Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus.

Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future.

Prevention and early detection of prostate cancer.

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.

Role of multiparametric magnetic resonance imaging (MRI) in focal therapy for prostate cancer: a Delphi consensus project.

OBJECTIVE: To define the role of multiparametric MRI (mpMRI) for treatment planning, guidance and follow-up in focal therapy for prostate cancer based on a multidisciplinary Delphi consensus project. MATERIALS AND METHODS: An online consensus process based on a questionnaire was circulated according to the Delphi method. Discussion points were identified by literature research and were sent to the panel via an online questionnaire in three rounds. A face-to-face consensus meeting followed the three rounds of questions that were sent to a 48-participant expert panel consisting of urologists, radiologists and engineers. Participants were presented with the results of the previous rounds. Conclusions formulated from the results of the questionnaire were discussed in the final face-to-face meeting. RESULTS: Consensus was reached in 41% of all key items. Patients selected for focal therapy should have biopsy-proven prostate cancer. Biopsies should ideally be performed after mpMRI of the prostate. Standardization of imaging protocols is essential and mpMRIs should be read by an experienced radiologist. In the follow-up after focal therapy, mpMRI should be performed after 6 months, followed by a yearly mpMRI. mpMRI findings should be confirmed by targeted biopsies before re-treatment. No consensus was reached on whether mpMRI could replace transperineal template saturation biopsies to exclude significant lesions outside the target lesion. CONCLUSIONS: Consensus was reached on a number of areas related to the conduct, interpretation and reporting of mpMRI for use in treatment planning, guidance and follow-up of focal therapy for prostate cancer. Future studies, comparing mpMRI with transperineal saturation mapping biopsies, will confirm the importance of mpMRI for a variety of purposes in focal therapy for prostate cancer.

The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel.

OBJECTIVE: To establish a consensus on the utility of multiparametric magnetic resonance imaging (mpMRI) to identify patients for focal therapy. METHODS: Urological surgeons, radiologists, and basic researchers, from Europe and North America participated in a consensus meeting about the use of mpMRI in focal therapy of prostate cancer. The consensus process was face-to-face and specific clinical issues were raised and discussed with agreement sought when possible. All participants are listed among the authors. Topics specifically did not include staging of prostate cancer, but rather identifying the optimal requirements for performing MRI, and the current status of optimally performed mpMRI to (i) determine focality of prostate cancer (e.g. localising small target lesions of ≥0.5 mL), (ii) to monitor and assess the outcome of focal ablation therapies, and (iii) to identify the diagnostic advantages of new MRI methods. In addition, the need for transperineal template saturation biopsies in selecting patients for focal therapy was discussed, if a high quality mpMRI is available. In other words, can mpMRI replace the role of transperineal saturation biopsies in patient selection for focal therapy? RESULTS: Consensus was reached on most key aspects of the meeting; however, on definition of the optimal requirements for mpMRI, there was one dissenting voice. mpMRI is the optimum approach to achieve the objectives needed for focal therapy, if made on a high quality machine (3T with/without endorectal coil or 1.5T with endorectal coil) and judged by an experienced radiologist. Structured and standardised reporting of prostate MRI is paramount. State of the art mpMRI is capable of localising small tumours for focal therapy. State of the art mpMRI is the technique of choice for follow-up of focal ablation. CONCLUSIONS: The present evidence for MRI in focal therapy is limited. mpMRI is not accurate enough to consistently grade tumour aggressiveness. Template-guided saturation biopsies are no longer necessary when a high quality state of the art mpMRI is available; however, suspicious lesions should always be confirmed by (targeted) biopsy.

Small renal mass biopsy--how, what and when: report from an international consensus panel.

To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician. The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics. A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point. A consensus was established and lack of agreement to topics or specific items was noted at this point. Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance. Pathological interpretation: 'non-diagnostic samples' should refer to insufficient material, inconclusive and normal renal parenchyma. For non-diagnostic samples, a repeat biopsy is recommended. Fine-needle aspiration may provide additional information but cannot substitute for core biopsy. Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful-waiting candidates. We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications.

