). Patient age (P = 0.03) and serum prostate-specific antigen level (P = 0.02) were significantly linked to the risk of cancer detection, but suspicious digital rectal examination findings (P = 0.1), the presence of HG-PIN (P = 0.2), and the histologic attributes of PIN were not (all with nonsignificant P values). HG-PIN found on the first repeat biopsy was associated with a 41% risk of subsequent detection of carcinoma compared with an 18% risk if benign prostatic tissue was found on the first repeat biopsy (P = 0.01)., Conclusions: The results of our study have shown that the current level of risk for the detection of prostate carcinoma in a screened population is 30.5% after a diagnosis of isolated HG-PIN in a needle biopsy. This risk level is lower than the previously reported risk of 33% to 50%. HG-PIN is a risk factor for carcinoma detection only when found on consecutive sextant biopsies. The data presented here should prompt reconsideration of repeat biopsy strategies for HG-PIN, and re-evaluation of the absolute necessity of repeat biopsy for all patients with HG-PIN.

The TGFBR1*6A (*6A) variant in exon 1 of the TGFBR1 gene has been postulated as a putative tumor susceptibility allele in several studies. We have performed a case-control study in 537 men with histologically verified prostate cancer and in 488 unrelated controls to investigate the association of *6A with prostate cancer. Our results revealed that the frequency of the (*)6A allele does not differ in men with prostate cancer compared to healthy controls, even in a subset of age-matched cases and controls. There is no compelling evidence for an association of the *6A variant with prostate cancer.

Purpose: The ability to estimate prostate weight is useful. Two commonly used methods for estimating prostate weight are digital rectal examination (DRE) and transrectal ultrasonography (TRUS). We evaluated the relative accuracy of these weight estimates by comparing them to prostate weight following radical retropubic prostatectomy (RRP)., Materials and Methods: Between 1989 and 2001 more than 36,000 community men participated in a large prostate cancer screening study. Of these men 2,238 underwent RRP. In this subset we examined the correlation between documented preoperative DRE and TRUS estimates of prostate weight with actual gland weight., Results: DRE estimates of prostate weight by multiple examiners correlated poorly with RRP specimen weight (r = 0.2743). However, TRUS estimates correlated moderately well (r = 0.6493). TRUS provided more accurate estimates of prostate weight for smaller glands, although it generally underestimated gland weight compared to the weight of the surgical specimen., Conclusions: In a large, community based prostate cancer screening study prostate weight estimated by DRE was shown to correlate poorly with actual prostate weight. Compared with DRE, TRUS provides a better estimate of prostate weight. In addition, TRUS measurements were more accurate in smaller prostate glands.

Purpose: We report results in a series of 3,477 consecutive patients treated with anatomical nerve sparing radical retropubic prostatectomy (RRP) in terms of recovery of erectile function, urinary continence and postoperative complications., Materials and Methods: From May 1983 through February 2003, 1 surgeon (WJC) performed anatomical RRP using a unilateral or bilateral nerve sparing modification when possible. Urinary continence and recovery of erections were evaluated in men with a minimum followup of 18 months. Excluded from potency analysis were men who were not reliably potent before surgery, those who did not undergo a nerve sparing procedure and those who received postoperative adjuvant radiotherapy or hormonal therapy within 18 months of surgery. Other postoperative complications in this patient population were also evaluated., Results: Erections sufficient for intercourse occurred in 76% of preoperatively potent men treated with bilateral (1,770) and 53% of men treated with unilateral or partial nerve sparing (64) surgery. Adequate erectile function was more common following bilateral than unilateral nerve sparing surgery in men younger than 70 years old (78% versus 53%, p = 0.001) compared with those 70 years old or older (52% versus 56%, p = 0.6). Recovery of urinary continence occurred in 93% of all men and was associated with younger age (p = 0.001) but not nerve sparing surgery, tumor stage, prostate specific antigen (PSA), Gleason grade or number of prior prostatectomies performed by the surgeon. Postoperative complications occurred in 320 (9%) of patients and were associated with older age (p <0.0001), nonnerve sparing surgery (p = 0.001), PSA era (p <0.0001) and surgeon experience. Complications were not significantly correlated with clinical stage, pathological stage, preoperative PSA or Gleason grade. There was no perioperative mortality., Conclusions: Nerve sparing RRP can be performed with favorable potency and urinary continence. Better results are achieved in younger men. Other complications are reduced with increasing surgeon experience.

