Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Targeted and Systematic Biopsy for Diagnosis and Management of Prostate Cancer.

The value of multi-parametric magnetic resonance imaging in the detection of clinically-significant prostate cancer is increasingly well-established, and has been adopted in current diagnostic pathways and clinical guidelines. Concurrently, the role of conventional ultrasound-guided systematic prostate biopsy is increasingly questioned. In this brief review, we evaluate the continued value of systematic biopsy including a review of prospective studies on targeted and systemic biopsies in the same patients. We also address current limitations of multi-parametric magnetic resonance imaging of the prostate.

A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue.

Prostate-specific antigen (PSA) is a widely used serum marker for prostate cancer (PCa), but in the critical diagnostic range of 4-10 ng/ml it has limited specificity for distinguishing early PCa from benign prostatic hyperplasia (BPH). PSA in serum is comprised of a variety of both "free" and "complexed" forms that have been used to improve the specificity of PSA for prostate cancer detection. We previously reported that pro PSA (pPSA), the zymogen or precursor form of PSA, is a component of free PSA in the serum of PCa patients. In the current study, we examined prostate tissues to understand the origin and specificity of pPSA. PSA was immuno-affinity purified from matched sets of prostate tissues including peripheral zone cancer (PZ-C); peripheral zone noncancer; and benign tissue from the transition zone (TZ), the primary site of BPH within the prostate. We found that pPSA is differentially elevated in PZ-C, but is largely undetectable in TZ. N-terminal sequencing revealed that the pPSA was comprised primarily of [-2]pPSA and minor levels of [-4]pPSA, containing pro leader peptides of 2 and 4 amino acids, respectively. The median value of pPSA was 3% in PZ-C and 0% (undetectable) in TZ (P < 0.0026). No pPSA was detected in 13 of 18 transition zone specimens (72%), but only 2 of the 18 matched cancer specimens (11%) contained no measurable pPSA. These results demonstrate that pPSA is more highly correlated with prostate cancer than with BPH. The pPSA in serum may represent a more cancer-specific form of PSA that could help distinguish prostate cancer from BPH.

Identification of a novel complex between human kallikrein 2 and protease inhibitor-6 in prostate cancer tissue.

Human kallikrein (hK) 2 is an arginine-selective serine protease expressed predominantly in the prostate that has an 80% sequence identity with prostate-specific antigen. Expression of hK2 is elevated in the tumor epithelium compared to benign prostate tissue. We have purified, sequenced, and identified a novel hK2 complex in prostate tissue consisting of hK2 and a serine protease inhibitor known as protease inhibitor-6 (PI-6). This 64-kDa SDS-PAGE stable complex is elevated in the tumor and is approximately 10% of total hK2. No comparable complex of prostate-specific antigen was detected. PI-6, also known as cytoplasmic antiprotease, has been characterized as an intracellular inhibitor of trypsin and chymotrypsin-like proteases, which has high homology to plasminogen activator inhibitor 1 and 2. The physiological role of PI-6 in the prostate and its relationship to hK2 and prostate cancer are under investigation.

Serial endoscopy following visual laser ablation of prostate (VLAP)

Visual laser ablation of the prostate (VLAP) was evaluated by serial video-endoscopy and six months of clinical correlation in 7 men suffering from advanced prostatism and urinary retention. Images of the prostatic urethra were obtained before and at various intervals from two to nineteen weeks after the procedure. A substantial tissue defect evolved within three months; complete healing required an even longer period. Except in the 1 patient with middle lobe obstruction, spontaneous urination was restored in all patients (including 2 cancer patients additionally treated with androgen deprivation). No operative complications were encountered. Thus, a safe and visually successful prostatectomy was the usual result of VLAP in the present patients. As a minimally invasive method to remove an obstructing prostate, laser treatment warrants further study.

Value of balloon dilation in treatment of youthful patients with prostatism.

