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.

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.

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.

Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens.

OBJECTIVES: To determine the effects of a saw palmetto herbal blend (SPHB) compared with finasteride on prostatic tissue androgen levels and to evaluate needle biopsies as a source of tissue for such determinations. METHODS: Prostate levels of testosterone and dihydrotestosterone (DHT) were measured on 5 to 10-mg biopsy specimens (18-gauge needle cores) in three groups of men with symptomatic benign prostatic hyperplasia: 15 men receiving chronic finasteride therapy versus 7 untreated controls; 4 men undergoing prostate adenomectomy to determine sampling variability (10 specimens each); and 40 men participating in a 6-month randomized trial of SPHB versus placebo, before and after treatment. RESULTS: Prostatic tissue DHT levels were found to be several times higher than the levels of testosterone (5.01 versus 1.51 ng/g), that ratio becoming reversed (1.05 versus 3.63 ng/g) with chronic finasteride therapy. The finasteride effect was statistically significant for both androgens (P <0.01), and little overlap of individual values between finasteride-treated and control patients was seen. In the randomized trial, tissue DHT levels were reduced by 32% from 6.49 to 4.40 ng/g in the SPHB group (P <0.005), with no significant change in the placebo group. CONCLUSIONS: For control versus finasteride-treated men, the tissue androgen values obtained with needle biopsy specimens were similar-both for absolute values and the percentage of change-to those previously reported using surgically excised volumes of prostatic tissue. The quantification of prostatic androgens by assay of needle biopsies is thus feasible and offers the possibility of serial studies in individual patients. The SPHB-induced suppression of prostatic DHT levels, modest but significant in a randomized trial, lends an element of support to the hypothesis that inhibition of the enzyme 5-alpha reductase is a mechanism of action of this substance.

Prostate-specific antigen and new serum biomarkers for evaluation of chemopreventive agents.

A great deal of effort regarding the basic understanding and clinical relevance of the prevention of prostate cancer has emerged over the past decade. Chemoprevention or the administration of a drug or other agent in an attempt to prevent, inhibit, or delay the progression of localized prostate cancer has gained the most recent attention. Efforts have focused primarily in the identification of bioactive chemopreventive agents, risk factors identifying individuals with the highest likelihood of developing prostate cancer, pathologic identification of premalignant lesions, and epidemiologic studies to better understand the natural history of early prostate cancer. However, less work has been focused on identifying and characterizing our presently available biomarkers in an attempt to validate their use as surrogate endpoints or documenting their clinical utility in chemoprevention. This update will focus on a critical evaluation of prostate-specific antigen (PSA), percentage of free PSA, and human glandular kallikrein-2 (hK2) and how they may be used or misused for chemoprevention studies.

The role of prostate needle biopsy in evaluation of chemopreventive agents.

Needle biopsy of the prostate safely furnishes tissue that can be studied for the effects of promising chemopreventive agents on biomarkers. The modulation of biomarkers, such as those for apoptosis (TUNEL, Bcl-2, or nuclear morphometry), angiogenesis (factor 8), and cell proliferation (Ki-67), can indicate the potential of a new agent without waiting for the definitive evaluation of traditional endpoints, such as reduction in cancer mortality. A recent modification of prostate biopsy technique, including additional cores taken from the lateral peripheral zone, may improve the cancer yield by as much as 35% without increasing major complications, facilitating serial in vivo tests on cancer tissue. The serial biopsy approach may be especially valuable in "watchful waiting" cohorts.

Seminal plasma contains "BPSA," a molecular form of prostate-specific antigen that is associated with benign prostatic hyperplasia.

