Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia.

BACKGROUND: Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. METHODS: Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. RESULTS: Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11-1.40; p-trendfor continuous BMI < 0.0001) and men who were either overweight or obese in late-life were more likely to report a prostate volume ≥ 30 cc (RRoverweight: 1.13, 95% CI 1.07-1.21; RRobese: 1.10, 95% CI 1.02-1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98-1.22; RRnormal to obese: 1.28, 95% CI 1.10-1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05-1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. CONCLUSIONS: We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO study.

BACKGROUND: Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear. METHODS: We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified. RESULTS: After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ≥ 1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk. CONCLUSION: Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.

Prostate cancer risk in men with prostate and breast cancer family history: results from the REDUCE study (R1).

BACKGROUND: To what degree the associations between PCa risk and family history of prostate cancer (PCa) and/or breast cancer (BCa) are attributable to screening biases is unclear. We examined these questions within the REDUCE study, where biopsies were largely independent of prostate specific antigen (PSA) minimizing screening biases. METHODS: Data were from REDUCE, which tested dutasteride 0.5 mg daily for PCa risk reduction in men with PSA 2.5-10.0 ng mL(-1) and a negative prestudy biopsy. Among men undergoing at least one on-study biopsy with complete data (n = 6415; 78.1%), the association between family history and PCa risk was tested using multivariate logistic regression adjusting for clinicodemographic characteristics. RESULTS: A family history of PCa alone was associated with increased PCa diagnosis (OR: 1.47, 95%CI: 1.22-1.77). In North America, PCa family history was not related to PCa diagnosis (OR: 1.02, 95%CI: 0.73-1.44), whereas outside North America, PCa family history was significantly related to diagnosis (OR: 1.72, 95%CI: 1.38-2.15) (P-interaction = 0.01). A family history of both PCa and BCa (OR: 2.54, 95%CI: 1.72-3.75) but not BCa alone (OR: 1.04, 95%CI: 0.84-1.29) was associated with increased PCa risk versus no family history and irrespective of geographical region. CONCLUSIONS: In REDUCE, PCa family history was significantly related to PCa diagnosis, although only for men outside North America. The presence of both PCa and BCa family history significantly increased risk versus PCa family history alone, irrespective of geographical region. Ultimately, our observations may support the need for changes in how we address family history in terms of both risk of PCa diagnosis and general risk stratification.

Baseline Basal Cell Hyperplasia Is not Associated With Baseline Lower Urinary Tract Symptoms, Baseline Clinical Prostatitis or Prostate Cancer in Repeat Biopsies.

OBJECTIVES: To evaluate whether the presence of basal cell hyperplasia (BCH) in negative biopsies is associated with concurrent lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), clinical prostatitis, and future prostate cancer (PCa) in repeat prostate biopsy. METHODS: We performed a retrospective analysis of 6471 men, 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/ml and prior negative biopsy who were enrolled in the Reduction by Dutasteride of PCa Events trial and underwent a 2-year repeat biopsy. The association between baseline BCH and risk of PCa, BPH/LUTS and clinical prostatitis measured at baseline were evaluated with logistic regression in uni/multivariable analysis, controlling for baseline patient characteristics. RESULTS: Among 6471 men enrolled, 84 (1.3%) had BCH in the baseline prostate biopsy. BCH was associated less chronic inflammation and more prostate atrophy (P < 0.05) and was unrelated to baseline patient characteristics. In both uni/multivariable analyses, BCH was not associated with PCa in repeat biopsy (univariable odds ratio [OR] = 0.98, 95% confidence interval [CI] = 0.53-1.82, P > 0.05; multivariable OR=1.15, 95% CI = 0.61-2.16, P > 0.05), BPH/LUTS (univariable OR = 1.13, 95% CI = 0.71-1.81, P > 0.05; multivariable OR = 1.20, 95% CI = 0.74-1.94, P > 0.05), or clinical prostatitis (univariable OR = 0.56, 95% CI = 0.18-1.81, P > 0.05; multivariable OR = 0.57, 95% CI = 0.18-1.83, P > 0.05). CONCLUSION: Among men undergoing repeat prostate biopsy with a baseline negative biopsy, BCH was associated with more histological atrophy and less chronic prostatitis, but was unrelated to LUTS/BPH, clinical prostatitis or future PCa risk.

The association of atrophy in baseline prostate biopsy and lower prostate cancer grade in radical prostatectomy specimens.