Forty-three youthful patients with uncomplicated prostatism were prospectively evaluated to test the safety and efficacy of transurethral balloon dilation (TUDP). Treatment consisted of cystoscopic placement of an intraprostatic balloon inflated to 25 mm diameter at 3 atm pressure for ten minutes. At longest follow-up (9.8 months, average; 3-24 months, range), 88 percent of patients were satisfied with overall treatment results. The average improvements in voiding symptom score and peak uroflow were 77 percent and 73 percent, respectively. Mean improvements over pretreatment levels were statistically significant at one month (p less than 0.01) and remained so for the entire follow-up period. No incontinence, impotency, retrograde ejaculation, sepsis, or serious bleeding developed. An intraprostatic fissure, which spared the bladder neck, was a uniform finding and the most likely mechanism of lasting action of TUDP. In the relief of uncomplicated prostatism in youthful patients, TUDP compares favorably with other treatment alternatives.

Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands.

OBJECTIVES: Morphometry, or quantitative image analysis, offers great promise in characterizing the various histologic types of benign prostatic hyperplasia (BPH), but to date, a systematic study of the tissue components is lacking. Thus we employed morphometry to examine the distribution of primary BPH tissues throughout whole human prostates. METHODS: The prostate glands of 20 men with BPH were removed for low-volume carcinoma and subjected to a uniform, comprehensive, systematic quantification of the primary BPH tissue components using the technique of digitization and point-count morphometry. RESULTS: We found the following average volumes among the 20 glands: epithelium, 19.9% (S.D. 5.1%, range 11.7% to 30.8%); fibromuscular stroma, 50.4% (S.D. 9.4%, range 32.2% to 74.4%); glandular lumina, 29.7% (S.D. 8.9%, range 11.9% to 47.5%). Within the individual prostates, we found symmetry in primary BPH tissue distribution, except that the outer prostate was on average 25% richer in epithelium than the inner prostate (p < 0.05). When tissue composition was determined in simulated biopsy specimens, corrected for radial (ie, inner vs outer gland) orientation, the correlation with whole-organ composition was statistically significant for "percentage epithelium" (r = 0.72, p < 0.01) and for "stromal/epithelial ratio" (r = 0.63, p < 0.01). CONCLUSIONS: Major differences in primary tissue composition may separate different hyperplastic prostates. Primary BPH tissues are rather symmetrically distributed within individual prostates. Quantitative histologic differences between prostates, potentially important in clinical decision-making may be accurately diagnosed by morphometry of radially oriented biopsy specimens.

Use of saralasin to detect renovascular hypertension in childhood.

Current methods to evaluate renovascular hypertension in the pediatric population often requires a general anesthetic. Saralasin, an angiotensin II competitive inhibitor, is a safe, noninvasive technique which can be utilized at the bedside in a salt-depleted child off antihypertensive medication. Two illustrative cases are presented.

Computer-generated graphical presentations: use of multimedia to enhance communication.

Personal computers may be used to create, store, and deliver graphical presentations. With computer-generated combinations of the five media (text, images, sound, video, and animation)--that is, multimedia presentations--the effectiveness of message delivery can be greatly increased. The basic tools are (1) a personal computer; (2) presentation software; and (3) a projector to enlarge the monitor images for audience viewing. Use of this new method has grown rapidly in the business-conference world, but has yet to gain widespread acceptance at medical meetings. We review herein the rationale for multimedia presentations in medicine (vis-à-vis traditional slide shows) as an improved means for increasing audience attention, comprehension, and retention. The evolution of multimedia is traced from earliest times to the present. The steps involved in making a multimedia presentation are summarized, emphasizing advances in technology that bring the new method within practical reach of busy physicians. Specific attention is given to software, digital image processing, storage devices, and delivery methods. Our development of a urology multimedia presentation--delivered May 4, 1996, before the Society for Urology and Engineering and now Internet-accessible at http://www.usrf.org--was the impetus for this work.

Three-dimensional ultrasound device for rapid determination of bladder volume.

