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Purpose: We evaluated prostate cancer (PCa) characteristics at diagnosis and changes in prostatic specific antigen (PSA) with time in males with screening detected PCa that was initially managed with a watchful waiting policy., Materials and Methods: Patients with histologically proven PCa and PSA less than 10 ng/ml were selected from the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. The choice of initiating a watchful waiting policy was patient desire or physician advice. PSA slope and PSA doubling time (PSADT) were calculated in patients with 3 or more PSA tests results available., Results: A total of 191 patients were included. Mean age at diagnosis was 69 years and mean PSA was 3.9 ng/ml. Of the patients 92.6% had a Gleason score of 3 + 3 or lower, 133 had a followup of greater than 12 months (mean 40) and 35 (29.2%) had a negative PSA slope. Mean PSADT was 9.7 years (range 0.3 to 155) in 85 males with a positive PSA slope. During followup 30 patients changed therapy., Conclusions: Watchful waiting remains a controversial prostate cancer treatment strategy. In select screening detected patients with PCa there appears to be a subgroup with stable or even decreasing PSA values with time. These males could profit from a watchful waiting policy with possible deferred treatment. Together with conventional tumor parameters at diagnosis PSADT and PSA slope during followup could be used to monitor tumor activity and possibly aid in determining the time of deferred treatment. Further followup is mandatory to validate these results.

Purpose: We developed a method to objectively compare methods for the quantification of bladder outlet resistance., Materials and Methods: We studied unselected voiding cystometries from 131 male patients. Several models proposed for bladder outlet resistance were fitted to the lowest monotonically increasing part (bottom) of the pressure flow plots. In conjunction with a parameter for bladder contractility, the model parameters were used as predictors of post-void residual greater than 20% of filled volume., Results: The pressure decrease in relaxed bladder outlet was best described by a linear function of the flow rate. The flow rate independent and dependent parts of that function were statistically significant predictors for residual. However, they could be combined into 1 index that was as efficient as the 2 numbers separately in predicting residual. This index is the average pressure of the bottom of the pressure flow plot., Conclusions: We describe how different models for the quantification of bladder outlet resistance can be compared objectively on the basis of their ability to predict a significant post-void residual. Using this criterion in an unselected group of measurements, the average pressure of the bottom of the pressure flow plot performed best as an index for bladder outlet resistance quantification. It combines (or weights) 2 components (dependent and independent flow rates) without losing its power to predict post-void residual.

Purpose: Currently bladder outlet obstruction in males is defined by the provisional International Continence Society nomogram which is partly based on expert opinion and partly on measurements before and after transurethral prostate resection. Recently there has been some interest in the development of a similar nomogram for females., Materials and Methods: We studied the possibility of defining bladder outlet obstruction based on a sign that it causes, namely post-void residual urine., Results: The probability of relative post-void residual urine exceeding 20% of bladder capacity was modeled in males and females using 1 parameter, that is URA/w20 or the ratio of the obstruction parameter urethral resistance factor (URA)-to-the bladder contractility parameter Watts factor at 20% (w20). URA/w20 represents relative bladder outlet resistance or bladder outlet resistance normalized to bladder contractility. Above a threshold of URA/w20 = 6.8 in females and 8.2 in males a relative post-void residual exceeding 20% was noted in 90% of measurements. These thresholds may be used to define relative obstruction. The provisional International Continence Society nomogram for obstruction in males was transformed into an identical nomogram for females by equating the probabilities of post-void residual urine in each gender. The latter differed from that in men, in that the lines demarcating the zones were horizontal or flow rate independent but the intercepts were approximately the same at 20 and 40 cm. water., Conclusions: Instead of defining obstruction as an absolute level of bladder outlet resistance we suggest that it is better to define it relatively, that is as a level of bladder outlet resistance that depends on bladder contractility.

Purpose: Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population., Materials and Methods: Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population., Results: Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years., Conclusions: PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.

