Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Pre-treatment neutrophil-to-lymphocyte ratio as predictor of adverse outcomes in patients undergoing radical cystectomy for urothelial carcinoma of the bladder.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor outcome in various tumours. Its prognostic utility in patients with urothelial carcinoma of the bladder (UCB) undergoing radical cystectomy (RC) is yet to be fully elucidated. METHODS: A cohort of patients undergoing RC for UCB in a tertiary referral centre between 1992 and 2012 was analysed. Neutrophil-to-lymphocyte ratio was computed using complete blood counts performed pre-RC, or before neo-adjuvant chemotherapy where applicable. Time-dependent receiver operating characteristic curves were used to determine the optimal cutoff point for predicting recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The predictive ability of NLR was assessed using Kaplan-Meier analyses and multivariable Cox proportional hazards models. The likelihood-ratio test was used to determine whether multivariable models were improved by including NLR. RESULTS: The cohort included 424 patients followed for a median of 58.4 months. An NLR of 3 was determined as the optimal cutoff value. Patients with an NLR⩾3.0 had significantly worse survival outcomes (5y-RFS: 53% vs 64%, log-rank P=0.013; 5y-CSS: 57% vs 75%, log-rank P<0.001; 5y-OS: 43% vs 64%, log-rank P<0.001). After adjusting for disease-specific predictors, an NLR ⩾3.0 was significantly associated with worse RFS (HR=1.49; 95% CI=1.12-2.0, P=0.007), CSS (HR=1.88; 95% CI=1.39-2.54, P<0.001) and OS (average HR=1.67; 95% CI=1.17-2.39, P=0.005). The likelihood-ratio test confirmed that prognostic models were improved by including NLR. CONCLUSIONS: Neutrophil-to-lymphocyte ratio is an inexpensive prognostic biomarker for patients undergoing RC for UCB. It offers pre-treatment prognostic value in addition to established prognosticators and may be helpful in guiding treatment decisions.

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.

BACKGROUND: Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease. METHODS: We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR. RESULTS: We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs-15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance). CONCLUSION: The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.

Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy.

BACKGROUND: Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. METHODS: 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. RESULTS: In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7-12.6, Wald p = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3-7.5, Wald p = 0.0085 in the Turku cohort). CONCLUSION: GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

Transurethral needle ablation of the prostate for treatment of benign prostatic hyperplasia: early clinical experience.

OBJECTIVES: Many attempts have been made to develop a method for treatment of benign prostatic hyperplasia (BPH) that is minimally invasive, efficacious, and low-cost. Transurethral needle ablation (TUNA) is a new, fast outpatient anesthesia-free procedure, using interstitial low-level radio frequency energy to produce a temperature above 100 degrees C. We describe our early clinical experience with TUNA as an outpatient procedure. METHODS: This technique was used in 20 patients with symptomatic BPH. All men were evaluated prior to treatment with flow rates, residual urine, International Prostate Symptom Score (IPSS), and quality of life. Follow-up occurred at 3 and 6 months after treatment, analyzing the same parameters. RESULTS: Tolerance using topical anesthetic and intravenous diazepam was excellent. Peak flow rate increased from a mean 9.5 +/- 3.3 mL/s to 14.7 +/- 6.3 mL/s (P < 0.05) at 3 months (19 patients) and to 15.0 +/- 4.9 mL/s (P < 0.05) at 6-month follow-up (12 patients). IPSS and quality of life improved from an average of 21.9 +/- 5.0 and 4.4 +/- 0.7 (P < 0.005) to 10.2 +/- 4.8 and 2.4 +/- 1.2 (P < 0.005), respectively, at 3-month follow-up. No significant complications were encountered. Retention was observed in 25% of the cases after the TUNA treatment. CONCLUSIONS: This initial study demonstrates the safety and effectiveness of TUNA. TUNA is a promising, anesthesia-free alternative treatment for men with symptomatic BPH. Long-term follow-up and randomized comparative studies with transurethral resection of the prostate (TURP) are planned to establish the place of this new alternative treatment of BPH in the urologist's armamentarium.

Transperineal radiofrequency interstitial tumor ablation of the prostate: correlation of magnetic resonance imaging with histopathologic examination.