The Post-Ureteroscopic Lesion Scale (PULS): a multicenter video-based evaluation of inter-rater reliability.

PURPOSE: The Post-Ureteroscopic Lesion Scale (PULS) offers a simple grading system for the description of ureteral lesions after ureteroscopy. In this article, we present the results of a video-based multicenter evaluation of the inter-rater reliability of clinically important PULS grades 0-3. METHODS: Video sequences at the end of ureteroscopy (final passage) were recorded for 100 consecutive patients at a single institution and assessed by experienced urologists (n = 20) and senior residents (n = 17) at 19 international centers. The cohort included only patients with lesions grades 0-3 (with grades 2 and 3 subsumed as 2 + since distinction is defined by an extravasation of contrast medium in fluoroscopy). The gradings were evaluated for inter-rater reliability and in terms of simplicity, validity, comprehensibility, reproducibility, and usefulness. RESULTS: Overall, inter-rater reliability was high (Kendall's W = 0.69, p < 0.001) and was comparable between specialists (Kendall's W = 0.69, p < 0.001) and residents (Kendall's W = 0.71, p < 0.001). The matched ratings showed grade 0 in 43.0 % of patients and grades 1 or 2 + in 44.0 and 13.0 % of patients, respectively. Results of the questionnaires indicated a high degree of acceptance, with an overall rating of 1.76 (1.64-1.93 for different items, scale 1-6). CONCLUSIONS: Inter-rater reliability of the endoscopically assessable PULS was high among urologists with different levels of experience in different countries worldwide. The validated PULS system may be used for standardized reporting of ureteral lesions/injuries after ureteroscopy. In addition, PULS will enable more selective standardization of indications for postoperative DJ stenting based on the randomized controlled trials.

Risk adapted chemoprevention for prostate cancer: an option?

A high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make diagnosis and therapy of prostate cancer a special challenge for urologists. Effective prevention of the disease may help to resolve some of the problems mentioned above. Two randomised, controlled studies prove that effective chemoprevention of prostate cancer is possible using 5-α reductase inhibitors (finasteride, dutasteride) (LoE 1) both in individuals at low and those at high risk developing prostate cancer. Furthermore, there is evidence that other compounds, e.g. selective estrogen receptor modulators (SERMs), non-steroidal anti-inflammatory drugs (NSAIDs) and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economic aspects. The authors conclude that chemoprevention in a high risk cohort using 5-α reductase inhibitors is a viable option and may even be cost effective. In consequence, the options of chemoprevention in prostate cancer should be further explored in an open and unbiased way.

Effect of dutasteride on the risk of prostate cancer.

BACKGROUND: We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. METHODS: In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. RESULTS: Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). CONCLUSIONS: Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)

New ablative treatments for small renal masses: HIFU ablation.

Solid renal tumours with a diameter <4cm comprise up to half of all renal tumours coming for a therapeutic decision in tertiary care centres today. ∼80% are renal cell cancers, and nephron-sparing excision is standard therapy. The approach has considerable morbidity , and as many of these tumours are diagnosed in elderly ,infirm patients less invasive focal ablation appears attractive. This is usually achieved with radiofrequency or cryoablation, either percutaneously under image guidance or by a laparoscopic approach. The quality of reports on the outcome with this treatment is moderate, with no prospective comparative studies, and in general short follow-up. Metanalyses suggest more reliable results with cyro- than with radiofrequency ablation . Morbidity is lower than with nephron-sparing surgery, but still substantial and almost entirely due to the perforating trauma at ablation. This would be avoided by energy ablation with high-intensity focused ultrasound from an extracorporeal energy source. Phase 1 clinical studies with several prototoypes have been disappointing, as multiple acoustic interphases and target mobility obviously render adequately precise focusing unreliable. New HIFU transducers that can be approximated directly to the tumour via a laparoscopic approach circumvent these problems. A phase 1 study with this technique in 31 patients demonstrates that complete ablation of tumours can be achieved in this manner, at least for tumours <3cm and in a peripheral position in the lower and middle third of the kidney. Perforating trauma to the kidney is avoided, and morbidity is minimized. Of course patients still need long - term follow-up with sequential imaging and even biopsies, and tumour control is most likely less reliable than with standard nephron-sparing surgery.

Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker.

BACKGROUND: Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell-free DNA. METHODS: Preoperative serum samples from 200 consecutive patients with sporadic, solid renal tumors were analyzed (157 patients with RCC and 43 patients with benign renal tumors). Quantitative real-time polymerase chain reaction was used to assess total cell-free DNA (ring finger protein 185 [RNF185]) and CpG island methylation of Ras association domain family member 1A (RASSF1A) von Hippel-Lindau (VHL), prostaglandin-endoperoxidase synthase 2 (PTGS2), and P16 (cyclin-dependent kinase inhibitor 2A). Associations with RCC, pathologic variables, and disease-specific survival were evaluated. RESULTS: Total cell-free DNA levels and CpG island methylation of RASSF1A and VHL were highly diagnostic for RCC with an area under the receiver operating characteristic curve of 0.755, 0.705, and 0.694, respectively. VHL methylation was detected more frequently in patients with clear cell RCC than in those with other subtypes (P = .007). Total cell-free DNA levels were higher in patients with metastatic RCC (P < .001) and necrotic RCC (P = .003) and were associated with poorer disease-specific survival (P < .001). In multivariate analysis, the tumor stage, size, grade, and necrosis (SSIGN) score (P < .001) and categorized total cell-free DNA levels (P = .028) were retained as independent prognostic factors. CONCLUSIONS: The current results indicated that cell-free DNA represents a novel serum-based diagnostic and prognostic biomarker for RCC. Total serum cell-free DNA levels and CpG island methylation of RASSF1A and VHL may be useful diagnostic biomarkers for RCC. VHL methylation of cell-free DNA is suggestive of clear cell RCC. Total serum cell-free DNA may be a useful prognostic biomarker that may assist in tailoring postoperative surveillance and therapy. External prospective validation of these data will be required.

High detection rate of Trichomonas vaginalis in benign hyperplastic prostatic tissue.

While Trichomonas vaginalis, a protozoan parasite, is a well-investigated pathogen in the female population, there is little awareness of its significance in the male uro-genital tract. The presence of T. vaginalis in the prostate gland has only been scarcely investigated and has never been attested in conditions other than clinical prostatitis. Still, by some authors, this organ is regarded as ecologic niche for T. vaginalis. Since normal prostate tissue of sufficient quality is hard to come by, we investigated samples from 86 patients (mean age 68.7 ± 7.6 years) suffering from benign prostatic hyperplasia (BPH), a medical condition currently ranked as noninfectious, but characterized by chronic inflammatory tissue infiltrates of unknown etiology. Applying two different PCR protocols and sequence analysis of the respective amplicons, we detected T. vaginalis DNA in 29/86 (34%) BPH tissue samples, whereas in only 2/86 (2.3%) cases T. vaginalis grew in culture. Detection of T. vaginalis DNA correlated significantly (P < 0.01) with elevated peripheral blood monocytic cell counts, appearing along with protozoan infections. Given the unexpected high prevalence of T. vaginalis in BPH tissue of a nonselected, elderly study population from Austria, further epidemiological studies have to confirm this finding. Potential interactions of T. vaginalis in its prostatic habitat may be investigated with respect to their possible contribution to the inflammatory pathogenesis of BPH, since inflammatory cytokines have been shown to sustain prostatic hyperplastic growth.