Purpose: Although early detection of prostate cancer by prostate specific antigen based screening results in a shift towards more clinically organ confined tumors, changes in prostate cancer characteristics after radical prostatectomy are less clear., Materials and Methods: We studied 121 totally embedded radical prostatectomy specimens that were obtained from consecutive participants of the European Randomized Study of Screening for Prostate Cancer who were systematically screened and treated surgically. In each specimen pathological stage, Gleason score and proportion of high grade cancer (Gleason pattern 4 or 5) were determined. Lymph node status at operation, stage and grade were compared to a historical series of 72 surgical procedures performed for clinically localized prostate cancer at our hospital before the introduction of serum prostate specific antigen as a diagnostic tool., Results: Although none of the screen detected cases had positive lymph nodes at surgery, operation was discontinued in 13 (18%) of the 72 historical cases because of positive lymph nodes. Compared with the remaining 59 historical prostatectomy specimens, the screen detected specimens showed a definite increase in the frequency of pathologically organ confined tumors and a relative decrease in Gleason score 8 to 10 tumors. However, 60% of screen detected tumors contained areas with high grade cancer (Gleason pattern 4 or 5) and 50% had a Gleason score of 7. The relative amount of high grade cancer in each tumor was related to volume (Kruskal-Wallis test p <0. 001)., Conclusions: Screening for prostate cancer leads to an increase in surgical treatment for relatively small tumors that have a higher probability of being organ confined. Although the frequency of positive lymph nodes at operation decreases dramatically and the proportion of organ confined tumors after surgery increases, there is a shift from Gleason 8 to 10 tumors towards lower grade tumors at radical prostatectomy. Still, judged by the high frequency of focal dedifferentiation in screen detected tumors, most of them and surgically treated tumors are likely to be clinically important. The relatively large accumulation of these tumors in the Gleason 7 category is a concern because it could lead to a decrease in the clinical usefulness of the Gleason score system.

Purpose: At low prostate specific antigen (PSA) the indication for prostate biopsy is usually an abnormal digital rectal examination. We evaluate the diagnostic value of PSA, digital rectal examination, transrectal ultrasonography and tumor characteristics at low PSA (0 to 4.0 ng./ml.). We confirm and add to recent evidence that digital rectal examination has a low predictive value and that many significant cancers at this PSA range may be missed., Materials and Methods: From 1994 to 1997 a total of 10,523 participants 54 to 74 years old were randomized to screening in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Of the participants 9,211 (87.5%) had PSA less than 4.0 ng./ml., and underwent digital rectal examination and transrectal ultrasonography. Expected rates of prostate cancer detection were calculated using logistic regression analysis. Radical prostatectomy was performed in about half of the 478 men diagnosed with prostate cancer. Tumors were characterized by pT category, Gleason score and cancer volume in 166 processed radical prostatectomy specimens. In 50 of these cases PSA was 0 to 4.0 ng./ml., Results: The positive predictive value of digital rectal examination and transrectal ultrasonography at PSA 0 to 4.0 ng./ml. was only 9.7%. Positive predictive value strongly depended on PSA. Sensitivity was calculated by using estimates of the prevalence of sextant biopsy detectable prostate cancers. Of 760 detectable cancers 478 (67%) were diagnosed irrespective of PSA in men screened with digital rectal examination, transrectal ultrasonography and PSA. Only 127 of 348 detectable prostate cancers (36.5%) were actually diagnosed in men with PSA 2 to 4 mg./ml. The importance of these missed cancers was evaluated with parameters of tumor aggressiveness within PSA ranges., Conclusions: Approximately half of the tumors missed with PSA 0 to 4 ng./ml. had aggressive characteristics (Gleason score 7 or greater, Gleason 4-5 components) and were organ confined. These tumors should be diagnosed and treated according to the present understanding of their natural history. More sensitive and selective screening strategies are needed. Presently a wrong "window of opportunity" is used for early detection of prostate cancer.

