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THE USE OF PERCENT FREE PROSTATE SPECIFIC ANTIGEN FOR STAGING CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer. MATERIALS AND METHODS In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10. RESULTS Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease. CONCLUSIONS These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.

Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer.

Aims of the study: Retrospective studies investigating the use of percent free-PSA for early detection of prostate cancer were limited for various reasons: by their use of long-term stored sera, poor mix of non-cancer to cancer cases and the use of only men with PSA values between 4.0 and 10.0 ng/mL. This prospective study investigates the clinical utility of percent free-PSA and complexed-PSA for early detection of prostate cancer in 219 consecutive men presenting for prostate biopsy.Methods: Of 246 consecutive men who underwent ultrasound guided sextant biopsy of the prostate for PSA elevation and/or suspicious digital rectal exam, 219 men had serum total PSA levels between 2.0 and 20.0 ng/mL and were included in this study. Serum total, free and complexed (PSA–ACT) were measured (Hybritech Inc.).Results: Pathologic examinations demonstrated that 72% and 28% of the biopsies were non-cancer and cancer respectively. The mean percent free-PSA was statistically different between the groups (cancer 14%±6.4 and non-cancer 18±9%, P<0.001) and improved cancer detection. PSA–ACT provided only modest improvement in cancer detection over that of total PSA. Among this cohort of men, the optimal total PSA reflex range for percent free-PSA was 3.0–7.0 ng/mL (38% specificity) with a percent free-PSA cut-off of 20% (95% sensitivity) yet only affected 56% of the cases.Conclusions: PSA–ACT added very little additional value to the clinical utility of total PSA for early detection. Percent free-PSA performed well for all reflex ranges. A sensitivity and specificity of 95% and 20% respectively were obtained using a single cut-off of 25% for percent free-PSA for the group of men with total PSA values between 4.0 and 10.0 and correlated well with recently reported prospective analyses.

The role of free/total prostate-specific antigen ratio in the prediction of final pathologic stage for men with clinically localized prostate cancer

OBJECTIVES The combined use of total prostate-specific antigen (PSA), clinical stage, and Gleason score accurately predicts final pathologic stage for men with clinically localized prostate cancer. Recently, the free/ total PSA ratio has been proposed as an adjunct for early detection of prostate cancer. We examined the association between free/total PSA and pathologic stage. METHODS In a prospective study, 301 consecutive men with clinically localized prostate cancer (average age 58.8 years, range 45-72) underwent a staging pelvic lymphadenectomy and radical prostatectomy. Total PSA and free PSA were measured from preoperative sera. Pathologic stage was determined as organ-confined (OC, n = 169), capsular penetration (CP+, n = 108), seminal vesicle involvement (SV+, n = 13) and lymph node involvement (LN+, n = 11). RESULTS Overall, 292/301 (97%) of the free/total PSA values were < 25%, and thus suspicious for prostate cancer. Combination of total PSA, Gleason score, and clinical stage predicted well OC (P = 0.00001) and LN+ (P = 0.023); whereas, replacing total PSA with free/total PSA ratio did not improve the prediction of OC (P = 0.0007) nor LN+ (P = 0.03). CONCLUSIONS The free/total PSA ratio cutoff point of 25% had high sensitivity for prostate cancer among a group of men with clinically localized disease. The free/total PSA ratio did not significantly improve the prediction of pathologic stage provided by total PSA when used alone or in combination with Gleason score and clinical stage. These preliminary data demonstrate that free/total PSA levels provide no additional information for pathologic stage prediction when combined with Gleason score and clinical stage in men with clinically localized prostate cancer.

INFLUENCE OF FINASTERIDE ON FREE AND TOTAL SERUM PROSTATE SPECIFIC ANTIGEN LEVELS IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

PURPOSE Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels. MATERIALS AND METHODS In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at -70C at baseline and for as long as 9 months of treatment. RESULTS In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p <0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo. CONCLUSIONS Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.

Sacral bladder denervation for treatment of detrusor hyperreflexia and autonomic dysreflexia.

OBJECTIVES Detrusor hyperreflexia after spinal cord injury may cause urinary incontinence and chronic renal failure. In patients refractory to conservative treatment and not eligible for ventral sacral root stimulation for electrically induced micturition, we investigated the therapeutic value of sacral bladder denervation as a stand-alone procedure. METHODS Nine patients (8 men and 1 woman) between 21 and 58 years old (mean 30.2) with traumatic suprasacral spinal cord lesions underwent sacral bladder denervation for treatment of detrusor hyperreflexia and/or autonomic dysreflexia. RESULTS Detrusor hyperreflexia and autonomic dysreflexia were eliminated in all cases. Bladder capacity increased from 177.8 +/- 39.6 to 668.9 +/- 64.3 mL; intravesical pressure decreased from 89.3 +/- 19.1 to 20.2 +/- 2.7 cm H(2)O. For facilitating clean intermittent catheterization (CIC), 4 patients received a continent vesicostomy in a second-stage procedure; one of them in combination with bladder augmentation. Four patients empty their bladder by way of urethral CIC. One completely tetraplegic patient has an indwelling urethral catheter. In the 5 patients with autonomic dysreflexia, the systolic blood pressure was lowered from 196 +/- 16.9 to 124 +/- 9.3 mm Hg and the diastolic blood pressure from 114 +/- 5.1 to 76 +/- 5.1. The annual frequency of urinary tract infections decreased from 9 +/- 1.2 to 1.8 +/- 0.7. In all patients, renal function remained stable. CONCLUSIONS In selected patients with detrusor hyperreflexia and/or autonomic dysreflexia, sacral bladder denervation is a valuable treatment option. It is only moderately invasive in nature, requires neither sophisticated nor expensive medical equipment, and is an attractive alternative to urinary diversion using intestinal segments.