Purpose: Hemospermia is uncommon clinical condition that usually follows a benign course. The association between hemospermia and prostate cancer has been reported but to our knowledge not thoroughly investigated. We studied the incidence of hemospermia and the association between prostate cancer and hemospermia in a large prostate cancer screening population., Materials and Methods: Between 1991 and 2001, 26,126 ambulatory men 50 years or older (40 years or older with a family history of prostate cancer or black race) underwent a community based prostate cancer screening study using serum prostate specific antigen (PSA) and digital rectal examination (DRE). PSA measurement and DRE were repeated at 6-month or 1-year intervals depending on PSA for the remainder of the study. Men underwent prostate biopsy due to increased serum PSA (greater than 4.0 ng/ml until May 1995 or greater than 2.5 ng/ml after May 1995) or suspicious DRE. Men with a history of prostate cancer were excluded from study. Men completed a questionnaire, including information about hemospermia, at each screening visit. Hemospermia information from the initial questionnaire was analyzed. The relative risk of prostate cancer diagnosis in the overall prostate cancer screening population and the cohort with hemospermia was determined. Detailed prostate cancer characteristics were evaluated in those who had hemospermia and underwent radical prostatectomy. We used a multivariate logistic regression model to test the independent significance of hemospermia after adjusting for other known predictors of prostate cancer detection., Results: Prostate cancer was detected in 1,708 of the 26,126 men (6.5%) who underwent prostate cancer screening. Prostate cancer was diagnosed in 19 of the 139 men (13.7%) who reported hemospermia upon entering the prostate cancer screening study. The median age of the 139 men was 61 years (range 40 to 89). Ten of the 13 men who underwent radical retropubic prostatectomy had stage pT2 disease, while 3 had stage pT3 disease. In the logistic regression model hemospermia was a significant predictor of prostate cancer diagnosis after adjusting for age, PSA and DRE results (OR 1.73, p = 0.054)., Conclusions: Hemospermia is rare (0.5%) in a prostate cancer screening population. When a man presents with hemospermia, prostate cancer screening should be vigilantly performed since hemospermia is associated with an increased risk of prostate cancer.

Objectives: To evaluate the association between the preoperative prostate-specific antigen (PSA) level and the interval to biochemical progression after radical retropubic prostatectomy (RRP) for prostate cancer., Methods: We studied 5534 men who underwent RRP for prostate cancer during a 15-year period and were enrolled in prospective follow-up studies. Of these men, 857 (15%) subsequently had biochemical evidence of cancer progression (PSA greater than 0.2 ng/mL). All men with biochemical progression after RRP were arbitrarily stratified into five groups according to their preoperative PSA level: less than 2.6 ng/mL, 2.6 to 4 ng/mL, 4.1 to 10 ng/mL, 10.1 to 20 ng/mL, and greater than 20 ng/mL. The time to biochemical progression after RRP was the primary endpoint of the analysis. Other prognostic factors were also evaluated in multivariable analysis., Results: The median time to progression for men with a PSA level greater than 20 ng/mL was significantly shorter (16 months) than for men with a PSA level of 10.1 to 20 ng/mL (27 months) or those with lower PSA levels (P = 0.0005). Men with a PSA level of 4.1 to 10 ng/mL did not have a statistically significantly different median time to progression (31 months) from men with a PSA level of 10.1 to 20 ng/mL (27 months; P = 0.3), 2.6 to 4 ng/mL (32 months; P = 0.8), or less than 2.6 ng/mL (38 months; P = 0.3). Also, no statistically significant difference was found in the median time to progression between men with a PSA level of 2.6 to 4 ng/mL and less than 2.6 ng/mL (P = 0.4). In an analysis of covariance multivariate analysis, the preoperative PSA level was not an independent predictor of the time to biochemical progression (P = 0.12), after accounting for tumor stage and Gleason grade., Conclusions: The preoperative PSA level was significantly associated with the interval to biochemical cancer progression after RRP; however, this association appeared to be because the preoperative PSA level serves as a surrogate marker for other prognostic factors, such as the tumor volume, tumor stage, and Gleason grade.