High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Novel therapeutic methods have emerged in recent years as 'focal' treatment alternatives in which cancer foci can be eradicated and greatly reducing the associated side-effects of radical treatment. High-intensity focused ultrasound (HIFU) seems to result in a well fitted technology, which has proven short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies. This is an up-to-date review of the available literature on HIFU as a definitive treatment of prostate cancer. It describes the technique in a comprehensive approach in terms of technical features, procedure, indications, and gives an overview of its historical background; finally, we present the future applications of HIFU and its development trend. OBJECTIVES: • To provide an up-to-date review of the available literature on high-intensity focused ultrasound (HIFU) as a definitive treatment of prostate cancer. • To present the technique in a comprehensive approach, comparing the available devices according to the existing evidence in terms of technical features, procedure, indications, and to give an overview of its historical background; and finally, to discuss future applications of HIFU and its development trend. MATERIALS AND METHODS: • A systematic literature search was conducted using MEDLINE and EMBASE via Ovid databases (January 2000 to December 2011), to identify studies on HIFU for treatment of prostate cancer. • Only English-language and human-based full manuscripts that reported on case series studies with >50 participants, patient characteristics, efficacy and safety data were included. RESULTS: • No randomised controlled trials were identified by the literature search. We identified 31 uncontrolled studies that examined the efficacy of HIFU as primary treatment and two studies that examined the efficacy of HIFU as salvage treatment. • Most treated patients had localised prostate cancer (stage T1-T2); Gleason scores of 2-10 and mean prostate specific antigen (PSA) values of 4.6-12.7 ng/mL. The mean age range of the patients was 64.1-72 years. The mean follow-up ranged from 6.4 to 76.8 months. Negative biopsy rates ranged from 35 to 95%. PSA nadirs ranged from 0.04 to 1.8 ng/mL. The 5-year disease-free survival rates ranged from 61.2 to 95%; 7- and 8-year disease free survival rates ranged from 69 to 84%. • The most common complications associated with the HIFU procedure as the primary treatment included: urinary retention (<1-20%); urinary tract infections (1.8-47.9%); stress or urinary incontinence (<1-34.3%); and erectile dysfunction (20-81.6%). • Recto-urethral fistula was reported in <2% of patients. • Treatment-related morbidity appeared to be reduced by the combination of transurethral resection (TURP) of the prostate and HIFU. CONCLUSIONS: • Novel therapeutic methods have emerged in recent years as 'focal' treatment alternatives, in which cancer foci could be eradicated by greatly reducing the associated side-effects of radical treatment. • HIFU seems to result in short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies. • However, longer-term follow-up studies are needed to evaluate cancer-specific and overall survival. If available promising results on HIFU for definitive treatment of prostate cancer are confirmed in future prospective trials, focal therapy could start to challenge the current standard of care.

Novel approaches to improve prostate cancer diagnosis and management in early-stage disease.

The reported incidence of prostate cancer has risen since the implementation of screening. It is felt that the introduction of widespread prostate-specific antigen testing is responsible for most patients with prostate cancer now being diagnosed with asymptomatic, clinically localised disease. Diagnosis at this stage is associated with significantly improved treatment outcomes and longer life expectancy. Although there is evidence that screening has reduced prostate cancer mortality, there is a risk of over-diagnosis and over-treatment of early state prostate cancers, including clinically insignificant and indolent cancers. Active surveillance and focal therapy have been advocated as potential management options for some patients. However, these approaches face several challenges. Biopsy sampling errors together with less than optimal imaging of tumours can lead to difficulties in selecting suitable low-risk patients for these options. To overcome these challenges, novel approaches to the staging and monitoring of patients with early prostate cancer are being developed. These include new imaging techniques, such as multi-parametric magnetic resonance imaging, and the development of new biomarkers and biopsy-based methods. These techniques aim to assess the potential of a specific tumour to be aggressive, and to improve patient outcomes. The aim of the present paper is to summarise presentations and debates at the third annual Interactive Genitourinary Cancer Conference concerning the use of population-based screening methods and the roles of active surveillance and focal therapy as prostate cancer treatments. The application of novel imaging biopsy-based methods and biomarkers in early-stage prostate cancer will also be explored.

The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance.