BACKGROUND: We previously reported that levels of BPSA, a modified form of prostate-specific antigen (PSA), are significantly elevated in prostate transition-zone tissue exhibiting nodular hyperplastic changes associated with the presence of benign prostatic hyperplasia (BPH). BPSA was purified and found to contain a characteristic clip between Lys182 and Ser183. We now describe the identification of BPSA in seminal plasma. METHODS: PSA was purified from seminal plasma by immunoaffinity chromatography. The purified PSA was further resolved by hydrophobic interaction chromatography, and the individual PSA forms were analyzed by gel electrophoresis and N-terminal amino-acid sequencing. RESULTS: BPSA comprised about 8% of the PSA in pooled seminal plasma, and was identical to BPSA purified from prostate tissues. BPSA was cleanly resolved from all active and inactive forms of PSA. Other inactive forms of PSA in seminal plasma consisted largely of PSA clipped at Lys145, though about 30% of the inactive seminal plasma PSA was intact, mature PSA. CONCLUSIONS: BPSA represents a distinct form of inactive PSA in the seminal plasma that may represent a specific marker for the biochemical changes associated with nodular development in the prostate transition zone found in patients with BPH.

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.

"BPSA," a specific molecular form of free prostate-specific antigen, is found predominantly in the transition zone of patients with nodular benign prostatic hyperplasia.

OBJECTIVES: The biologic mechanism for the increased proportion of noncomplexed ("free") prostate-specific antigen (PSA) found in the serum of patients with benign prostate disease is unknown. We recently reported that most of the PSA found in benign, hyperplastic, and cancerous prostatic tissue is in the free form. To determine whether specific molecular forms of free PSA are associated differentially with normal, hyperplastic, or cancerous prostatic tissue, we have further characterized the free PSA in each type of prostatic tissue. METHODS: PSA was purified by immunoaffinity chromatography from matched prostatic tissue samples of peripheral zone cancer (PZ-C), PZ noncancer (PZ-N), and transition zone (TZ) tissue from 10 large-volume (greater than 50 g) and 8 small-volume (less than 25 g) radical prostatectomy specimens. Eight TZ specimens obtained during transurethral resection of the prostate for benign prostatic hyperplasia (BPH) were also analyzed. The different molecular forms of PSA were further resolved by high-performance hydrophobic interaction chromatography. Clipped forms of PSA were identified by N-terminal amino acid sequencing. RESULTS: More than 99% of the PSA in prostatic tissues was in the free, noncomplexed form. Specimens from the prostate TZ were found to contain elevated levels of an altered form of PSA, which we designated BPSA. Purified BPSA contained a distinctive cleavage at lysine 182. The median percent BPSA (%BPSA) was 11.4 in the TZ of specimens with nodular BPH compared with a %BPSA of 4.1 in the TZ of specimens without nodular BPH (P <0.0014). The median %BPSA levels of the PZ-N and PZ-C tissues ranged from 3.2 to 4.9 and were not significantly different from one another or from the %BPSA level of TZ tissues without nodular BPH. CONCLUSIONS: We have identified a specific molecular form of clipped free PSA, called BPSA, that is increased within the prostatic TZ of patients exhibiting nodular BPH. Higher levels of percent free PSA in serum have been found to correlate strongly with prostate volume, which in turn is closely associated with the progressive enlargement of nodular BPH tissue within the TZ of the prostate. Thus, it is possible that a proportion of the serum percent free PSA found in patients with BPH may be composed of BPSA released into the serum.

Neural network prediction of prostate tissue composition based on magnetic resonance imaging analysis. A pilot study.

OBJECTIVE: To develop a neural network model that estimates prostate histology using magnetic resonance imaging (MRI). STUDY DESIGN: Fifty-three men with lower urinary tract symptoms (average age = 63.8 +/- 8.9 years) underwent a prostate MRI (T2) and sextant biopsy of the prostate. Masson Trichome and immunohistochemical prostate-specific antigen staining of the biopsy material were used to calculate the amount of stroma and epithelium in the inner gland (central plus transition zone). MRIs were normalized to the mean intensity of the obturator internus muscle for comparative analyses. Gray scale and texture features were extracted from the inner gland in the midsection transverse MRI slice. Clinical and image variables were used in two neural networks predicting a high amount of stroma and a high amount of epithelium, respectively. RESULTS: The positive and negative predictive values of the stroma and epithelium neural networks were 95%, 69% and 65%, 92%, respectively. CONCLUSION: These data suggest that the combined use of these neural networks may predict patient response to medical therapy targeting prostatic stroma or epithelium.

Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia.