Purpose: We updated a long-term cancer control outcome in a large anatomical radical retropubic prostatectomy (RRP) series. We also evaluated the perioperative parameters that predict cancer specific outcomes following surgery., Materials and Methods: From May 1983 to February 2003, 1 surgeon (WJC) performed RRP in 3,478 consecutive men. Patients were followed with semiannual serum prostate specific antigen (PSA) tests and annual digital rectal examinations. We used Kaplan-Meier product limit estimates to calculate actuarial 10-year probabilities of biochemical progression-free survival, cancer specific survival and overall survival. Multivariate Cox proportional hazards models were used to determine independent perioperative predictors of cancer progression., Results: At a mean followup of 65 months (range 0 to 233) actuarial 10-year biochemical progression-free, cancer specific and overall survival probabilities were 68%, 97% and 83%, respectively. On multivariate analysis biochemical progression-free survival probability was significantly associated with preoperative PSA, clinical tumor stage, Gleason sum, pathological stage and treatment era. Cancer specific survival and overall survival rates were also significantly associated with clinicopathological parameters., Conclusions: RRP can be performed with excellent survival outcomes. Favorable clinicopathological parameters and treatment in the PSA era are associated with improved cancer control.

Purpose: Previous studies of archived blood samples from nonscreened populations have shown an association between the prostate specific antigen (PSA) and the subsequent detection of prostate cancer. In the current study we evaluated the relationship between the initial screening PSA and the subsequent risk of prostate cancer detected in a prospective, longitudinal screening study. We also examined the relationship between initial PSA and the clinicopathological features of the cancers detected., Materials and Methods: Between May 1991 and November 2001 we enrolled 26,111 volunteers in our PSA and digital rectal examination based prostate cancer screening study. The men were followed biannually or annually depending on the results of previous screening tests. The chi-square and Kruskal-Wallis tests were used to compare the clinical stage, pathological stage and Gleason score of subsequently detected prostate cancers as well as the time to cancer detection in different initial screening PSA strata., Results: The initial screening PSA stratum was strongly associated with the subsequent detection of prostate cancer as well as the clinicopathological stage and grade of the cancers detected., Conclusions: Even in the lower PSA ranges initial screening serum PSA can help identify men at increased risk for subsequent prostate cancer detected in a longitudinal screening study.

Purpose: We evaluated tumor size, measured as the percent of the prostate involved by cancer, as a predictor of tumor recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer., Materials and Methods: One of us (WJC) performed radical retropubic prostatectomy in 1,850 men who had pathologically organ confined prostate cancer with tumor size recorded between January 1988 and February 2003. The percent of prostate tissue involved by carcinoma in the radical prostatectomy specimen was estimated by visual inspection. We compared clinicopathological characteristics in patients who did and did not have tumor recurrence and stratified them by percent of tumor in the prostatectomy specimen. We also evaluated the relationship between percent of cancer and biochemical evidence of cancer recurrence., Results: Patients who had recurrence were slightly older (mean age 62 vs 60 years, p = 0.004), and had higher mean preoperative prostate specific antigen (8.6 vs 6.3 ng/ml, p <0.0001) and a higher proportion of poorly differentiated tumors (Gleason grades 8 to 10) (7% vs 1%, p = 0.001). The mean percent of cancer was higher in men with recurrence (11% vs 7%, p <0.0001). Men with 10% or greater of the gland involved by cancer had a 10% recurrence rate compared with a 5% rate in men in whom cancer involved less than 10% of the gland (p = 0.001). The 5-year recurrence-free survival rate was 94%, 91% and 82% in patients with less than 10%, 10% to 20% and greater than 20% of the gland involved. The multivariate Cox model indicated that the percent of cancer involvement of the prostate provides unique predictive information about the risk of cancer recurrence (p = 0.0001). The estimated 5-year recurrence-free survival rate based on the Cox model indicated that patients with greater than 20% of the gland involved by tumor, clinical stage T2/T3 and Gleason sum >/=7 were at substantial risk of cancer recurrence., Conclusions: Tumor size measured as the percent of cancer is an independent predictor of cancer recurrence after radical prostatectomy in patients with pathologically organ confined prostate cancer.