OBJECTIVES: Radiofrequency (RF) energy has recently been employed to destroy human tissue in vivo. The purpose of this study was to investigate the safety of this approach in localized carcinoma of the prostate (CaP) and specifically, the predictability of lesions obtained with radiofrequency interstitial tumor ablation (RITA). METHODS: Using RITA, a total of 21 lesions were induced in 10 patients with localized CaP (mean age 70.4 years). RF was delivered transperineally under transrectal ultrasound (TRUS) guidance. All patients underwent endorectal magnetic resonance imaging (MRI) before and after treatment. Radical prostatectomy was performed in all patients 1 to 7 days after RITA. Three of the patients were treated with local anesthesia only. The predictability of the thermal lesion was assessed by correlating the findings of intraoperative TRUS, pre- and post-RITA endorectal MRI, and the histologic examination of the specimen. RESULTS: Postoperatively, patients were catheterized for an average of 1.8 days (1 to 3 days). Lesions of 2 x 2 x 2 cm were targeted. Average lesion diameters obtained on MRI were 2.08 +/- 0.23 x 2.09 +/- 0.36 x 2.28 +/- 0.21 cm. Average lesion diameters defined by coagulative necrosis at histologic examination were 2.20 +/- 0.23 x 2.10 +/- 0.31 x 2.38 +/- 0.14 cm. There were no statistically significant differences (P = 0.377) between average lesion volume on MRI (5.37 +/- 1.83 cm3) and average lesion volume at histology (5.86 +/- 1.63 cm3). No complications or adverse events were noted. CONCLUSIONS: In this Phase I study, RITA was shown to be safe and feasible, and to result in lesions that were predictable in size and location. MRI accurately visualized and verified the area of coagulative necrosis as documented at histology. The procedure is technically simple and can even be performed under local anesthesia.

Biological markers in superficial bladder tumors and their prognostic significance.

This article reviews the literature on some of the available biomarkers such as p53 and its down-stream effector p21 on superficial bladder tumor biology and their prognostic significance. The role of p53 tumor suppressor gene is controversial in superficial bladder cancer, possibly because analyzing one single effector of a pathway might hide the role of downstream effectors. The aggressiveness of this condition is related to proliferative activity as measured by Ki-67. Further studies are still necessary to draw definitive conclusions about the role of these different biological markers in superficial bladder cancer.

Radiofrequency interstitial tumor ablation (RITA) is a possible new modality for treatment of renal cancer: ex vivo and in vivo experience.

Small renal tumors are increasingly diagnosed and are frequently treated by nephron-sparing surgery. Tumors can be ablated by radiofrequency (RF) energy, which allows the operator to create very localized necrotic lesions. Radiofrequency interstitial tumor ablation (RITA) has been used in human kidneys in an ex vivo experiment to assess the necrotic lesions produced in a model close to physiologic conditions and then in three patients with localized renal cancer prior to radical nephrectomy. In the ex vivo model, four freshly removed kidneys were treated. Bipolar RF energy was delivered by a generator connected to two needles introduced parallel to each other into the renal parenchyma. A thermocouple was inserted between the two active electrodes. The renal artery at physiologic conditions was maintained at a constant temperature of perfusion of 37 degrees C by a computer-assisted Hot-line monitor. Two lesions were produced in each pole of each kidney including the cortex and the medulla. In an initial human study focusing on safety, feasibility, and pathology, three patients were treated by RITA with bipolar and monopolar energy. One patient with a peripheral 2-cm upper-pole tumor was treated percutaneously under ultrasound guidance with local anesthesia only 1 week prior to surgery. The other patients, with 3- and 5-cm tumors, were treated during surgery under general anesthesia just before nephrectomy. Ex vivo, the maximum temperature at the active needles ranged from 84 degrees C to 130 degrees C with 10 to 14 W applied during 10 to 14 minutes. Lesions were on average 2.2 x 3 x 2.5 cm.3 Microscopic examination showed stromal edema with intensive pyknosis. No damage was seen to adjacent untreated tissue. In the in vivo procedure, tolerance of RTA as an anesthesia-free procedure was excellent. The size of the observed lesions was comparable to the forecast size depending on the needle deployment. No side effects were noted, and no adjacent structures were affected by the RF ablation. These preliminary studies demonstrate the ability of RITA to produce localized extensive necrosis in kidney parenchyma and tumors safely under local anesthesia. Further studies could evaluate this new minimally invasive treatment in small kidney tumors considered for nephron-sparing surgery.

Prevention of prostate cancer.