Molecular forms of prostate-specific antigen and human kallikrein 2 (hK2) in urine are not clinically useful for early detection and staging of prostate cancer

OBJECTIVES Prostate-specific antigen (PSA), a member of the human kallikrein (hK) family, is the most important tumor marker for early detection, staging, and monitoring of men with prostate cancer today. However, the sensitivity of serum PSA is not sufficient to be used alone for prostate cancer screening. Recently, it was reported that the serum-to-urinary total PSA ratio improves the detection of men with prostate cancer, especially in men with a serum total PSA level between 4.0 and 10.0 ng/mL. We tested this hypothesis by evaluating the clinical usefulness of this PSA ratio as well as the use of the different molecular forms of PSA and human kallikrein 2 (hK2) in urine for detection and staging of prostate cancer. METHODS One hundred ten fresh, midstream urine specimens (prostate cancer 62, benign prostatic hyperplasia [BPH] 38, healthy male control 5, women 5) were collected. Serum total PSA, urine total PSA, urinary free PSA, urinary alpha 1-antichymotrypsin-bound PSA, and urinary hK2 levels were determined by monoclonal antibody assays (Hybritech Inc.). The serum-to-urinary total PSA ratio was calculated. RESULTS The serum-to-urinary total PSA ratio did not accurately distinguish between men with BPH and men with prostate cancer. There was no significant difference between the urinary levels of any of the molecular forms of PSA or hK2 between men with prostate cancer and men with BPH. Among men with prostate cancer, neither urinary hK2 nor urinary levels of any of the molecular forms of PSA correlated with age, pathologic stage, or Gleason grade. CONCLUSIONS In our study, the serum-to-urinary total PSA ratio did not improve the detection of men with prostate cancer. Furthermore, measurement of the molecular forms of PSA and hK2 in urine did not improve the detection or staging of prostate cancer over serum PSA alone.

Detection of intact prostate cancer cells in the blood of men with prostate cancer

OBJECTIVES To develop a procedure to be used to find, identify, and characterize the living prostate cancer cells in the blood of patients with prostate cancer. METHODS The procedure is based on a negative selection approach that removes most of the blood cells and collects the remaining prostate cancer cells, which are identified and characterized by fluorescent in situ hybridization with deoxyribonucleic acid probes and by indirect fluorescent immunocytochemical staining. The blood cells are removed via density gradient centrifugation. RESULTS Using the prostate cancer LNCaP cells as a model, the recovery rate of the added prostate cancer cells to 10 mL of blood was about 85%, with a dilution of 1 LNCaP cell to 10,000 white blood cells or more. Blood samples varying from 9 to 27 mL were collected and analyzed from 8 men aged 54 to 79 years who had varying levels of PSA in serum. In one blood sample, prostate cancer cells were not found; in the seven other samples, the number of prostate cancer cells found per milliliter of blood varied from 1 to 20. Prostate cancer cells were not found in 7.5 to 15-mL blood samples from 3 healthy younger men. The prostate cells were found to be aneuploid for chromosomes 7 and 8, highly suggestive that these cells were cancerous. CONCLUSIONS Using a negative selection approach, prostate cells can be found in the blood of patients with prostate cancer, as identified by prostate cell-specific probes and antibodies. These cells were found to be aneuploid.

Urodynamic results, clinical efficacy, and complication rates of sacral intradural deafferentation and sacral anterior root stimulation in patients with neurogenic lower urinary tract dysfunction resulting from complete spinal cord injury

To investigate the outcome and complications of sacral deafferentation (SDAF) and sacral anterior root stimulation (SARS) in patients with neurogenic lower urinary tract dysfunction (NLUTD) resulting from complete spinal cord injury (SCI).

Functional outcome of supratrigonal cystectomy and augmentation ileocystoplasty in adult patients with refractory neurogenic lower urinary tract dysfunction

To investigate the functional outcome after supratrigonal cystectomy and augmentation ileocystoplasty in adult patients with refractory neurogenic lower urinary tract dysfunction (NLUTD).

Cell turnover in human seminal vesicles and the prostate: an immunohistochemical study

The human prostate and seminal vesicles are both androgen-dependent sex accessory organs. Their growth behavior, response to hormone manipulation, susceptibility to benign and malignant processes and sex accessory functions, however, differ greatly. The growth behavior of most tissues correlates well with the cell turnover rate of that tissue. Therefore, we compared the cell turnover of normal human prostate and seminal vesicles. Immunohistochemical expression of MIB-1 (proliferation), bcl-2 and transforming growth factor (TGF β) were examined in 20 different samples taken from histologically normal human prostatic and seminal vesicle tissue. For the quantification of apoptosis, the TUNEL technique was used. The apoptosis rates in normal prostatic tissue (0.73±0.60) were significantly greater (P=0.003) than those seen in seminal vesicles (0.02±0.01). The proliferation rates also differed significantly (P=0.002) between these tissues (prostate: 0.77±0.78; seminal vesicles: 0.02±0.02). Eighty percent of the prostate tissue stained for bcl-2, whereas only 55% of the seminal vesicle tissue showed staining for bcl-2. All seminal vesicles and 75% of the prostate samples stained for TGF β. For both androgen-dependent tissues, apoptotic rates closely equaled proliferation rates. The cell turnover, however, was much higher in the prostate than in the seminal vesicles. TGF β seems to be more important for the regulation of cell turnover in the seminal vesicles than bcl-2. These differences in the proliferative behavior may explain why disturbances of apoptotic regulation lead to a more extensive net cell gain in prostatic tissue compared to the seminal vesicles. This might help explain the vastly different incidence of benign and malignant tumors in these organs.