Purpose: The ratio between free and total prostate specific antigen (PSA) in serum improves the specificity of total serum PSA for the detection of prostate carcinoma in select populations. The value of the free-to-total PSA ratio for a PSA of 4.0 to 10.0 ng./ml. was analyzed in a screening population., Materials and Methods: From 4,800 participants 55 to 76 years old 977 biopsies were obtained because of an abnormal digital rectal examination, suspicious transrectal ultrasonography and total serum PSA 4.0 ng./ml. or more. Of 191 patients with prostate carcinoma detected 101 had a serum PSA of 4.0 to 10.0 ng./ml. and 54 of them underwent radical prostatectomy. A free-to-total PSA ratio of 0.20, age specific PSA reference ranges and a PSA density of 0.12 ng./ml./cc were evaluated for the ability to increase the specificity of total serum PSA in predicting positive prostate biopsy results., Results: Receiver operating characteristics curves for the free-to-total PSA ratio showed a significant increase in specificity compared to PSA. Retrospective application of age specific PSA reference ranges, the free-to-total PSA ratio and the PSA density decreased the number of biopsies significantly by up to 40% in our study, with a decrease in cancer detection rate of 12%. When used in combination with digital rectal examination, the pathological stage of undetected carcinomas appeared favorable., Conclusions: The free-to-total PSA ratio may be used to decrease biopsies in patients with an intermediate PSA of 4.0 to 10.0 ng./ml.

Purpose: We analyzed the relationship between the free-to-total PSA ratio and prostate cancer tumor stage and grade compared to total serum PSA., Materials and Methods: In 123 patients clinical and pathological grade and stage were related to total serum PSA and free-to-total PSA ratio., Results: Total serum PSA paralleled clinical staging of prostate cancer. The distributions of total serum PSA and the free-to-total PSA ratio were significantly different between benign and malignant diseases (any stage), and between any T category and nodal disease. For serum PSA significant differences were noted between the distributions of men with locally confined (stages T1 and T2) and locally extended (stage T3) disease, and between all T categories and systemic metastatic disease. This finding was not noted for the free-to-total PSA ratio., Conclusions: The free-to-total PSA ratio has no additional value in clinical staging of prostate carcinoma compared to serum PSA. The free-to-total PSA ratio may be considered the result of cell differentiation and not an indicator of tumor load.

The influence of age, urethral resistance and bladder contractility on voiding efficiency was evaluated by pressure-flow studies in 138 men of a mean age of 60 years (range 18 to 86). From these studies the urethral resistance parameter was calculated and the maximum bladder contraction strength was determined. Premature fading of the bladder contraction was quantified by a bladder contraction strength decay factor. Voiding efficiency was expressed by the parameter of post-void residual urine volume as a percentage of the initial bladder volume. Multiple regression analysis showed that voiding efficiency depended significantly in descending order of importance on urethral resistance, maximum bladder contraction strength and bladder contraction strength decay factor. Patient age was not an independent factor. Maximum bladder contraction strength and bladder contraction strength decay factor were not correlated, suggesting that maximum bladder contraction strength and its decay constitute different properties of bladder contractile function. A voiding efficiency nomogram is proposed, making use of the values for maximum bladder contraction strength and urethral resistance in individual patients. Such a nomogram may have predictive value for the occurrence of acute retention but it must be tested prospectively.

In an attempt to increase our understanding of the clinical syndrome of benign prostatic hyperplasia (BPH) an analysis was made of the association between prostate volume as measured by transrectal ultrasound and several reported urodynamically determined urethral resistance parameters. Two types of obstruction can be recognized on the basis of urodynamic data: a compressive type characterized by a high urethral opening pressure and a prolonged isovolumetric contraction phase before urine flow can start, and a constrictive type characterized by a normal opening pressure and an increased slope of the urethral resistance relation. A combination of both types is often seen in BPH. In our study, parameters that selectively quantify compression correlate weakly to moderately with prostate volume, whereas parameters that mainly quantify constriction do not correlate at all with prostate volume. Parameters that combine a measure for compression and constriction correlate less well with prostate volume than parameters that mainly quantify compression. The variation in prostate volume was found to determine the variation in urethral resistance by 15% or less depending on the parameter used, which implies that the different pathophysiological mechanisms that can increase urethral resistance in the complex process of clinical BPH are mainly determined by factors other than the volume of the prostate. Thus, despite the lack of correlation between prostate volume and urethral resistance, pressure-flow studies and the determination of urethral resistance parameters provide a valuable contribution to the understanding of the pathophysiology of voiding dysfunction in men with symptoms of prostatism.