Prostate cancer lends itself ideally to chemoprevention due to a number of specific features of the disease. These include a high prevalence, long latency time, hormone dependency, the availability of an ideal marker (prostate serum antigen) and, last but not least, the availability of a defined precursor lesion (prostatic intraepithelial neoplasia) among the pathways leading to clinical disease. The large variability in the incidence of the tumor in different geographical regions suggests the possibility of nutritional influences regarding the stimulation and/or inhibition of clinical cancer, as there is a similar prevalence worldwide of the precursor lesion. A great number of publications have dealt with a number of nutritional factors, including fat, phytoestrogens, vitamins (especially vitamin E) and minerals such as selenium and calcium. These are among the most reported substances with a possible influence on disease development; however, unfortunately there are no conclusive results or study outcomes at present which satisfy accepted standards of evidence. Ongoing studies on nutrition and prostate cancer may bring the required evidence to support what is still only an hypothesis at present.

[Use of transrectal ultrasonography in prostate pathology: determination and clinical usefulness of the prostate transition zone]. / Utilisation de l'échographie transrectale dans la pathologie prostatique: détermination et utilité clinique de la zone de transition de la prostate.

The prostate gland comprises a central or transition zone which is the object of an important hypertrophy in case of benign prostatic hypertrophy and a peripheral zone where the vast majority of cancers occurs. The ultrasonographic measurement of the prostate transition zone volume has become a very important parameter to consider in the assessment of the severity of symptoms or the therapeutic options in case of benign prostatic hyperplasia. When a prostate cancer is suspected, a new concept, the prostate specific antigen density related to the transition zone volume, has been demonstrated as a very effective mean for prostate cancer early detection in men with PSA levels below 10 ng/ml.

[Can we prevent prostatic cancer: role of nutrition?]. / Peut-on prevenir le cancer de la prostate: role de la nutrition?

The present paper gives a comprehensive overview of recent data, especially prospective randomized trials, which support an important role for nutrition in the development of prostate cancer. Prostate cancer seems to be an ideal candidate for chemoprevention, in order to interfere by modification of nutritional habits with its onset, its incidence and ultimately with its progression, especially in high risk groups.

[Laparoscopy in urology]. / La laparoscopie en urologie.

Since the past 10 years, results have established laparoscopy's efficacy. It is actually a consistent surgical option for a lot of indications met in urology. The rational behind performing laparoscopic procedures includes shorter hospital stays, less postoperative pain and a more rapid return to usual activity. Drawbacks of laparoscopy include significant learning curve, longer operative times and higher overall costs. One particular focus is the oncologic applications of laparoscopy for nephrectomy and specially for radical prostatectomy. Laparoscopy become nowadays an usual part of the armamenturium of urological teams.

Role of surgery in high-risk localized prostate cancer.

Men with high-risk localized prostate cancer (PCa) remain a challenge for clinicians. Until recently, surgery was not the preferred approach, in part because risk of subclinical metastatic disease, elevated rates of positive surgical margins, absence of randomized studies, and suboptimal cancer control did not justify the morbidity of surgery. No randomized data comparing surgery with radiation therapy are yet available. Data for and comparisons between treatment options should therefore be analyzed with extreme caution.When selecting the best treatment for patients with clinically localized high-risk PCa, considerations should include the life expectancy of the patient, the natural history of PCa, the curability of the disease, and the morbidity of treatment. High-grade PCa managed with noncurative intent greatly reduces life expectancy, but overall, it must also be remembered that radical prostatectomy (RP) and radiotherapy (RT) appear to have similar effects on quality of life. In this population, RP necessitates an extended pelvic lymph node dissection (PLND), but in selected cases, nerve-sparing is a therapeutic possibility and may offer a significant advantage over rt in terms of local control and-although absolutely not yet proved-maybe even in survival. One clear advantage is the ease of administering adjuvant or salvage external-beam rt (EBRT) after rp; conversely, salvage rp after failed EBRT is an exceedingly difficult surgery, with major complications. Surgery therefore has its place, but must be considered in the context of multimodality treatment and the risk of micrometastatic disease. Awaited trial results will help to further refine management in this group of patients.

Transurethral needle ablation (TUNA): histopathological, radiological and clinical studies of a new office procedure for treatment of benign prostatic hyperplasia.