Purpose: Pro forms of prostate specific antigen (PSA) have been reported to be more cancer specific markers of prostate cancer than total PSA and they also may preferentially detect the more aggressive forms of the disease., Materials and Methods: Research immunoassays with high specificity for pro-PSA forms were used to study 1091 retrospective serum specimens, including 555 with 2 to 4 and 536 with 4 to 10 ng/ml PSA, from men enrolled in prostate cancer screening studies who underwent prostate biopsy., Results: In the 2 to 4 ng/ml PSA range the ratio of pro- to free-PSA (percent pro-PSA) using a cutoff of 1.8% for recommending prostate biopsy detected 90% of cancers, including 16 of 16 extracapsular tumors and 28 of 29 tumors with a pathology Gleason score of 7 or greater, while avoiding 19% of unnecessary biopsies. Serum percent pro-PSA was significantly increased for Gleason score 7 or greater vs less than 7 (p = 0.0018). In the PSA range of 4 to 10 ng/ml percent pro-PSA had the highest cancer specificity, avoiding 31% of unnecessary biopsies, while detecting 34 of 35 cancers with a pathology Gleason score of 7 or greater and 29 of 31 extracapsular tumors. Neither percent free PSA nor complexed PSA enhanced the detection of aggressive cancers in the 4 to 10 ng/ml PSA range., Conclusions: Percent pro-PSA was superior to percent free and calculated complexed PSA for the detection of prostate cancer in the PSA range of 2 to 10 ng/ml and it had selectivity for detecting more aggressive cancers, as indicated by Gleason score 7 or greater and/or extracapsular tumor extension.

Introduction: Pro or precursor forms of prostate-specific antigen (PSA) have emerged as potentially important diagnostic serum markers for prostate cancer detection. Immunoassays were developed to measure specific proPSA forms containing propeptides of 2, 4, and 7 amino acids [(-2)proPSA, (-4)proPSA, and (-7)proPSA, respectively]., Methods: Research-use dual monoclonal antibody immunoassays using europium-labeled detection monoclonal antibodies were developed for each form of proPSA. Sera from patients with prostate cancer or benign prostate disease containing 4-10 microg/L PSA were assayed and analyzed by area under the ROC curve (AUC) for specificity and sensitivity., Results: The proPSA forms had quantification limits of 0.015-0.025 microg/L in serum, with cross-reactivities <1% with PSA. The sum of the proPSA forms divided by free PSA (percentage proPSA) had a higher AUC than did percentage of (-2)proPSA, free PSA, and complexed PSA with AUC (95% confidence intervals) of 0.69 (0.64-0.74), 0.64 (0.58-0.68), 0.63 (0.58-0.68), and 0.57 (0.51-0.62), respectively. The proPSA comprised a median of 33% of the free PSA in cancer and 25% in noncancer sera (P <0.0001). One-third (33%) of cancer samples had >40% proPSA, whereas only 8% of noncancer samples did (P <0.0001). In men with cancer and >25% free PSA, the (-2)proPSA had an AUC of 0.77 (0.66-0.86), with 90% sensitivity and 36% specificity at 0.04 microg/L., Conclusions: The percentage of proPSA gave better cancer detection in the 4-10 microg/L range than did percentage of free PSA and complexed PSA. (-2)proPSA significantly discriminated cancer in men whose serum had >25% free PSA, for whom there is currently no good marker for cancer detection.