INTRODUCTION: To evaluate whether the presence of prostate atrophy (P.A.) in negative prostate biopsy is associated with prostate cancer (P.C.a) grade at surgical pathology among men who are ultimately diagnosed with P.C.a and undergo radical prostatectomy (R.P.). METHODS: A retrospective analysis was performed of 136 men from the placebo arm of the Reduction by Dutasteride of P.C.a Events (R.E.D.U.C.E.) trial who had a baseline prostate biopsy negative for P.C.a, and were later diagnosed with P.C.a on biopsy and underwent radical prostatectomy over the 4-year study period. The association of baseline P.A. (present/absent) with P.C.a grade (W.H.O./I.S.U.P. grade group 1 or ≥2) at surgical pathology was evaluated with logistic regression in uni- and multivariable analyses, controlling for baseline patient characteristics. RESULTS: P.A. was observed in 74 prostate biopsies (54%). P.A. was not associated with baseline characteristics (age, body mass index, prostate-specific antigen level, prostate volume, race, family history of P.C.a, and digital rectal exam), except for chronic inflammation (p = 0.001). The presence of P.A. in baseline prostate biopsies was associated with lower risk of W.H.O./I.S.U.P. grade group ≥2 P.C.a in R.P. specimens on both univariable (O.R. = 0.39, 95% C.I. = 0.19-0.78, p = 0.008) and multivariable (O.R. = 0.43, 95% C.I. = 0.20-0.92, p = 0.029) analyses. CONCLUSIONS: Among men with a baseline prostate biopsy negative for P.C.a who were later found to have P.C.a and underwent R.P., baseline P.A. is independently associated with lower risk of W.H.O./I.S.U.P. grade group ≥2 P.C.a on surgical pathology. P.A. may be used to identify subjects at lower risk for W.H.O./I.S.U.P. ≥ 2 P.C.a and select optimal candidates for active surveillance.

The combination of histological prostate atrophy and inflammation is associated with lower risk of prostate cancer in biopsy specimens.

BACKGROUND: To evaluate whether the presence of both prostate atrophy (PA) and chronic prostate inflammation (CPI) in the same biopsy and in the same biopsy core are associated with prostate cancer (PCa) risk and grade in repeat biopsies. METHODS: Retrospective analyses of 6132 men who were 50-75 years old undergoing 2-year repeat prostate biopsy after a negative baseline biopsy for PCa in the REduction by DUtasteride of prostate Cancer Events (REDUCE) study. PA, CPI and PCa were determined by central pathology. The association of baseline PA and CPI with 2-year repeat biopsy cancer status and grade was evaluated with χ2 test and logistic regression controlling clinicopathological features. RESULTS: PA, CPI and both were detected in 583 (9.5%), 1063 (17.4%) and 3675 (59.9%) baseline biopsies, respectively. Compared with biopsies with neither PA nor CPI, the presence of PA (odds ratio (OR)=0.73, 95% confidence interval (CI)=0.57-0.93), CPI (OR=0.72, 95% CI=0.58-0.88) and both (OR=0.54, 95% CI=0.45-0.64) were associated with lower PCa risk in the 2-year repeat prostate biopsy. Results were similar in multivariable analysis. Among subjects with both PA and CPI, those with both findings in the same core had even lower PCa risk compared with PA and CPI in different cores (univariable OR=0.68, 95% CI=0.51-0.91; multivariable OR=0.73, 95% CI=0.54-0.99). Combination of PA and CPI was associated with lower risk of high-grade PCa. CONCLUSIONS: The presence of both PA and CPI in baseline biopsies, especially in the same core, was associated with lower PCa risk and grade. The presence and topographical distribution of PA and CPI may be used in PCa risk stratification.

Greater extent of prostate inflammation in negative biopsies is associated with lower risk of prostate cancer on repeat biopsy: results from the REDUCE study.