Many attempts have been made to develop a method for treating benign prostatic hyperplasia (BPH) that is minimally invasive, efficacious, and low cost. The transurethral needle ablation (TUNA) device has recently been developed to treat BPH by selectively ablating hyperplastic prostatic tissue. A special catheter incorporates needles that deliver low-level radiofrequency power directly to a very localized area of the prostate. The needles have adjustable shields to protect the urethra if desired or necessary. It is positioned via transrectal ultrasound or direct vision. A pilot study was performed in patients to evaluate TUNA feasibility via histopathological measurement of the size of the thermal lesion and TUNA safety. Fifty patients have been treated, twenty-five patients were treated using TUNA prior to scheduled retropubic prostatectomy. The surgical prostatic specimens were recovered from 1 day to 1 month after TUNA, were step-sectioned, and examined histologically. Patients were 69 years old on average with a prostate weight varying from 14 to 88 g. The TUNA procedure averaged 30 minutes, 4 lesion treatments per prostate, and 4-15 W of power applied for 3 to 5 minutes. Proximal lesion temperature was about 40-70 degrees C with central lesion temperatures of about 110 degrees C. Urethral temperature averaged 37-42 degrees C and rectal temperature remained unchanged. Macroscopic examination of the specimens demonstrated localized lesions averaging 12 x 7 mm for 3 mins. and 10 x 17 for 5 mins. treatment. Microscopic examination showed larger lesions of extensive coagulative necrosis up to 35 x 15 mm. Specific immunohistochemical staining showed destruction of all tissue components. Preservation of the urethra and capsule integrity were noted. Magnetic resonance imaging performed in vivo and ex vivo showed lesions in the prostate corresponding to the recovered surgical specimen. All patients were treated without anesthesia and tolerated the procedure well. Of the 9 patients treated for chronic retention, 6 recovered voiding within 48 hours. Three month follow-up in 11 patients showed significant improvement in both objective and subjective parameters. Because of good lesion localization and maintenance of a normal rectal temperature TUNA appears to be safe. The feasibility of its widespread use was shown by the creation and sustainability of adequately sized lesions and good tolerance as an outpatient treatment. Ongoing clinical studies are evaluating the sustained efficacy of the procedure.

Biological response modifiers for the treatment of superficial bladder tumors.

BACKGROUND: For more than 20 years, superficial bladder tumors have been demonstrated to be sensitive to several biological response modifiers and especially to immunomodulators. The best-known and studied immunomodulator is the bacillus Calmette-Guérin (BCG). However, despite its well-recognized efficacy, BCG is not a universal panacea and is associated with potentially significant side effects. METHODS: New perspectives in BCG therapy aiming to increase BCG efficacy or to decrease side effects include the use of genetically engineered BCG strains producing cytokines as well as the use of purified BCG subcomponents. Because a cascade of immunological reactions including the secretion of several cytokines has been demonstrated in the BCG mode of action, many other biological response modifiers and especially immunomodulators have been studied for superficial transitional cell carcinoma therapy. Some were investigated in human trials, others are still in laboratory studies; some are administered intravesically whereas others are given orally. Interferon-alpha (IFN-alpha) intravesical instillations have been evaluated in several controlled studies. RESULTS: Although toxicity of intravesical IFN is minimal, its optimal dose, schedule and efficacy remain to be defined. Recent prospective studies comparing IFN to BCG intravesical therapy have been somewhat disappointing although this cytokine may be effective in some patients with T(a)-T(1) disease who have failed BCG therapy. Other immunomodulators administered intravesically investigated in clinical studies include interleukin 2 (recently used in a clinical study with a marker tumor response), levamisole, Rubratin, a Nocardia rubra cell wall skeleton, and keyhole limpet hemocyanin. Several biological response modifiers administered orally such as vitamin A (and its derivatives), Lactobacillus casei or bropirimine have been tested in clinical trials as well. In contrast, Allium sativum (garlic) or OK-432 (a streptococcal preparation) or BCG subfractions have been tested in laboratory studies only. CONCLUSIONS: Published reports on several of these biological response modifiers suggest that these compounds may be an alternative in patients with superficial bladder cancer who have failed or have not tolerated BCG, but further evaluation to improve efficacy, durability and understand their mechanism of action is warranted.

Clinical evolution of prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (PIN) is most likely a precursor of prostate cancer and is frequently associated with it whereas the direct link between low-grade PIN and cancer is not established. The clinical evolution of isolated high-grade PIN has been the object of much concern because of the possibility of undiagnosed prostate cancer or the evolution of this premalignant lesion in invasive carcinoma. Parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN are of evident interest and we have reviewed our experience and recent data from the literature on this topic as well as on the clinical management of these patients. Low-grade PIN is not by itself a risk of later cancer found on repeat biopsy unless other factors such as PSA increase the cancer suspicion. Patients with low-grade PIN and high serum PSA should therefore undergo repeat biopsies. Patients with low-grade PIN and without additional factors should be followed. Patients with high-grade PIN should systematically be rebiopsied. If a second set is still consistent with PIN, they should undergo additional biopsies again within 3-6 months because they are likely to have an undiagnosed cancer.