OBJECTIVE: To evaluate the relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance. PATIENTS AND METHODS: Clinical data from two multi-centre European open-label, prospective studies evaluating the clinical utility of the PCA3 assay in guiding initial and repeat biopsy decisions were analysed. First-catch urine was collected after digital rectal examination (three strokes per lobe) and the PCA3 score was determined using the PROGENSA(®) PCA3 assay. Transrectal ultrasound-guided biopsy (≥8 cores) and radical prostatectomy (RP) specimens were analysed by the local pathologist. The relationship between biopsy and RP outcomes with the PCA3 score was assessed. RESULTS: Of the 1009 men enrolled, 348 (34%) had a positive biopsy. The median and mean PCA3 scores were statistically significantly lower in men with biopsy Gleason score <7 vs ≥7, with clinical stage T1c vs T2a-T2c, T3a cancers, with ≤33% vs >33% positive biopsy cores and with 'biopsy indolent' vs 'biopsy significant' prostate cancer (indolent prostate cancer defined by biopsy Epstein criteria). In all, 175 men with a positive biopsy had a RP: median and mean PCA3 scores were statistically significantly lower in men with pathological Gleason score <7 vs ≥7, and with pathological stage T2a-T2c vs T3a-T3b cancers. CONCLUSIONS: The PCA3 score may combined with traditional tools aid in identifying men with clinically insignificant prostate cancer, as shown by biopsy and RP pathological features including biopsy Epstein criteria, who could be candidates for active surveillance. Treatment selection should be based on a combination of clinical and pathological variables. If one wants to use a threshold point to guide treatment decisions in clinical practice, a PCA3 score threshold of 20 may have the highest utility for selecting men with clinically insignificant prostate cancer in whom active surveillance may be appropriate; a PCA3 score threshold of 50 may be used to identify men at high risk of harbouring significant prostate cancer who are candidates for RP. Although the association between the PCA3 score and prostate cancer aggressiveness needs further evaluation, the inclusion of the PCA3 score into patient management strategies may provide clinicians with another tool to more accurately determine the course of treatment.

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study.

OBJECTIVES: To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. To analyse whether the use of treatment-specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS: The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS: Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8-10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8-10 cancers would have been missed in the placebo group. In both groups, the incidence of Gleason 7 and Gleason 8-10 cancers generally increased with greater rises in PSA. Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7-10 cancers in men treated with dutasteride vs placebo. Men with Gleason 7 and Gleason 8-10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION: Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8-10) or higher than (Gleason 7-10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.

Role of transrectal ultrasonography (TRUS) in focal therapy of prostate cancer: report from a Consensus Panel.

What's known on the subject? and What does the study add? Focal therapy techniques are emerging in prostate cancer treatment. However, several key questions about patient selection, treatment and monitoring still have to be addressed. The concept of focal therapy is barely discussed in current urological guidelines. In the present manuscript, we report the results of a consensus meeting focused on ultrasonography, the most common used urological imaging method, in relation to focal therapy of prostate cancer. • To establish a consensus on the utility of ultrasonography (US) to select patients for focal therapy. Topics were the current status of US to determine focality of prostate cancer, to monitor and assess outcome of focal therapy and the diagnostic advantages of new US methods. In addition, the biopsy techniques required to identify focal lesions were discussed. • Urological surgeons, radiation oncologists, radiologists, and basic researchers from Europe and North America participated in a consensus meeting on the use of transrectal US (TRUS) in focal therapy of prostate cancer. The consensus process was face-to-face and specific clinical issues were raised and discussed with agreement sought when possible. • TRUS is commonly used and essential for diagnosing men with prostate cancer. It is particularly useful for targeting specific anatomical regions or visible lesions. However, it has several limitations and there is a need for improvement. Newer visualisation techniques, e.g. colour Doppler US, contrast-enhanced US and elastography, are being developed but currently there is no US technique that can accurately characterise a cancer suitable for focal therapy. Systematic biopsy is the only known procedure that allows the identification of prostate cancers suitable for focal therapy. Scarce data exist about the role of US for monitoring patients during or after ablative therapy. • Consensus was reached on all key aspects of the meeting. • US cannot reliably identify focal prostate cancer. New US methods show promising results in identifying prostate cancer focality. • Currently selecting appropriate candidates for focal therapy should be performed using dedicated protocols and biopsy schemes.