PURPOSE: We tested the effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled trial. MATERIALS AND METHODS: We randomized 44 men 45 to 80 years old with symptomatic BPH into a trial of a saw palmetto herbal blend versus placebo. End points included routine clinical measures (symptom score, uroflowmetry and post-void residual urine volume), blood chemistry studies (prostate specific antigen, sex hormones and multiphasic analysis), prostate volumetrics by magnetic resonance imaging, and prostate biopsy for zonal tissue morphometry and semiquantitative histology studies. RESULTS: Saw palmetto herbal blend and placebo groups had improved clinical parameters with a slight advantage in the saw palmetto group (not statistically significant). Neither prostate specific antigen nor prostate volume changed from baseline. Prostate epithelial contraction was noted, especially in the transition zone, where percent epithelium decreased from 17.8% at baseline to 10.7% after 6 months of saw palmetto herbal blend (p <0.01). Histological studies showed that the percent of atrophic glands increased from 25. 2% to 40.9% after treatment with saw palmetto herbal blend (p <0.01). The mechanism of action appeared to be nonhormonal but it was not identified by tissue studies of apoptosis, cellular proliferation, angiogenesis, growth factors or androgen receptor expression. We noted no adverse effects of saw palmetto herbal blend. When the study was no longer blinded, 41 men elected to continue therapy in an open label extension. CONCLUSIONS: Saw palmetto herbal blend appears to be a safe, highly desirable option for men with moderately symptomatic BPH. The secondary outcome measures of clinical effect in our study were only slightly better for saw palmetto herbal blend than placebo (not statistically significant). However, saw palmetto herbal blend therapy was associated with epithelial contraction, especially in the transition zone (p <0.01), indicating a possible mechanism of action underlying the clinical significance detected in other studies.

Use of a shape-memory alloy (nitinol) in a removable prostate stent.

An easily removable prostate stent would be useful in various clinical situations but is not currently available. Thus, we studied the safety, tolerability, and ease of removal of a nitinol (nickel-titanium alloy) prostate stent in 10 men with symptomatic benign prostatic hyperplasia. The circular-coil stent becomes hourglass in shape following deployment, with the narrowest diameter approximately 35F. A working hypothesis was that the temperature-sensitive shape memory of nitinol would allow for its easy removal vis-à-vis other available stents. Using several modifications of a prototype insertion device, we found that the nitinol stents were easily inserted, retained their shape during retention periods of 1 to 4 weeks, caused no gross tissue reaction, and were removed easily with gentle traction after in situ cooling with iced saline lavage. Stent migration was observed in two patients, but otherwise, the stents were well tolerated. Nitinol prostate stents appear to fulfill a theoretical promise of being biologically inert, "superelastic," and pliable when cooled, allowing for easy removal. Further clinical investigation appears warranted.

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.

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.

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.

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.

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.

Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia.

PURPOSE: We sought to quantify prostate tissue changes induced by finasteride and to identify a predictor of finasteride response in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled, double-blind clinical trial. MATERIALS AND METHODS: Men with symptomatic BPH (52 to 78 years old) were randomly assigned to 6 months of treatment with finasteride (26) or placebo (15). Outcome measures were clinical (urinary symptom score and flow rate), chemical (serum prostate specific antigen and dihydrotestosterone levels), volumetric (transrectal ultrasound, and magnetic resonance imaging for whole and zonal prostate volumes) and histological (morphometry of prostate sextant biopsies, separated into inner and outer gland segments, to measure the percent epithelium, stroma and glandular lumen). RESULTS: In the finasteride group we found a suggestion of decreasing symptom scores and increasing flow rates (not significant) with significant decreases (p < 0.01) in prostate specific antigen (48%), dihydrotestosterone (74%) and prostate volume (21%). Finasteride treatment induced a 55% decrease in inner gland epithelium (p < 0.01) with little effect on stroma or lumina. We also found a linear correlation between pretreatment inner gland epithelial content and prostate volume decrease induced by the drug (tau = 0.58, p = 0.01). CONCLUSIONS: Finasteride treatment results in a major suppression of prostate epithelium, which is most pronounced in the inner gland. Moreover, a finasteride induced prostate volume decrease was predictable by quantification of epithelial tissues of the inner gland. These data lend additional support to the emerging concept of transition zone primacy in symptomatic BPH.