OBJECTIVES: We sought to assess the accuracy, reliability, and clinical utility of the noninvasive determination of bladder volume using an automated, compact three-dimensional (3-D) ultrasound device. METHODS: We prospectively tested 249 adult outpatients for accuracy (n = 182), by comparing scan versus catheter volumes, or reliability (n = 67), by comparing the scan readings of two independent observers. Two models of the bladder scan device were tested (BVI-2500, 1994 and 1995 models). RESULTS: Scan and catheter volumes were correlated (y = 1.02x + 12.6, R2 = 0.90, P < 0.001) across a range of zero to 1015 cc, regardless of which machine model was used. Scan volume underestimated catheter volume by an average of 10 cc in men and 20 cc in women. If a scan-predicted volume of 100 cc or greater were used as a cutpoint for clinical importance, the device exhibited a sensitivity of 97%, a specificity of 91%, and an overall accuracy of 94%. These results were not affected by age, gender, height, weight, diagnosis, uterine presence/prostate size, or user experience. The two observers, one a graduate physician and the other a college student, achieved essentially the same volume determinations (y = 0.96x + 0.13, R2 = 0.90, P < 0.001). CONCLUSIONS: Volume determinations obtained with the bladder scan device are accurate and reliable in adult outpatients. A special technician is not required. These results may be attributable to use of automated planimetry and 3-D volumetry, rather than a fixed geometric formula, to custom measure each bladder shape.

Treatment of erectile dysfunction with sildenafil.

OBJECTIVES: To determine the efficacy of sildenafil for the treatment of erectile dysfunction (ED) in a clinical practice setting; to evaluate the correlation between patient and partner perceptions of treatment outcomes; and to assess the relation between the severity of ED and response to treatment. METHODS: Among the first 100 men to receive sildenafil in a urology practice setting, 74 (mean + SD age 64+/-11 years) completed a validated sexual function questionnaire (International Index of Erectile Function [IIEF]) before and after a 4 to 6-week treatment period. A modified version of the same questionnaire was independently completed by partners. ED was categorized into a severity class of I to IV. RESULTS: Sildenafil treatment improved erections by 71% to 95%, according to responses in key IIEF questions 3 and 4. Overall, 57 (77%) of 74 patients desired to continue treatment after the test period. Patient score on the IIEF was correlated with partner score on the modified questionnaire before and after treatment (r = 0.67 to 0.81, P <0.01). IIEF scores were reflected in a simple severity classification system. Men with the best preservation of erections (severity class I) exhibited the best responses to sildenafil, whereas men with no erections (severity class IV) were much less likely to respond to the drug and desire continuation of treatment (P <0.01). Patients with a radical prostatectomy were relatively refractory to sildenafil, except for 2 of 5 who had undergone a nerve-sparing operation. CONCLUSIONS: In clinical practice, sildenafil is an effective treatment of ED, according to partner-validated questionnaire responses; and the results of treatment are predictable with an ED severity classification system.

Long-term effects of finasteride on prostate tissue composition.

OBJECTIVES: To determine the long-term effects of finasteride treatment on prostate tissue composition; to relate these effects to clinical outcomes; and to test the hypothesis that finasteride exerts a selective or preferential action on the transition zone. METHODS: Nineteen men with symptomatic benign prostatic hyperplasia (BPH) who completed a 6-month double-blind trial of finasteride were enrolled in a 24-month open-label extension study of drug responders. Magnetic resonance imaging and prostate biopsy for morphometric analysis were performed together 70 times: at baseline (n = 19), after treatment periods of intermediate duration (6 to 18 months, n = 32), and after long-term drug treatment (24 to 30 months, n = 19). At baseline, prostate volume averaged 51 cc, of which 57% was transition zone. RESULTS: Decreases in symptom score, dihydrotestosterone and prostate-specific antigen levels, and prostate volume occurred at 6 months (P <0.01), stabilized, and were maintained without further long-term decreases. Prostate epithelium contracted progressively from baseline (19.2% tissue composition; 6.0-cc volume; 3.2 stroma/epithelial ratio) to intermediate (12.5%, 3.3 cc, and 5.6, respectively) to long-term treatment (6.4%, 2.0 cc, and 17.4, respectively, P <0.01 for all). Percent epithelial contraction was similar in the peripheral and transition zones (P = NS). The transition zone remained a relatively constant proportion (53% to 58%) of whole-prostate volume from baseline to long-term observation. CONCLUSIONS: Long-term finasteride treatment (24 to 30 months) results in a marked involution of the prostate epithelium, which continues to progress for many months after clinical effects stabilize. The effect on the epithelium is similar in the peripheral and transition zones for both morphometric and volumetric changes. Progressive contraction of the prostate epithelium appears to constitute the underlying mechanism for sustained action of finasteride.