BACKGROUND: To evaluate whether the extent of baseline acute prostate inflammation (API) and chronic prostate inflammation (CPI) was associated with risk of prostate cancer (PCa) at 2-year repeat prostate biopsy in a clinical trial with systematic biopsies independent of PSA. METHODS: A retrospective analysis of 6065 men with a negative baseline biopsy in the reduction by dutasteride of PCa events (REDUCE) trial undergoing 2-year biopsy. API and CPI extent (percentage of cores involved) and PCa (present or absent) were assessed by central pathology. The association of baseline API and CPI with PCa at the 2-year biopsy was evaluated with logistic regression in uni- and multivariable analyses. RESULTS: API extent was classified as absent or involving 1-25%, 26-50%, 51-75% and >75% cores in 5140 (85%), 742 (12%), 151 (2%), 17 (<1%) and 15 (<1%) cases, respectively. CPI extent was classified as absent or involving 1-25%, 26-50%, 51-75% and >75% cores in 1367 (22%), 2532 (42%), 1474 (24%), 397 (7%) and 295 (5%) cases, respectively. More extensive API was associated with younger age, lower PSA and lower prostate volume, while more extensive CPI was associated with older age, lower PSA and higher prostate volume (all P<0.01). In both uni- and multivariable analyses, API and CPI extent were associated with lower risk of PCa at the 2-year biopsy (both P<0.01). CONCLUSIONS: In a cohort of men undergoing repeat prostate biopsy 2 years after a negative baseline biopsy, a greater extent of baseline API and CPI was independently associated with lower PCa risk.

Baseline subject characteristics predictive of compliance with study-mandated prostate biopsy in men at risk of prostate cancer: results from REDUCE.

BACKGROUND: Study compliance is crucial when the study outcome is determined by an invasive procedure, such as prostate biopsy. To investigate predictors of compliance in study-mandated prostate biopsies, we analyzed demographic, clinical and reported lifestyle data from the REDUCE trial. METHODS: We retrospectively identified 8025 men from REDUCE with at least 2 years of follow-up, and used multivariable logistic regression to test the association between baseline demographic and clinical characteristics and undergoing the study-mandated prostate biopsy at 2 years. We then examined whether missing any of these data was associated with undergoing a biopsy. RESULTS: In REDUCE, 22% of men did not undergo a 2-year biopsy. On multivariable analysis, the non-North American region was predictive of 42-44% increased likelihood of undergoing a 2-year biopsy (P⩽0.001). Being enrolled at a center that enrolled >10 subjects (2nd and 3rd tertile) was associated with a 42-48% increased likelihood of undergoing a 2-year biopsy (P<0.001). In addition, black race predicted 44% lower rate of on-study 2-year biopsy (odds ratio (OR)=0.56; P=0.001). Finally, missing one or more baseline variables was associated with a 32% decreased likelihood of undergoing a 2-year biopsy (OR=0.68; P<0.001). CONCLUSIONS: In REDUCE, men outside North America, those at higher volume centers and those with complete baseline data were more likely to undergo study-mandated 2-year biopsies. Given prostate biopsy is becoming increasingly utilized as an endpoint in trials that are often multi-national, regional differences in compliance should be considered when designing future trials. Likewise, efforts are needed to ensure compliance in low-volume centers or among subjects missing baseline data.

NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence.

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1ß, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy.

We examined the possibility of continuing oxazaphosphorine therapy in patients with previously documented cyclophosphamide- or ifosfamide-induced hematuria by concomitant use of the uroprotective agent, mesna. Twenty-six patients with oxazaphosphorine-induced hematuria received additional cyclophosphamide or ifosfamide with mesna. Twelve, who had previously experienced hematuria with ifosfamide, received a median of 3.5 more cycles of ifosfamide/mesna. One patient developed further hematuria (grade 1). Of seven patients who experienced acute hematuria with cyclophosphamide, one experienced further hematuria after an additional course of cyclophosphamide with mesna, but none of the other six patients developed further hematuria when administered either cyclophosphamide/mesna (two) or ifosfamide/mesna (four). Seven patients who had chronic cyclophosphamide-induced hematuria had further oxazaphosphorine with mesna without worsening of their hematuria. Mesna is an effective uroprotective agent that prevents recurrent acute hemorrhagic cystitis, or worsening of chronic hemorrhagic cystitis, in patients receiving further oxazaphosphorine after previous ifosfamide- or cyclophosphamide-induced hematuria.

Biochemical response to testicular androgen ablation among patients with prostate cancer for whom flutamide and/or finasteride therapy failed.