BPH and sexuality.

Quality of life has become a very important parameter in benign prostatic hyperplasia (BPH) and one of the major concepts identified by the patients to be important is related to sexuality after BPH therapy. The impact on sexuality resulting from the various treatment modalities of BPH, either medical, surgical or instrumental has been too often neglected in the past and poorly investigated. The present article reviews the influence on sexual function of current therapies for symptomatic BPH.

Transurethral needle ablation (TUNA): histopathological, radiological and clinical studies of a new office procedure for treatment of benign prostatic hyperplasia.

Many attempts have been made to develop a method for treating benign prostatic hyperplasia (BPH) that is minimally invasive, efficacious, and low cost. The transurethral needle ablation (TUNA) device has recently been developed to treat BPH by selectively ablating hyperplastic prostatic tissue. A special catheter incorporates needles that deliver low-level radiofrequency power directly to a very localized area of the prostate. The needles have adjustable shields to protect the urethra if desired or necessary. It is positioned via transrectal ultrasound or direct vision. A pilot study was performed in patients to evaluate TUNA feasibility via histopathological measurement of thermal lesion size and TUNA safety. Fifty patients have been treated, twenty-five patients were treated using TUNA prior to scheduled retropubic prostatectomy. The surgical prostatic specimens were recovered from 1 day to 1 month after TUNA, were stepsectioned, and examined histologically. Patients were 69-years-old on average with prostate weight varying from 14 to 88 g. The TUNA procedure averaged 30 minutes, 4 lesion treatments per prostate, and 4-15 W of power applied for 3 to 5 minutes. Proximal lesion temperature was about 40-70 degrees C with central lesion temperatures of about 110 degrees C with central lesion temperatures of about 110 degrees C. Urethral temperature averaged 37-42 degrees C and rectal temperature remained unchanged. Macroscopic examination of the specimens demonstrated localized lesions averaging 12 x 7 mm for 3 min and 10 x 17 for 5 min treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical prognostic criteria for later diagnosis of prostate carcinoma in patients with initial isolated prostatic intraepithelial neoplasia.

Prostatic intraepithelial neoplasia (PIN) is considered as a precursor of prostate cancer and is frequently associated with it. Diagnosis of PIN on a prostate needle biopsy without associated carcinoma is a difficult problem since high-grade PIN does not necessarily mean that prostate cancer is always present and low-grade PIN is associated with cancer as well. Definition of parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN is of evident interest and we have reviewed our experience and recent data from the literature on this topic. High grade is a strong predictor of later cancer found on repeat biopsy (50-100%) and in these patients, serum prostate-specific antigen (PSA), digital rectal examination and transrectal ultrasound are predictors of later cancer found on repeat biopsy. High-grade PIN is, however, frequently associated with later cancer whatever PSA, even when < or = ng/ml. Low-grade PIN seems to behave like BPH since the incidence of later cancer is extremely low when PSA is < 4 ng/ml and is high when PSA > 10 ng/ml. Patients with high-grade PIN should systematically be rebiopsied after 3-6 months to exclude cancer because they are likely to have undiagnosed cancer. Patients with low-grade PIN and low PSA seem to have a low risk of later cancer found on repeat biopsy. Patients with low-grade PIN and high serum PSA should have repeat biopsies because the incidence of subsequent cancer is high and comparable to high-grade PIN. Further investigations are needed to optimize the management of patients with low-grade PIN and intermediate PSA level.

Neoadjuvant hormonal treatment prior to radical prostatectomy: facts and open questions.

Since the advent of reversible androgen deprivation, its use for a short period of time (usually 3 months) before radical prostatectomy has been advocated by an increasing number of urologists without clear and definitive proof of its advantage. Most authors have demonstrated downsizing of the prostate by some 30-50%. Clinical downstaging was demonstrated in about 30% but this could not be confirmed at final pathological staging although downgrading was noted in some 10% of the series analyzed. Reduction of positive margins in patients receiving neoadjuvant treatment varies between 15% and 25% compared to control group. Several biases may however complicate the analysis of these results, the main cause of misinterpretation being the difficulty encountered by the pathologist to properly grade and score the tumor after hormonal deprivation. Even if some early significant advantages can be observed such as a decrease of positive margins and anecdotal complete disappearance of tumor in some specimens, this may not necessarily alter the metastatic spread and the overall survival rate. Only long follow-up in large prospective randomized studies evaluating biological (PSA) and clinical failures, time to progression and survival will allow definitive conclusions on this still controversial approach.