Renal vein renin: value and limitations in the prediction of operative results.

Renal vein renin determinations, in contrast to isolated peripheral venous renin determinations, provide great help in the selection of patients who can benefit from an operation for renal hypertension. Patients with essential hypertension usually have renal vein renin ratios, larger/smaller, close to unity, but the available cumulative data show that, statistically, ratios as large as 2.0 may occur in this group (95 per cent confidence limits). In patients with unilateral stenosis of a main renal artery, large renal vein renin ratios (stenotic/normal) have been followed by operative success in more than 90 per cent of patients. However, many operative successes have also been achieved in patients without a large renal vein renin ratio. This may be explained by inaccurate renal vein catheterization, inactive renin secretion, nonsimultaneous sampling, assay variability, and problems related to bilateral or segmental lesions. Recent refinements in the interpretation of renal vein renin data (contralateral suppression, ipsilateral hypersecretion in absolute terms, and a combination analysis scoring system) appear to increase the accuracy of the test. Detailed anatomic information, provided by arteriography, is essential for proper interpretation of renal vein renin data.

Prostatic aperture resulting from visual laser ablation: classification system based on follow-up endoscopy.

To study the evolving prostatic aperture created by visual laser ablation (VLAP), we performed 38 video-endoscopies in 24 men with prostatism at various intervals 2 weeks to 1 year after treatment. Complete healing was generally observed within 3 to 4 months, never before 6 weeks; and in some patients, tissue sloughing was still apparent beyond 6 months. By review of the cystoscopic findings and video hard copies, three independent observers classified the healed prostatic apertures with great uniformity into one of four categories: (I) minimal change (lateral lobes still meet in midline throughout gland length) (N = 3); (II) minor aperture (opening less than 50% of cystoscopic field over less than 50% of gland length) (N = 5); (III) major aperture (opening more than 50% of cystoscopic field over more than 50% of gland length) (N = 11); and (IV) full ablation (nearly complete replacement of lobar configuration with a general concavity) (N = 5). Clinical outcomes (symptom scores, uroflow rates) matched with follow-up cystoscopic categories but not with any other readily identifiable measures. The four-category system proved to be simple, reproducible, and clinically relevant. If a standardized tissue aperture is the ultimate aim of new methods to ablate the prostate, the proposed system for classifying the aperture could have a considerable future application.

Phase I/II examination of transurethral ethanol ablation of the prostate for the treatment of symptomatic benign prostatic hyperplasia.

PURPOSE: We assessed the safety of transurethral ethanol ablation of the prostate as a treatment for men with symptomatic benign prostatic hyperplasia and determined the efficacy of this procedure. MATERIALS AND METHODS: We performed a multicenter randomized trial on 79 men, 50 to 79 years old, who had drug refractory voiding symptoms (International Prostate Symptom Score greater than 12) and prostate volumes of 30 to 80 cc. Ethanol was injected transurethrally into the prostate with a curved cystoscopic needle in men randomly assigned to 1 of 3 doses: 15%, 25% or 40% of prostate volume by transrectal ultrasound. Followup evaluations were performed 1, 3 and 6 months later. Postoperative cystoscopy was performed on all patients to evaluate ablation extent and extraprostatic effects. Transrectal ultrasound volume determinations were obtained before and 6 months after transurethral ethanol ablation of the prostate. RESULTS: Adverse events were generally mild or moderate, and included hematuria (42.9%), irritative voiding symptoms (40.3%), pain/discomfort (25.6%) and urinary retention (22.1%). No serious adverse events were reported. Statistically significant improvements were seen in International Prostate Symptom Score, quality of life, maximum flow rate and prostate volume reduction (p<0.05). Improvements were consistently observed across the 3 groups without an apparent dose effect. CONCLUSIONS: In this randomized clinical trial transurethral ethanol ablation of the prostate was safe and effective at 6-month followup. No serious adverse events were encountered. Although ethanol can safely ablate prostatic tissue, further studies will be necessary before widespread clinical application.