OBJECTIVES: To evaluate the response of testicular androgen ablation in patients with advanced prostate cancer with a biochemical recurrence after finasteride or combined finasteride and flutamide therapy. METHODS: Eighteen hormone naïve men with advanced prostate cancer (10 with detectable prostate-specific antigen [PSA] levels after radical prostatectomy, 4 with rising PSA levels after definitive radiation therapy, and 4 with Stage D2 disease) were treated with finasteride (5 mg/day) alone or in combination with flutamide (250 mg three times a day). All men experienced an initial reduction in serum PSA, but later had treatment failure with two consecutive rising PSA measurements. All men were then treated with testicular androgen ablation (bilateral orchiectomy in 15 and luteinizing hormone-releasing hormone analogue in 3). RESULTS: Overall, serum PSA declined by more than 80% in 15 (83%) of 18 and to undetectable levels in 14 (78%) of 18. With a median+/-semi-interquartile range follow-up of 22+/-14.5 months from the initiation of hormone therapy, 12 (67%) of 18 currently have undetectable PSA levels. Two men having rising serum PSA levels above 100 ng/mL and 1 man has died from complications of metastatic prostate cancer. CONCLUSIONS: Testicular androgen ablation effectively lowers serum PSA levels in most men with advanced prostate cancer who have experienced a biochemical recurrence despite initial response and subsequent relapse on finasteride or combined finasteride and flutamide therapy.

Unusual behavior of low-grade, low-stage transitional cell carcinoma of bladder.

A case report of low-grade, low-stage transitional cell cancer of the bladder with isolated metastases to the uterus, fallopian tube, and ovary is presented. The pathogenesis of such unusual behavior for a local bladder malignancy is discussed along with a review of similar cases from the literature.

Laparoscopic gonadectomy in a case of testicular feminization.

Laparoscopy provides a minimally invasive technique for the accurate diagnosis of intersex problems and may also provide the opportunity for therapeutic management of these patients. Herein, we report our management of a patient with complete testicular feminization, by laparoscopic bilateral gonadectomy of fully developed intra-abdominal testes.

Combined finasteride and flutamide therapy in men with advanced prostate cancer.

OBJECTIVES: To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels. METHODS: Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage D0, and 7 with rising PSA levels after radical prostatectomy [n = 2] or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized. RESULTS: Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P > 0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P > 0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P > 0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13] and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19). CONCLUSIONS: Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy.

Comparison of percent free prostate-specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin, or watchful waiting.

OBJECTIVES: Finasteride is known to lower total serum prostate-specific antigen (PSA) levels by approximately 50%. Terazosin is thought to have little or no effect on serum PSA concentration. The objective of our study was to determine the effect of finasteride and terazosin on serum total and serum free PSA levels and the ratio of free to total PSA. METHODS: We identified 69 men with symptomatic benign prostatic hyperplasia (BPH) who had been receiving 5 mg/day (n = 33) of finasteride or 2 to 5 mg/day (n = 14) of terazosin or no therapy ("watchful waiting") (n = 22). The three groups were compared with respect to pretreatment total serum PSA levels and post-treatment total, free, and percent free serum PSA levels. RESULTS: Median (+/- semi-interquartile range [SIR]) pretreatment total serum PSA levels (ng/mL) were not significantly different in men taking finasteride (2.8 +/- 1.9), terazosin (2.2 +/- 2.5), or undergoing watchful waiting (5.5 +/- 1.4) (P = 0.12). The median (+/- SIR) post-treatment total serum PSA levels (ng/mL) were significantly lower in the finasteride group (1.1 +/- 1) when compared with the terazosin (2.5 +/- 1.5) or watchful waiting (4.3 +/- 2.8) groups (P = 0.016). Only the finasteride group had significantly lower post-treatment total serum PSA levels compared with pretreatment levels. The median (+/- SIR) post-treatment free PSA levels were significantly lower in the finasteride group (0.26 +/- 0.16) compared with the terazosin (0.54 +/- 0.5) and watchful waiting (0.85 +/- 0.5) groups (P = 0.0015). However, the median (+/- SIR) percent free PSA was not significantly different in the finasteride (23 +/- 6), terazosin (22 +/- 4), and watchful waiting (25 +/- 5) groups (P = 0.66). CONCLUSIONS: Finasteride appears to lower total and free PSA levels equally in men with BPH and does not appear to change the ratio of free to total serum PSA. Terazosin does not appear to alter total or free serum PSA levels in men with BPH. The percent free PSA could potentially be used to screen for prostate cancer in men taking finasteride. Prospective studies are needed to further evaluate this issue.

Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study.