This article discusses prostate-specific antigen (PSA) and screening for prostate cancer. Topics explored include the history of PSA testing, the biology of PSA, clinical uses of PSA testing, improving the accuracy of PSA testing, and controversies in prostate cancer screening.

Purpose: Free and total serum prostate specific antigen (PSA) levels are frequently used for early prostate cancer detection in men with a total PSA in the 2.6 to 10 ng/ml range. Results from a longitudinal study suggested that the free-to-total PSA ratio (F/T PSA), declining the decade before prostate cancer diagnosis, is the earliest serum marker predicting a subsequent diagnosis of prostate cancer. Other than this study, there are limited data on the predictive value of longitudinal F/T PSA measurements for subsequent cancer. To evaluate the clinical importance of a decreasing F/T PSA, we compared longitudinal F/T PSA in volunteers in a prostate cancer screening study., Materials and Methods: We evaluated 657 volunteers in a screening study with a total PSA of 2.6 to 10 ng/ml but whose initial biopsies were either negative for cancer or were waived. To obtain meaningful F/T PSA slopes, the patients have been followed with at least 3 F/T PSA levels measured for 3 or greater years (mean 3.5, median 3.5, range 3 to 5.3). Of these men 22 subsequently were diagnosed with prostate cancer. We calculated the F/T PSA slope as the last F/T PSA minus the first F/T PSA divided by the interval between the measurements. The F/T PSA slopes of the patients with and without cancer were compared using chi-square analysis., Results: Mean F/T PSA slope for the patients with cancer was -0.06 (median -0.03, range -0.63 to 0.22) compared to mean slope of -0.02 (median -0.01, range -0.57 to 0.69) for patients without cancer (p = 0.21). Of the patients with cancer 61% had a negative slope compared with 54% of patients without cancer (p = 0.59). The positive predictive value of a negative F/T PSA slope for subsequent cancer detection to date is only 4%., Conclusions: A decreasing F/T PSA during a 3 to 5-year interval has little value in predicting subsequent diagnosis of prostate cancer. Further followup of a larger number of patients will be required to determine the value of longitudinal F/T PSA measurements in early prostate cancer detection.

Considerable evidence demonstrates that genetic factors are important in the development and aggressiveness of prostate cancer. To identify genetic variants that predispose to prostate cancer we tested candidate SNPs from genomic regions that show linkage to prostate cancer susceptibility and/or aggressiveness, as well as genes that show a significant difference in mRNA expression level between tumor and normal tissue. Cases had histologically verified prostate cancer. Controls were at least 65 years old, never registered a PSA above 2.5 ng/ml, always had digital rectal examinations that were not suspicious for cancer, and have no known family history of prostate cancer. Thirty-nine coding SNPs and nine non-coding SNPs were tested in up to 590 cases and 556 controls resulting in over 40,000 SNP genotypes. Significant differences in allele frequencies between cases and controls were observed for ID3 (inhibitor of DNA binding), p = 0.05, HPN (hepsin), p = 0.009, BCAS1 (breast carcinoma amplified sequence 1), p = 0.007, CAV2 (caveolin 2), p = 0.007, EMP3 (epithelial membrane protein 3), p < 0.0001, and MLH1 (mutL homolog 1), p < 0.0001. SNPs in three of these genes (BCAS1, EMP3 and MLH1) remained significant in an age-matched subsample., (Copyright (c) 2004 S. Karger AG, Basel.)