Quantification of extraprostatic perineural spread and its prognostic value in pT3a pN0 M0 R0 prostate cancer patients.

BACKGROUND: The prognostic relevance of the amount of extraprostatic cancer spread in nerves in prostate cancer patients is not well established. METHODS: Eighty-eight patients were included in our study with pT3a pN0 M0 R0 prostate cancer treated with retropubic prostatectomy. Eighty-seven of them showed perineural invasion, 54 were confined to the prostate, 33 showed cancer spread in extraprostatic nerves, which was quantified by counting each transverse section of nerves infiltrated by cancer in totally embedded specimens. Biochemical relapse was established by serum PSA levels of ≥0.2 ng/ml as well as PSA ≥ 0.4 ng/ml and higher according to the EAU guidelines. RESULTS: Extraprostatic but not intraprostatic perineural infiltration was significantly more often found in tumors of higher Gleason score. Intraprostatic number of infiltrated nerves (NIN) correlated with extraprostatic NIN. There was no association between extraprostatic or intraprostatic NIN and Gleason score, lymphatic, or blood vessel invasion. Extraprostatic neural infiltration in ≤10 nerves extended relapse free survival in univariate analysis for PSA 0.2 and 0.4 ng/ml (P = 0.002 and P < 0.000001, respectively) and remained significant in multivariate analysis for PSA 0.4 ng/ml (P = 0.039). CONCLUSIONS: High amount of extraprostatic NIN correlates with tumor progression and seems to be an independent prognostic parameter.

Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis.

BACKGROUND: Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision-making. METHODS: The current study included 2222 patients who had a history of nonmuscle-invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle-invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true-positives), subtracting the harms (false-positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy. RESULTS: After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design. CONCLUSIONS: For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision-making. For less risk-averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure.

The effect of dutasteride on the usefulness of prostate specific antigen for the diagnosis of high grade and clinically relevant prostate cancer in men with a previous negative biopsy: results from the REDUCE study.

PURPOSE: We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. MATERIALS AND METHODS: The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. RESULTS: Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7-10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7-10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7-10 cancer. CONCLUSIONS: In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer.

Low serum testosterone levels are poor predictors of sexual dysfunction.

OBJECTIVE: • To identify predictors of sexual dysfunction using baseline data from the reduction by dutasteride of prostate cancer events (REDUCE) study. PATIENTS AND METHODS: • REDUCE was a 4-year randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of once-daily dutasteride 0.5 mg in over 8000 men aged 50-75 years with a prostate-specific antigen (PSA) level of 2.5-10 ng/mL (50-60 years) or 3.0-10 ng/mL (>60 years) and a negative prostate biopsy within 6 months of enrolment. • Baseline values (mean serum testosterone, age, International Prostate Symptom Score [IPSS], total prostate volume [TPV], body mass index [BMI], and presence of diabetes/glucose intolerance) were compared in subjects with and without sexual dysfunction (sexual inactivity, impotence, decreased libido or a Problem Assessment Scale of the Sexual Function Index [PAS-SFI] score <9). RESULTS: • Multivariate logistic regression showed that baseline age and IPSS were significant predictors of all four sexual function criteria examined (P < 0.0001). • BMI was a significant predictor of decreased libido, impotence and a PAS-SFI score <9, while diabetes/glucose intolerance was a significant predictor of sexual inactivity, impotence and a PAS-SFI score <9. • Testosterone and TPV were not significant predictors of any sexual function criterion examined. CONCLUSIONS: • Age, IPSS, BMI and diabetes/glucose intolerance, but not serum testosterone or TPV, were significant independent predictors of sexual dysfunction in the REDUCE study population. • The lack of association between sexual dysfunction and serum testosterone questions the value of modestly reduced or low normal testosterone levels as criteria for choosing testosterone replacement in older men with sexual dysfunction.