OBJECTIVES: To evaluate prostate cancer detection and prostate-specific antigen (PSA) among men with benign prostatic hyperplasia treated with finasteride. METHODS: Three thousand forty men 45 to 78 years of age with PSA less than 10 ng/mL and no history of prostate cancer were randomized in a double-blind, placebo-controlled trial to finasteride (n = 1524) or placebo (n = 1516) for up to 4 years. A prerandomization biopsy negative for prostate cancer was obtained in 98% of patients with a screening PSA of 4.0 ng/mL or more, and an end-of-study biopsy was requested of all such patients without a recent second negative biopsy or a prostate cancer diagnosis. RESULTS: Overall, 644 patients (21%) underwent biopsy and 201 (6.6%) underwent transurethral resection of the prostate. Prostate cancer was diagnosed in 4.7% of men on finasteride and 5.1% on placebo (P = 0.7). Elevated PSA prompted diagnosis in 35% of cases on finasteride and 34% on placebo. The area under the receiver operating characteristic curve for last PSA was 0.84 on finasteride and 0.79 on placebo (P = 0.07). Use of an upper limit of normal for last PSA of 2.0 ng/mL for finasteride and 4.0 ng/mL for placebo yielded similar sensitivity (66% versus 70%, P = 0.6), higher specificity (82% versus 74%, P < 0.0001), and a higher likelihood ratio (3.6 versus 2.7, P < 0.05) for finasteride than for placebo. CONCLUSIONS: In men treated with finasteride, multiplying PSA by 2 and using normal ranges for untreated men preserves the usefulness of PSA for prostate cancer detection.

Who is best benefited by radical prostatectomy?

The last few years have taught us much about prostate cancer. We now recognize that prostate cancer, even if it is of low stage and low grade, is a relentlessly progressive disease, especially if found in men with prolonged (greater than 15 years) life expectancy. We now know that serum PSA is a valid endpoint after radical prostatectomy to definitively assess its ability to eradicate prostate cancer. We are learning better how to use a variety of clinical parameters to predict pathologic stage, and we are in the process of developing other markers that may be exploited to predict which patients with early-stage prostate cancer have surgically curable lesions. From these observations it is reasonable to conclude that the best candidates for radical prostatectomy are young men (those with 10 to 20 years of life expectancy) with impalpable, clinically organ-confined low- or moderate-grade prostate cancers.

Testicular circulatory isolation: a phase I study.

Antineoplastic agents may damage germinal epithelium. Testicular circulatory isolation (TCI) is a regional drug exclusion technique designed to minimize this. We evaluated the technical and anaesthetic aspects of TCI in 10 patients who underwent bilateral orchiectomy immediately thereafter. A modified aortic clamp was placed trans-scrotally across the left testicular pedicle without pre-medication or anaesthesia and left in place for 1 h, occluding testicular blood flow. Minimal pain and anxiety were reported during the procedure. There were no complications related to TCI in any patient. This study supports the institution of trials of TCI in young men about to receive fertility-threatening chemotherapy.

Using PSA to screen for prostate cancer. The Washington University experience.

The evidence is mounting that PSA-based screening for prostate cancer is rational and effective at detecting a high proportion of cancer that is both clinically significant and curable by radical prostatectomy. However, more information is necessary to define the optimal ages at which screening should be performed and to determine the appropriate role of repetitive PSA measurement, PSA density, and PSA slope in serial screening. Formal demonstration of a significant screening-induced reduction of cancer-specific morbidity and mortality is necessary to unambiguously justify screening for prostate cancer. A randomized trial evaluating prostate cancer screening will soon be started under the auspices of the National Cancer Institute. Additionally, refinements in serum PSA testing that consider the variable binding of PSA derived from benign and malignant prostatic tissues to serum proteins may further enhance the performance of PSA testing in the screening setting. For these reasons, PSA-based screening for prostate cancer seems destined to remain an important strategy for minimizing the health consequences of this disease.

Serum PSA after antiandrogen therapy.

Patients who present with advanced prostate cancer and who are treated with primary endocrine therapy have a significantly longer time to progression and a clear survival advantage if their serum PSA concentration normalizes. The prognostic significance of normalization of PSA is independent of other prognostic measures. Normalization of serum PSA at month 3 is the earliest and most highly correlated predictor of response. Most patients (80%-85%) who have disease progression while on hormonal therapy will show a rising PSA 6 to 12 months before other clinical findings become abnormal. A rising PSA in the hormonally treated patient, even if the values are within the "normal" range, signals impending clinical progression. These patients should be considered for second-line hormonal therapies or alternative salvage protocols, as a theoretically favorable window of opportunity may exist when the PSA begins to rise. Patients treated with second-line therapies should also undergo serial PSA measurements; those responding with an 80% to 90% decrease in serum PSA are statistically more likely to enjoy a prolonged response.