Prostate cancer is the most frequently diagnosed neoplasia in men and one of the leading causes of cancer-related deaths in men over 60. In an effort to understand the molecular events leading to prostate cancer, we have identified PCAN1 (prostate cancer gene 1) (also known as GDEP), a gene that is highly expressed in prostate epithelial tissue and frequently mutated in prostate tumors. Here we demonstrate its expression in neural retina, and retinoblastoma cell culture but not retinal pigment epithelial cell culture. We further characterize PCAN1 expression in the prostate cell lines RWPE1, RWPE2, and LnCAP FGC. We demonstrate an increase in expression when the cells are grown in the presence of Matrigel, an artificial extracellular basement membrane. Expression was time dependent, with expression observed on d 6 and little or no expression on d 12. Testosterone was not found to increase PCAN1 expression in this culture system. In addition, normal prostate epithelial cells co-cultured with normal prostate stromal cells did not exhibit PCAN1 expression at any time. To definitively locate the transcription initiation sites, we performed restriction-ligase-mediated 5' RACE, to selectively amplify only mRNA with a 5' cap. An initial characterization of the sequence upstream of the initiation sites determined six possible binding sites for the prostate specific regulatory protein NKX3.1 and four potential binding sites for the PPAR/RXR heterodimer that is involved in the control of cell differentiation and apoptosis.

Purpose: Pro prostate specific antigen (pPSA) is a precursor form of PSA enriched in tumor compared to benign prostate tissues that may be a more specific serum marker for prostate cancer. Serum pPSA was measured in the clinically relevant early detection PSA range of 2 to 10 ng/ml., Materials and Methods: Research use immunoassays were used to measure native and truncated forms of pPSA. The subject cohort contained 1,091 serum specimens from men enrolled in prostate cancer screening studies at 2 sites who had undergone prostate biopsy and were divided into PSA ranges of 2 to 4 ng/ml (benign 320, cancer 235) and 4 to 10 ng/ml (benign 315, cancer 221)., Results: In PSA ranges 2 to 4, 2 to 6, 4 to 10 and 2 to 10 ng/ml, pPSA in a ratio with free PSA (%pPSA) gave the highest cancer specificity. At 2 to 4 ng/ml and 90% sensitivity, %pPSA spared 19% of unnecessary biopsies compared to 10% for free PSA and 11% for complexed PSA(p <0.001). Similar results were obtained at PSA 2 to 6 ng/ml. At 90% sensitivity in the PSA 4 to 10 ng/ml range, %pPSA spared 31% of unnecessary biopsies compared to 20% for % free PSA and 19% for complexed PSA (p <0.0001). In the combined 2 to 10 ng/ml range, %pPSA spared 21% of unnecessary biopsies compared to 13% for % free PSA and 9% for complexed PSA (p <0.0001)., Conclusions: The %pPSA significantly improved specificity for cancer detection and decreased the number of unnecessary biopsies in the PSA 2 to 4 ng/ml range. This relative improvement of %pPSA compared to % free PSA and complexed PSA was maintained throughout the PSA range of 2 to 10 ng/ml.

Background: Substantial evidence suggests that genetic factors play an important role in both the risk of prostate cancer and its biologic aggressiveness. Here we investigate prostate cancer susceptibility and aggressiveness with genome-wide linkage analyses of affected brothers., Methods: We first undertook a new genome-wide linkage study of 259 brothers with prostate cancer. Our analyses tested whether the proportion of marker alleles shared by brothers was correlated with disease status or Gleason score. To further clarify 11 linkage regions observed here or previously, we genotyped and analyzed an additional 101 finely spaced markers in the 259 men, and in 594 previously studied brothers, allowing for a pooled genome-wide analysis of 853 affected brothers., Results: In the new study, we detected linkage to prostate cancer on chromosome 16q23 (P = 0.009), replicating previous results, and to chromosome 11q24 (P = 0.001). In the pooled analysis, the 16q23 linkage was strengthened (P = 0.0005), as was our previous linkage to chromosome 16p (P = 0.0001), and we detected linkage to chromosome 2q32 (P = 0.009). When evaluating Gleason score, our new study detected linkage to chromosome 7q32 (P = 0.0009), again replicating previous results, and to chromosomes 5p15 (P = 0.003), 9q34 (P = 0.009), 10q26 (P = 0.03), and 18p11 (P = 0.02). In the pooled analysis of Gleason score, we observed stronger linkage to chromosome 7q32 (P = 0.0002), but slightly weaker linkage to chromosomes 5q33 (P = 0.005) and 19q13 (P = 0.009) than previously reported. In addition, the new linkages to chromosomes 10q26 and 18p11 were strengthened (P = 0.0002 and P = 0.002, respectively)., Conclusions: Our results provide compelling evidence for loci harboring prostate cancer susceptibility and tumor aggressiveness genes, especially on chromosomes 16q23 and 7q32., (Copyright 2003 Wiley-Liss, Inc.)

Background: Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified., Methods: We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided., Results: The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001)., Conclusions: Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.

A multigenic model of prostate cancer susceptibility has been proposed, in which common polymorphic variants of genes, such as the androgen and vitamin D receptor, contribute to tumorigenesis. The discovery of additional genetic factors that contribute to prostate cancer risk should provide opportunities for new approaches to the detection and treatment of this common malignancy. Herein, we examined single nucleotide polymorphic variants in the 3'-untranslated region of CDKN1A (p21(cip1)) and in codon 109 of CDKN1B (p27(kip1)) for association with advanced prostate cancer in a European-American population. Ninety-six cases and 106 controls were analyzed using PCR amplification and restriction digestion assays. CDKN1A genotype was scored as CC, CT, and TT on the basis of the digestion products. The CDKN1A genotypes CT and TT were associated with an increased risk of advanced prostate carcinoma compared with the CC genotype [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.02-4.95]. The CDKN1B genotype was scored as VV, VG, or GG, again on the basis of the digestion products. The CDKN1B genotype VV was also associated with an increased risk of advanced prostate carcinoma (OR, 1.95; 95% CI, 1.09-3.47). These associations were particularly strong in those patients with androgen-independent disease [OR = 2.88 (95% CI, 1.19-6.97) and 2.11 (95% CI, 1.05-4.22) for high-risk genotypes of CDKN1A and CDKN1B, respectively]. In addition, the association of CDKN1B was particularly strong in the cohort of patients under the median age of diagnosis (OR, 2.23; 95% CI, 1.08-4.59). These results suggest that in a European-American population, CDKN1A and CDKN1B variants are associated with advanced prostate cancer. Analysis of CDKN1A and/or CDKN1B genotypes may prove useful in determining which patients are at risk for developing advanced prostate carcinoma and therefore would gain the most from aggressive screening, prophylaxis, and/or treatment.

Whole-genome scan studies recently identified a locus on chromosome segments 19q12-q13.11 linked to prostate tumor aggressiveness by use of the Gleason score as a quantitative trait. We have now completed finer-scale linkage mapping across this region that confirmed and narrowed the candidate region to 2 cM, with a peak between markers D19S875 and D19S433. We also performed allelic imbalance (AI) studies across this region in primary prostate tumors from 52 patients unselected for family history or disease status. A high level of AI was observed, with the highest rates at markers D19S875 (56%) and D19S433 (60%). Furthermore, these two markers defined a smallest common region of AI of 0.8 Mb, with 15 (29%) prostate tumors displaying interstitial AI involving one or both markers. In addition, we noted a positive association between AI at marker D19S875 and extension of tumor beyond the margin (P = 0.02) as well as a higher Gleason score (P = 0.06). These data provide strong evidence that we have mapped a prostate tumor aggressiveness locus to chromosome segments 19q12-q13.11 that may play a role in both familial and non-familial forms of prostate cancer., (Copyright 2003 Wiley-Liss, Inc.)

Prostate cancer is the most frequently diagnosed visceral cancer of men, responsible for approximately 40,000 deaths in adult males per year. To identify the genetic causes of prostate cancer, we performed a whole genome scan of affected sib pairs, using DNA markers spaced evenly across the human genome. We demonstrated that regions on chromosomes 1, 4, 5, 7, 8, 11, 16 and 19 might harbor genes that predispose individuals to prostate cancer and may affect tumor growth rate and tumor aggressiveness. Here we present DNA sequence analysis of KIAA 0872 and 17-beta hydroxysteroid dehydrogenase that are located on chromosome 16 within the mapped region, and we demonstrate that neither of these genes carries mutations in the protein coding region or their splice junction sites. These results suggest that these genes are less likely to be associated with the cause of familial prostate cancer.

RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk.