Steven Joniau

To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on screening, diagnosis, and local treatment with curative intent of clinically localised prostate cancer (PCa).The working panel performed a literature review of the new data (2013-2015). The guidelines were updated and the levels of evidence and/or grades of recommendation were added based on a systematic review of the evidence.BRCA2 mutations have been added as risk factors for early and aggressive disease. In addition to the Gleason score, the five-tier 2014 International Society of Urological Pathology grading system should now be provided. Systematic screening is still not recommended. Instead, an individual risk-adapted strategy following a detailed discussion and taking into account the patient's wishes and life expectancy must be considered. An early prostate-specific antigen test, the use of a risk calculator, or one of the promising biomarker tools are being investigated and might be able to limit the overdetection of insignificant PCa. Breaking the link between diagnosis and treatment may lower the overtreatment risk. Multiparametric magnetic resonance imaging using standardised reporting cannot replace systematic biopsy, but robustly nested within the diagnostic work-up, it has a key role in local staging. Active surveillance always needs to be discussed with very low-risk patients. The place of surgery in high-risk disease and the role of lymph node dissection have been clarified, as well as the management of node-positive patients. Radiation therapy using dose-escalated intensity-modulated technology is a key treatment modality with recent improvement in the outcome based on increased doses as well as combination with hormonal treatment. Moderate hypofractionation is safe and effective, but longer-term data are still lacking. Brachytherapy represents an effective way to increase the delivered dose. Focal therapy remains experimental while cryosurgery and HIFU are still lacking long-term convincing results.The knowledge in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for the use in clinical practice. These are the first PCa guidelines endorsed by the European Society for Radiotherapy and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office and online (http://uroweb.org/guideline/prostate-cancer/).The 2016 EAU-STRO-IOG Prostate Cancer (PCa) Guidelines present updated information on the diagnosis, and treatment of clinically localised prostate cancer. In Northern and Western Europe, the number of men diagnosed with PCa has been on the rise. This may be due to an increase in opportunistic screening, but other factors may also be involved (eg, diet, sexual behaviour, low exposure to ultraviolet radiation). We propose that men who are potential candidates for screening should be engaged in a discussion with their clinician (also involving their families and caregivers) so that an informed decision may be made as part of an individualised risk-adapted approach.

The most recent summary of the European Association of Urology (EAU) guidelines on prostate cancer (PCa) was published in 2011. To present a summary of the 2013 version of the EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined PCa. A literature review of the new data emerging from 2011 to 2013 has been performed by the EAU PCa guideline group. The guidelines have been updated, and levels of evidence and grades of recommendation have been added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. A full version of the guidelines is available at the EAU office or online (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. Systematic prostate biopsies under ultrasound guidance and local anesthesia are the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. A biopsy progression indicates the need for active intervention, whereas the role of PSA doubling time is controversial. In men with locally advanced PCa for whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT), with equivalent oncologic efficacy. Active treatment is recommended mostly for patients with localized disease and a long life expectancy, with radical prostatectomy (RP) shown to be superior to WW in prospective randomized trials. Nerve-sparing RP is the approach of choice in organ-confined disease, while neoadjuvant ADT provides no improvement in outcome variables. Radiation therapy should be performed with ≥74 Gy in low-risk PCa and 78 Gy in intermediate- or high-risk PCa. For locally advanced disease, adjuvant ADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment of choice. Follow-up after local therapy is largely based on PSA and a disease-specific history, with imaging indicated only when symptoms occur. Knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice. A summary is presented of the 2013 EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined prostate cancer (PCa). Screening continues to be done on an individual basis, in consultation with a physician. Diagnosis is by prostate biopsy. Active surveillance is an option in low-risk PCa and watchful waiting is an alternative to androgen-deprivation therapy in locally advanced PCa not requiring immediate local treatment. Radical prostatectomy is the only surgical option. Radiation therapy can be external or delivered by way of prostate implants. Treatment follow-up is based on the PSA level.

To present a summary of the 2007 version of the European Association of Urology (EAU) guidelines on prostate cancer (PCa).A literature review of the new data emerging from 2004 to 2007 was performed by the working panel. The guidelines have been updated, and the level of evidence/grade of recommendation was added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.A full version is available at the EAU Office or at www.uroweb.org. Systemic prostate biopsy under ultrasound guidance is the preferred diagnostic method. Active treatment is mostly recommended for patients with localized disease and a long life expectancy, with radical prostatectomy being shown to be superior to watchful waiting in a prospective randomized trial. Nerve-sparing radical prostatectomy represents the approach of choice in organ-confined disease; neoadjuvant androgen deprivation demonstrates no improvement of outcome variables. Radiation therapy should be performed with at least 72 and 78 Gy in low-risk and intermediate- to high-risk PCa, respectively. Monotherapeutic androgen deprivation is the standard of care in metastatic PCa; intermittent androgen deprivation might be an alternative treatment option for selected patients. Follow-up is largely based on prostate-specific antigen and a disease-specific history with imaging only indicated when symptoms occur. Cytotoxic therapy with docetaxel has emerged as the reference treatment for metastatic hormone-refractory PCa.The knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice.

Our aim was to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the screening, diagnosis, and treatment of clinically localised cancer of the prostate (PCa).The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and level of evidence and grade of recommendation were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.A full version is available at the EAU office or Web site (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. PSA doubling time in <3 yr or a biopsy progression indicates the need for active intervention. In men with locally advanced PCa in whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT) with equivalent oncologic efficacy. Active treatment is mostly recommended for patients with localised disease and a long life expectancy with radical prostatectomy (RP) shown to be superior to WW in a prospective randomised trial. Nerve-sparing RP represents the approach of choice in organ-confined disease; neoadjuvant androgen deprivation demonstrates no improvement of outcome variables. Radiation therapy should be performed with at least 74 Gy and 78 Gy in low-risk and intermediate/high-risk PCa, respectively. For locally advanced disease, adjuvant ADT for 3 yr results in superior disease-specific and overall survival rates and represents the treatment of choice. Follow-up after local therapy is largely based on PSA, and a disease-specific history with imaging is indicated only when symptoms occur.The knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice.

To present a summary of the 2013 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC).The working panel performed a literature review of the new data (2011-2013). The guidelines were updated, and levels of evidence and/or grades of recommendation were added to the text based on a systematic review of the literature that included a search of online databases and bibliographic reviews.Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). LHRH antagonists decrease testosterone without any testosterone surge, and they may be associated with an oncologic benefit compared with LHRH analogues. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation results in noninferior oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir and after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT (SRT) at PSA levels <0.5 ng/ml and SRP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (PET/CT) are of limited importance if the PSA is <1.0 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include analysis of PSA and testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Treatment of CRPC includes sipuleucel-T, abiraterone acetate plus prednisone (AA/P), or chemotherapy with docetaxel at 75mg/m(2) every 3 wk. Cabazitaxel, AA/P, enzalutamide, and radium-223 are available for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.The knowledge in the field of advanced, metastatic, and castration-resistant PCa is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or at www.uroweb.org.We present a summary of the 2013 version of the European Association of Urology guidelines on treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). LHRH antagonists decrease testosterone without any testosterone surge, and they might be associated with an oncologic benefit compared with LHRH analogues. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation results in noninferior oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir and after radiation therapy. Therapy for PSA relapse after RP includes salvage radiation therapy at PSA levels <0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Multiparametric magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (PET/CT) are of limited importance if the PSA is <1.0 ng/ml; bone scans, and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include analysis of PSA and testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Treatment of castration-resistant CRPC includes sipuleucel-T, abiraterone acetate plus prednisone (AA/P), or chemotherapy with docetaxel 75 mg/m(2) every 3 wk. Cabazitaxel, AA/P, enzalutamide, and radium-223 are available for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. The guidelines reported should be adhered to in daily routine to improve the quality of care in PCa patients. As we have shown recently, guideline compliance is only in the area of 30-40%.

To present a summary of the 2016 version of the European Association of Urology (EAU) – European Society for Radiotherapy & Oncology (ESTRO) – International Society of Geriatric Oncology (SIOG) Guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (CRPC). The working panel performed a literature review of the new data (2013–2015). The guidelines were updated, and the levels of evidence and/or grades of recommendation were added based on a systematic review of the literature. Relapse after local therapy is defined by a rising prostate-specific antigen (PSA) level >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir after radiation therapy (RT). 11C-choline positron emission tomography/computed tomography is of limited importance if PSA is <1.0 ng/ml; bone scans and computed tomography can be omitted unless PSA is >10 ng/ml. Multiparametric magnetic resonance imaging and biopsy are important to assess biochemical failure following RT. Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5 ng/ml and salvage RP, high-intensity focused ultrasound, cryosurgical ablation or salvage brachytherapy of the prostate in radiation failures. Androgen deprivation therapy (ADT) remains the basis for treatment of men with metastatic prostate cancer (PCa). However, docetaxel combined with ADT should be considered the standard of care for men with metastases at first presentation, provided they are fit enough to receive the drug. Follow-up of ADT should include analysis of PSA, testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Level 1 evidence for the treatment of metastatic CRPC (mCRPC) includes, abiraterone acetate plus prednisone (AA/P), enzalutamide, radium 223 (Ra 223), docetaxel at 75 mg/m2 every 3 wk and sipuleucel-T. Cabazitaxel, AA/P, enzalutamide, and radium are approved for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with mCRPC and osseous metastases to prevent skeletal-related complications. The knowledge in the field of advanced and metastatic PCa and CRPC is changing rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for use in clinical practice. These PCa guidelines are the first endorsed by the European Society for Therapeutic Radiology and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office or online (http://uroweb.org/guideline/prostate-cancer/). In men with a rise in their PSA levels after prior local treatment for prostate cancer only, it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients. For patients diagnosed with metastatic castrate-resistant prostate cancer, several new drugs have become available which may provide a clear survival benefit but the optimal choice will have to be made on an individual basis.

Purpose Retrospective studies suggest that metastasis-directed therapy (MDT) for oligorecurrent prostate cancer (PCa) improves progression-free survival. We aimed to assess the benefit of MDT in a randomized phase II trial. Patients and Methods In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography-computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy). Surveillance was performed with prostate-specific antigen (PSA) follow-up every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (≤ 3 v > 3 months) and nodal versus non-nodal metastases. The primary end point was androgen deprivation therapy (ADT)-free survival. ADT was started at symptomatic progression, progression to more than three metastases, or local progression of known metastases. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11). Quality of life was similar between arms at baseline and remained comparable at 3-month and 1-year follow-up. Six patients developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.

There is controversy regarding the therapeutic role of pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy for prostate cancer (PCa).To systematically review the relevant literature assessing the relative benefits and harms of PLND for oncological and non-oncological outcomes in patients undergoing radical prostatectomy for PCa.MEDLINE, MEDLINE In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched up to December 2015. Comparative studies evaluating no PLND, limited, standard, and (super)-extended PLND that reported oncological and non-oncological outcomes were included. Risk-of-bias and confounding assessments were performed. A narrative synthesis was undertaken.Overall, 66 studies recruiting a total of 275,269 patients were included (44 full-text articles and 22 conference abstracts). Oncological outcomes were addressed by 29 studies, one of which was a randomized clinical trial (RCT). Non-oncological outcomes were addressed by 43 studies, three of which were RCTs. There were high risks of bias and confounding in most studies. Conflicting results emerged when comparing biochemical and clinical recurrence, while no significant differences were observed among groups for survival. Conversely, the majority of studies showed that the more extensive the PLND, the greater the adverse outcomes in terms of operating time, blood loss, length of stay, and postoperative complications. No significant differences were observed in terms of urinary continence and erectile function recovery.Although representing the most accurate staging procedure, PLND and its extension are associated with worse intraoperative and perioperative outcomes, whereas a direct therapeutic effect is still not evident from the current literature. The current poor quality of evidence indicates the need for robust and adequately powered clinical trials.Based on a comprehensive review of the literature, this article summarizes the benefits and harms of removing lymph nodes during surgery to remove the prostate because of PCa. Although the quality of the data from the studies was poor, the review suggests that lymph node removal may not have any direct benefit on cancer outcomes and may instead result in more complications. Nevertheless, the procedure remains justified because it enables accurate assessment of cancer spread.

It remains unclear whether patients with a suspicion of prostate cancer (PCa) and negative multiparametric magnetic resonance imaging (mpMRI) can safely obviate prostate biopsy. To systematically review the literature assessing the negative predictive value (NPV) of mpMRI in patients with a suspicion of PCa. The Embase, Medline, and Cochrane databases were searched up to February 2016. Studies reporting prebiopsy mpMRI results using transrectal or transperineal biopsy as a reference standard were included. We further selected for meta-analysis studies with at least 10-core biopsies as the reference standard, mpMRI comprising at least T2-weighted and diffusion-weighted imaging, positive mpMRI defined as a Prostate Imaging Reporting Data System/Likert score of ≥3/5 or ≥4/5, and results reported at patient level for the detection of overall PCa or clinically significant PCa (csPCa) defined as Gleason ≥7 cancer. A total of 48 studies (9613 patients) were eligible for inclusion. At patient level, the median prevalence was 50.4% (interquartile range [IQR], 36.4–57.7%) for overall cancer and 32.9% (IQR, 28.1–37.2%) for csPCa. The median mpMRI NPV was 82.4% (IQR, 69.0–92.4%) for overall cancer and 88.1% (IQR, 85.7–92.3) for csPCa. NPV significantly decreased when cancer prevalence increased, for overall cancer (r = –0.64, p < 0.0001) and csPCa (r = –0.75, p = 0.032). Eight studies fulfilled the inclusion criteria for meta-analysis. Seven reported results for overall PCa. When the overall PCa prevalence increased from 30% to 60%, the combined NPV estimates decreased from 88% (95% confidence interval [95% CI], 77–99%) to 67% (95% CI, 56–79%) for a cut-off score of 3/5. Only one study selected for meta-analysis reported results for Gleason ≥7 cancers, with a positive biopsy rate of 29.3%. The corresponding NPV for a cut-off score of ≥3/5 was 87.9%. The NPV of mpMRI varied greatly depending on study design, cancer prevalence, and definitions of positive mpMRI and csPCa. As cancer prevalence was highly variable among series, risk stratification of patients should be the initial step before considering prebiopsy mpMRI and defining those in whom biopsy may be omitted when the mpMRI is negative. This systematic review examined if multiparametric magnetic resonance imaging (MRI) scan can be used to reliably predict the absence of prostate cancer in patients suspected of having prostate cancer, thereby avoiding a prostate biopsy. The results suggest that whilst it is a promising tool, it is not accurate enough to replace prostate biopsy in such patients, mainly because its accuracy is variable and influenced by the prostate cancer risk. However, its performance can be enhanced if there were more accurate ways of determining the risk of having prostate cancer. When such tools are available, it should be possible to use an MRI scan to avoid biopsy in patients at a low risk of prostate cancer.

The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history.To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN.Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade.PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival.Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival.PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

Prostate cancer is the most prevalent cancer in men and predominantly affects older men (aged ≥70 years). The median age at diagnosis is 68 years; overall, two‐thirds of prostate cancer‐related deaths occur in men aged ≥75 years. With the exponential ageing of the population and the increasing life‐expectancy in developed countries, the burden of prostate cancer is expected to increase dramatically in the future. To date, no specific guidelines on the management of prostate cancer in older men have been published. The International Society of Geriatric Oncology (SIOG) conducted a systematic bibliographic search based on screening, diagnostic procedures and treatment options for localized and advanced prostate cancer, to develop a proposal for recommendations that should provide the highest standard of care for older men with prostate cancer. The consensus of the SIOG Prostate Cancer Task Force is that older men with prostate cancer should be managed according to their individual health status, which is mainly driven by the severity of associated comorbid conditions, and not according to chronological age. Existing international recommendations (European Association of Urology, National Comprehensive Cancer Network, and American Urological Association) are the backbone for localized and advanced prostate cancer treatment, but need to be adapted to patient health status. Based on a rapid and simple evaluation, patients can be classified into four different groups: 1, ‘Healthy’ patients (controlled comorbidity, fully independent in daily living activities, no malnutrition) should receive the same treatment as younger patients; 2, ‘Vulnerable’ patients (reversible impairment) should receive standard treatment after medical intervention; 3, ‘Frail’ patients (irreversible impairment) should receive adapted treatment; 4, Patients who are ‘too sick’ with ‘terminal illness’ should receive only symptomatic palliative treatment.

Opinions about the optimal lymph node dissection (LND) template in prostate cancer differ. Drainage and dissemination patterns are not necessarily identical.To present a precise overview of the lymphatic drainage pattern and to correlate those findings with dissemination patterns. We also investigated the relationship between the number of positive lymph nodes (LN+) and resected lymph nodes (LNs) per region.Seventy-four patients with localized prostate adenocarcinoma were prospectively enrolled. Patients did not show suspect LNs on computed tomography scan and had an LN involvement risk of ≥ 10% but ≤ 35% (Partin tables) or a cT3 tumor.After intraprostatic technetium-99m nanocolloid injection, patients underwent planar scintigraphy and single-photon emission computed tomography imaging. Then surgery was performed, starting with a sentinel node (SN) procedure and a superextended lymphadenectomy followed by radical prostatectomy.Distribution of scintigraphically detected SNs and removed SNs per region were registered. The number of LN+, as well as the percentage LN+ of the total number of removed LNs per region, was demonstrated in combining data of all patients. The impact of the extent of LND on N-staging and on the number of LN+ removed was calculated.A total of 470 SNs were scintigraphically detected (median: 6; interquartile range [IQR]: 3-9), of which 371 SNs were removed (median: 4; IQR: 2.25-6). In total, 91 LN+ (median: 2; IQR: 1-3) were found in 34 of 74 patients. The predominant site for LN+ was the internal iliac region. An extended LND (eLND) would have correctly staged 32 of 34 patients but would have adequately removed all LN+ in only 26 of 34 patients. When adding the presacral region, these numbers increased to 33 of 34 and 30 of 34 patients, respectively.Standard eLND would have correctly staged the majority of LN+ patients, but 13% of the LN+ would have been missed. Adding the presacral LNs to the template should be considered to obtain a minimal template with maximal gain. NOTE: This manuscript was invited based on the 2011 European Association of Urology meeting in Vienna.

Radiolabelled choline positron emission tomography has changed the management of prostate cancer patients. However, new emerging radiopharmaceutical agents, like radiolabelled prostate specific membrane antigen, and new promising hybrid imaging will begin new challenges in the diagnostic field.The continuous evolution in nuclear medicine has led to the improvement in the detection of recurrent prostate cancer (PCa), particularly distant metastases. New horizons have been opened for radiolabelled choline positron emission tomography (PET)/computed tomography (CT) as a guide for salvage therapy or for the assessment of systemic therapies. In addition, new tracers and imaging tools have been recently tested, providing important information for the management of PCa patients. Herein we discuss: (1) the available evidence in literature on radiolabelled choline PET and their recent indications, (2) the role of alternative radiopharmaceutical agents, and (3) the advantages of a recent hybrid imaging device (PET/magnetic resonance imaging) in PCa.Data from recently published (2010-2015), original articles concerning the role of choline PET/CT, new emerging radiotracers, and a new imaging device are analysed. This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.In the restaging phase, the detection rate of choline PET varies between 4% and 97%, mainly depending on the site of recurrence and prostate-specific antigen levels. Both 68gallium (68Ga)-prostate specific membrane antigen and 18F-fluciclovine are shown to be more accurate in the detection of recurrent disease as compared with radiolabelled choline PET/CT. Particularly, Ga68-PSMA has a detection rate of 50% and 68%, respectively for prostate-specific antigen levels < 0.5ng/ml and 0.5-2ng/ml. Moreover, 68Ga- PSMA PET/magnetic resonance imaging demonstrated a particularly higher accuracy in detecting PCa than PET/CT. New tracers, such as radiolabelled bombesin or urokinase-type plasminogen activator receptor, are promising, but few data in clinical practice are available today.Some limitations emerge from the published papers, both for radiolabelled choline PET/CT and also for new radiopharmaceutical agents. Efforts are still needed to enhance the impact of published data in the world of oncology, in particular when new radiopharmaceuticals are introduced into the clinical arena.In the present review, the authors summarise the last evidences in clinical practice for the assessment of prostate cancer, by using nuclear medicine modalities, like positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging.

The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making.To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment.Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011.Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS).With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise.T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression.Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

Current evidence-based management for clinically localised prostate cancer includes active surveillance, surgery, external beam radiotherapy (EBRT) and brachytherapy. The impact of these treatment modalities on quality of life (QoL) is uncertain. To systematically review comparative studies investigating disease-specific QoL outcomes as assessed by validated cancer-specific patient-reported outcome measures with at least 1 yr of follow-up after primary treatment for clinically localised prostate cancer. MEDLINE, EMBASE, AMED, PsycINFO, and Cochrane Library were searched to identify relevant studies. Studies were critically appraised for the risk of bias. A narrative synthesis was undertaken. Of 11 486 articles identified, 18 studies were eligible for inclusion, including three randomised controlled trials (RCTs; follow-up range: 60–72 mo) and 15 nonrandomised comparative studies (follow-up range: 12–180 mo) recruiting a total of 13 604 patients. Two RCTs recruited small cohorts and only one was judged to have a low risk of bias. The quality of evidence from observational studies was low to moderate. For a follow-up of up to 6 yr, active surveillance was found to have the lowest impact on cancer-specific QoL, surgery had a negative impact on urinary and sexual function when compared with active surveillance and EBRT, and EBRT had a negative impact on bowel function when compared with active surveillance and surgery. Data from one small RCT reported that brachytherapy has a negative impact on urinary function 1 yr post-treatment, but no significant urinary toxicity was reported at 5 yr. This is the first systematic review comparing the impact of different primary treatments on cancer-specific QoL for men with clinically localised prostate cancer, using validated cancer-specific patient-reported outcome measures only. There is robust evidence that choice of primary treatment for localised prostate cancer has distinct impacts on patients’ QoL. This should be discussed in detail with patients during pretreatment counselling. Our review of the current evidence suggests that for a period of up to 6 yr after treatment, men with localised prostate cancer who were managed with active surveillance reported high levels of quality of life (QoL). Men treated with surgery reported mainly urinary and sexual problems, while those treated with external beam radiotherapy reported mainly bowel problems. Men eligible for brachytherapy reported urinary problems up to a year after therapy, but then their QoL returned gradually to as it was before treatment.

High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory.To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors.We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers.Retropubic radical prostatectomy with pelvic lymphadenectomy.Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups.The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period.This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

Depending on the pathologic tumour stage, up to 60% of prostate cancer patients who undergo radical prostatectomy will develop biochemical relapse and require further local treatment.We reviewed the results of early salvage radiation therapy (RT), defined as prostate-specific antigen (PSA) values prior to RT ≤ 0.5 ng/ml in the setting of lymph node-negative disease.Ten retrospective studies, including one multicentre analysis, were used for this analysis. Among them, we received previously unpublished patient characteristics and updated outcome data from five retrospective single-centre trials to perform a subgroup analysis for early salvage RT.Patients treated with early salvage RT have a significantly improved biochemical recurrence-free survival (BRFS) rate compared with those receiving salvage RT initiated after PSA values are >0.5 ng/ml. Similarly, within the cohort of patients with pre-RT PSA values <0.5 ng/ml, improved BRFS rates were noted among those with lower rather higher pre-RT PSA levels. It is possible that higher RT dose levels and the use of adjunctive androgen-deprivation therapy improve biochemical control outcomes in the salvage setting.Based on a literature review, improved 5-yr BRFS rates are observed for patients who receive early salvage RT compared with patients treated with salvage RT with a pre-RT PSA value >0.5 ng/ml. Whether the routine application of early salvage RT in patients with initially undetectable PSA levels will be associated with demonstrable clinical benefit awaits the results of ongoing prospective trials.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

<h3>Background</h3> Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette–Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. <i>FGFR</i> alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select <i>FGFR3/2</i> alterations following recurrence after BCG treatment. <h3>Patients and methods</h3> Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select <i>FGFR</i> alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. <h3>Results</h3> Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (<i>n</i> = 49) and chemotherapy (<i>n</i> = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal <i>P</i> value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. <h3>Conclusions</h3> Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring <i>FGFR</i> alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers.

A substantial subset of breast, colorectal, ovarian, endometrial and prostatic cancers displays markedly elevated expression of immunohistochemically detectable fatty acid synthase, a feature that has been associated with poor prognosis and that may be exploited in anti-neoplastic therapy. Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancer fatty acid synthase expression is up-regulated at the mRNA level together with other enzymes of the same metabolic pathway. Contrary to the observations that in many cell systems (including androgen-stimulated LNCaP prostate cancer cells) fatty acid and cholesterol metabolism are co-ordinately regulated so as to supply balanced amounts of lipids for membrane biosynthesis, storage or secretion, no changes in the expression of genes involved in cholesterol synthesis were found. These findings point to selective activation of the fatty acid synthesis pathway and suggest a shift in the balance of lipogenic gene expression in a subgroup of prostate cancers.

Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined.To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP.This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers.Open SRP.BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥ 0.1 or ≥ 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death.Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period.In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

The optimal management of locally advanced prostate cancer (cT3) is still a matter of debate. The objective of this study is to present 10-year outcomes of radical prostatectomy (RP) in unilateral cT3a disease. Between 1987 and 2004, 2273 patients underwent RP at our institution. Two hundred and thirty-five (10.3%) patients were assessed as unilateral cT3a disease by digital rectal examination. Thirty-five patients who received neoadjuvant treatment before surgery were excluded from further analysis. Mean follow-up was 70.6 months. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS), and overall survival (OS) rates. Cox uni- and multivariate regression analyses were used to identify predictive factors in BPFS and CPFS. Clinical overstaging (pT2) occurred in 23.5%. One hundred and twelve (56%) patients received adjuvant or salvage therapy. OS at 5 and 10 years was 95.9% and 77.0%, respectively, and CSS was 98.7% and 91.6%. BPFS at 5 and 10 years was 59.5% and 51.1%, respectively, and CPFS was 95.9% and 85.4%. Margin status was a significant independent predictor in BPFS; cancer volume was a significant independent predictor in CPFS. Clinically advanced prostate cancer is still frequently overstaged. In a well-selected patient group with locally advanced prostate cancer, RP—with adjuvant or salvage treatment when needed—can yield very high long-term cancer control and survival rates. Margin status and cancer volume are significant predictors of outcome after RP.

Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP). To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0–R1 PCa. Using a European multi-institutional cohort, 890 men with pT3pN0, R0–R1 PCa were identified. All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods. Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p = 0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p = 0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5). The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT.

Abstract Purpose: To prospectively evaluate multiparametric magnetic resonance imaging (MRI) for accurate localization of intraprostatic tumor nodules, with whole‐mount histopathology as the gold standard. Materials and Methods: Seventy‐five patients with biopsy‐proven, intermediate, and high‐risk prostate cancer underwent preoperative T2‐weighted (T2w), dynamic contrast‐enhanced (DCE) and diffusion‐weighted (DW) MRI at 1.5T. Localization of suspicious lesions was recorded for each of 24 standardized regions of interest on the different MR images and correlated with the pathologic findings. Generalized estimating equations (GEE) were used to estimate the sensitivity, specificity, accuracy, positive, and negative predictive value for every MRI modality, as well as to evaluate the influence of Gleason score and pT‐stage. Tumor volume measurements on histopathological specimens were correlated with those on the different MR modalities (Pearson correlation). Results: DW MRI had the highest sensitivity for tumor localization (31.1% vs. 27.4% vs. 44.5% for T2w, DCE, and DW MRI, respectively; P &lt; 0.005), with more aggressive or more advanced tumors being more easily detected with this imaging modality. Significantly higher sensitivity values were obtained for the combination of T2w, DCE, and DW MRI (58.8%) as compared to each modality alone or any combination of two modalities ( P &lt; 0.0001). Tumor volume can most accurately be assessed by means of DW MRI ( r = 0.75; P &lt; 0.0001). Conclusion: Combining T2w, DCE, and DW imaging significantly improves prostate cancer localization. J. Magn. Reson. Imaging 2013;37:1392–1401. © 2012 Wiley Periodicals, Inc.

Contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging for lymph node (LN) staging of prostate cancer (PCa) are largely inadequate.Our aim was to assess prospectively the sensitivity, specificity, and positive and negative predictive values for the LN staging by (11)C-choline positron emission tomography (PET)-CT and MR diffusion-weighted imaging (DWI) of the pelvis before retropubic radical prostatectomy (RRP) with extended pelvic LN dissection (PLND).From February 2008 to August 2009, 36 patients with histologically proven PCa and no pelvic LN involvement on contrast-enhanced CT with a risk ≥ 10% but ≤ 35% at LN metastasis according to the Partin tables were enrolled in this study.Patients preoperatively underwent (11)C-choline PET-CT and DWI. Subsequently all patients underwent a wide RRP and an extended PLND.Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for LN status of (11)C-choline PET-CT and DWI were calculated with the final histopathology of the LNs as comparator.Seventeen patients (47%) had a pN1 stage, and 38 positive LNs were identified. On a LN region-based analysis, sensitivity, specificity, PPV, NPV, and the number of correctly recognised cases at (11)C-choline PET-CT were 9.4%, 99.7%, 75.0%, 91.0%, and 7.9%, respectively, and at DWI these numbers were 18.8%, 97.6%, 46.2%, 91.7%, and 15.8%, respectively. Twelve LN regions containing macrometastases, of which 2 had capsular penetration, were not detected by (11)C-choline PET-CT; 11 LNs, of which 2 had capsular penetration, were not detected by DWI. This is a small study with 36 patients, but we intend to recruit more patients.From this prospective histopathology-based evaluation of (11)C-choline PET-CT and DWI for LN staging in high-risk PCa patients, it is concluded that these techniques cannot be recommended at present to detect occult LN metastases before initial treatment.

Prostate cancer (PCa) patients with pretreatment prostate-specific antigen (PSA) >20 ng/ml have a high risk of biochemical and clinical failure and even cancer-related death after local therapy. Pretreatment predictors of outcome after radical prostatectomy (RP) in this patient group are necessary.Our aim was to assess how the use of additional high-risk factors (biopsy Gleason score [bGS] > or = 8 or clinical stage 3-4) can improve prediction of treatment failure and cancer-related death after RP in patients with PSA >20.In a retrospective multicentre cohort study from six European centres between 1987 and 2005, 712 patients with PSA >20 ng/ml underwent RP and bilateral pelvic lymphadenectomy.Subgroups were analysed to determine the relationship between the number of high-risk factors and histopathology, biochemical progression-free survival, clinical evidence of progressive disease, prostate cancer-specific mortality (PCSM), and overall mortality. Kaplan-Meier analysis with log-rank test and Cox multivariable analysis were applied.Median follow-up was 77 mo. The number of high-risk factors was significantly associated with unfavourable histopathology. Among patients with only PSA >20 ng/ml, 33% had pT2 PCa, 57.9% had bGS <7, 54% had negative surgical margins, and 85% were lymph node negative (pN0), whereas among patients with all three high-risk factors, 4.5% had pT2 PCa, 2.3% had bGS <7, 20.5% had negative margins, and 49% were pN0 (p<0.001). The strongest predictor of progression and mortality was bGS. PSA >20 ng/ml associated with bGS < or =7 resulted in 10-yr PCSM of 5%; when associated with bGS > or =8, PCSM was 35%. The main limitations of the study were retrospective design and varying treatment modalities.PCa patients with PSA >20 ng/ml have varying risk levels of disease progression and PCSM. Considering additional risk factors further stratifies this group into four subgroups that can guide the clinician in preoperative patient counselling.

Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples. A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. A urine sample was classified as valid when ≥10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (≥90%) sensitive and specific, noninvasive approach for detecting primary BCa. BlCa-001 study – EudraCt 2006-003303-40.

To compare perioperative outcome and health-related quality of life (HRQOL) after open partial and radical nephrectomy for renal tumours.Literature search of Medline and additional references from non-Medline-indexed journals for documents concerning treatment of renal tumours, perioperative outcome, and HRQOL after radical and partial nephrectomy.A total of 39 references were used of which 7 discussed complications, 3 included hospital costs and length of stay, and 7 each discussed renal function and QOL. No statistical difference was found concerning perioperative complications although there seems to be a trend towards a slightly higher complication rate after partial nephrectomy. No statistical difference was reported between the two procedures concerning hospital costs and length of stay. For postoperative renal function, a higher incidence of chronic renal failure was noted after radical nephrectomy. When considering the HRQOL a benefit was found after elective partial nephrectomy. In case of mandatory partial nephrectomy the fear of recurrence and the worry about having fewer than two normal kidneys were significantly higher.Partial nephrectomy achieves a better HRQOL due to better preservation of renal function and overall quality of life. Considering perioperative outcome no statistical difference was found for hospital costs and length of stay. A trend towards a higher perioperative complication rate was found after partial nephrectomy.

• To investigate the pathological characteristics and the rates of biochemical recurrence (BCR) -free survival after radical prostatectomy (RP) in men with high-risk prostate cancer.• Of 4760 patients treated with RP for prostate cancer at three institutions, 293 patients (6.2%) had clinical stage T3, 269 (5.7%) had a biopsy Gleason sum ≥ 8, 370 (7.8%) had preoperative PSA ≥ 20 ng/mL and 887 (18.6%) were considered high-risk according to the D'Amico classification (clinical stage ≥ T2c or prostate-specific antigen (PSA) ≥ 20 ng/mL or biopsy Gleason sum ≥ 8). • Actuarial BCR-free survival probabilities after RP and the rate of favourable pathology (organ-confined cancer, negative surgical margin and Gleason ≤ 7) were assessed.• Median follow up was 2.4 years and 1179 (24.8%) patients had follow up beyond 5 years. • The rate of favourable pathology increased in the following order: clinical stage T3 (13.7%), biopsy Gleason ≥ 8 (16.4%), the D'Amico high-risk group (21.4%) and PSA ≥ 20 ng/mL (21.6%). • The 5-year BCR-free survival probabilities were 35.4% for Gleason ≥ 8, 39.8% for PSA ≥ 20 ng/mL, 47.4% for D'Amico high-risk group and 51.6% for clinical stage T3. • Patients with only one risk factor had the most favourable 5-year BCR-free survival (50.3%), relative to patients with two or more risk factors (27.5%)• Men with clinically localized high-risk prostate cancer do not have a uniformly poor prognosis after RP. • The rate of favourable pathology and of BCR-free survival may vary substantially, depending on the definition used. • RP should be considered a valid treatment modality for high-risk prostate cancer patients, as many can be surgically down-staged.

The therapeutic scenario for metastatic renal cell carcinoma (mRCC) has been evolving rapidly, with sunitinib, sorafenib, bevacizumab, everolimus, pazopanib, and temsirolimus being successfully tested and approved in a short period of time. Oncologists must be familiar with the management of toxicity that these biologic agents cause, as such toxicity is different from that of conventional chemotherapeutic agents.To describe toxic effects associated with targeted therapy of mRCC and their proper management on the basis of currently available evidence.We conducted a systematic analysis of the literature on 15th October 2010 by performing a search of Medical Subject Headings (MeSH) on PubMed using the words sorafenib, sunitinib, bevacizumab, everolimus, pazopanib, or temsirolimus combined with the MeSH term kidney neoplasms. Consideration for inclusion was given to articles providing data concerning (1) incidence and grading and (2) management of targeted therapy-related toxic effects. A separate search was conducted on PubMed to retrieve meta-analyses using each drug name and the word meta-analysis.Hypertension, fatigue, bone marrow toxicity, skin toxicity, and gastrointestinal side-effects are common with the six targeted agents. Everolimus and temsirolimus are associated with immunosuppression, metabolic alterations, and interstitial pneumonitis, while sunitinib is associated with hypothyroidism. Recommendations for treating these conditions usually follow those for the general population because of the lack of experimental data in this setting (eg, for management of sunitinib-induced hypertension).The treating oncologist should try to manage side-effects associated with targeted therapy using supportive and pharmacologic interventions. Severe toxicity requires external specialist consultation and treatment suspension and/or dose reduction. Experimental data about the management of targeted therapy-related toxicity in mRCC is lacking and required in this setting.

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

The current role of radical prostatectomy (RP) in patients with high-risk disease remains controversial.To identify which high-risk prostate cancer (PCa) patients might have favorable pathologic outcomes when surgically treated.We evaluated 1366 patients with high-risk PCa (ie, at least one of the following risk factors: prostate-specific antigen [PSA]>20 ng/ml, cT3, biopsy Gleason 8-10) treated with RP and pelvic lymph node dissection (PLND) at eight European centers between 1987 and 2009. A favorable pathologic outcome was defined as specimen-confined (SC) disease-namely, pT2-pT3a, node negative PCa with negative surgical margins.All patients underwent radical retropubic prostatectomy and PLND.Univariable and multivariable logistic regression models tested the association between predictors and SC disease. A logistic regression coefficient-based nomogram was developed and internally validated using 200 bootstrap resamples. The Kaplan-Meier method was used to depict biochemical recurrence (BCR) and cancer-specific survival (CSS) rates.Overall, 505 of 1366 patients (37%) had SC disease at RP. All preoperative variables (ie, age and PSA at surgery, clinical stage, and biopsy Gleason sum) were independent predictors of SC PCa at RP (all p≤0.04). Patients with SC disease had significantly higher 10-yr BCR-free survival and CSS rates than patients without SC disease at RP (66% vs 47% and 98 vs 88%, respectively; all p<0.001). A nomogram including PSA, age, clinical stage, and biopsy Gleason sum demonstrated 72% accuracy in predicting SC PCa. This study is limited by its retrospective design and by the lack of an external validation of the nomogram.Roughly 40% of patients with high-risk PCa have SC disease at final pathology. These patients showed excellent long-term outcomes when surgically treated, thus representing the ideal candidates for RP as the primary treatment for PCa. Prediction of such patients is possible using a nomogram based on routinely available clinical parameters.

Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP). To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP. Using a multi-institutional cohort, 472 node-negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) ≤0.5 ng/ml. BCR after eSRT was defined as two consecutive PSA values ≥0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation. Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p ≤ 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p ≤ 0.04). A coefficient-based nomogram demonstrated a bootstrap-corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point. eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP. Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy.

More than 50% of prostate cancers have undergone a genomic reorganization that juxtaposes the androgen-regulated promoter of TMPRSS2 and the protein coding parts of several ETS oncogenes. These gene fusions lead to prostate-specific and androgen-induced ETS expression and are associated with aggressive lesions, poor prognosis, and early-onset prostate cancer. In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene when tested in bacterial artificial chromosomal vectors. Within this enhancer, we identified the exact androgen receptor binding sequence. This newly identified androgen response element is situated next to two binding sites for the pioneer factor GATA2, which were identified by DNase I footprinting. Both the androgen response element and the GATA-2 binding sites are involved in the enhancer activity. Importantly, a single nucleotide polymorphism (rs8134378) within this androgen response element reduces binding and transactivation by the androgen receptor. The presence of this SNP might have implications on the expression and/or formation levels of TMPRSS2 fusions, because both have been shown to be influenced by androgens.

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette-Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

Metastases-directed therapy (MDT) with surgery or stereotactic body radiotherapy (SBRT) is emerging as a new treatment option for prostate cancer (PCa) patients with a limited number of metastases (≤3) at recurrence – so called “oligometastases”. One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life. However, the lack of a control group, selection bias and the use of adjuvant androgen deprivation therapy prevent strong conclusions from published studies. The aim of this multicenter randomized phase II trial is to assess the impact of MTD on the start of palliative ADT compared to patients undergoing active surveillance. Patients with an oligometastatic recurrence, diagnosed on choline PET/CT after local treatment with curative intent, will be randomised in a 1:1 ratio between arm A: active surveillance only and arm B: MTD followed by active surveillance. Patients will be stratified according to the location of metastasis (node vs. bone metastases) and PSA doubling time (≤3 vs. > 3 months). Both surgery and SBRT are allowed as MDT. Active surveillance means 3-monthly PSA testing and re-imaging at PSA progression. The primary endpoint is ADT-free survival. ADT will be started in both arms at time of polymetastatic disease (>3 metastatic lesions), local progression or symptoms. The secondary endpoints include progression-free survival, quality of life, toxicity and prostate-cancer specific survival. This is the first randomized phase 2 trial assessing the possibility of deferring palliative ADT with MDT in oligometastatic PCa recurrence. Clinicaltrials.gov identifier: NCT01558427

Because pelvic lymph node (LN)-positive prostate cancer (PCa) is generally considered a regionally metastatic disease, surgery needs to be better defined.To review the impact of radical prostatectomy (RP) and pelvic lymph node dissection (PLND), possibly in conjunction with a multimodal approach using local radiotherapy and/or androgen-deprivation therapy (ADT), in LN-positive PCa.A systematic Medline search for studies reporting on treatment regimens and outcomes in patients with LN-positive PCa undergoing RP between 1993 and 2012 was performed.RP can improve progression-free and overall survival in LN-positive PCa, although there is a lack of high-level evidence. Therefore, the former practice of aborting surgery in the presence of positive nodes might no longer be supported by current evidence, especially in those patients with a limited LN tumor burden. Current data demonstrate that the lymphatic spread takes an ascending pathway from the pelvis to the retroperitoneum, in which the internal and the common iliac nodes represent critical landmarks in the metastatic distribution. Sophisticated imaging technologies are still under investigation to improve the prediction of LN-positive PCa. Nonetheless, extended PLND including the common iliac arteries should be offered to intermediate- and high-risk patients to improve nodal staging with a possible benefit in prostate-specific antigen progression-free survival by removing significant metastatic load. Adjuvant ADT has the potential to improve overall survival after RP; the therapeutic role of a trimodal approach with adjuvant local radiotherapy awaits further elucidation. Age is a critical parameter for survival because cancer-specific mortality exceeds overall mortality in younger patients (<60 yr) with high-risk PCa and should be an impetus to treat as thoroughly as possible.Increasing evidence suggests that RP and extended PLND improve survival in LN-positive PCa. Our understanding of surgery of the primary tumor in LN-positive PCa needs a conceptual change from a palliative option to the first step in a multimodal approach with a significant improvement of long-term survival and cure in selected patients.

No data exist on the patterns of biochemical recurrence (BCR) and their effect on survival in patients with high-risk prostate cancer (PCa) treated with surgery. The aim of our investigation was to evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone.Overall, 2,065 patients with high-risk PCa treated with RP at 7 tertiary referral centers between 1991 and 2011 were identified. First, we calculated the probability of experiencing BCR after surgery. Particularly, we relied on conditional survival estimates for BCR after RP. Competing-risks regression analyses were then used to evaluate the effect of time to BCR on the risk of cancer-specific mortality (CSM).Median follow-up was 70 months. Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by+7.6%,+4.1%,+4.8%,+3.2%, and+3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001).Increasing time from surgery is associated with a reduction of the risk of subsequent BCR. Additionally, time to BCR represents a predictor of CSM in these patients. These results might help provide clinicians with better follow-up strategies and more aggressive treatments for early BCR.

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 upper lamina propria (ULP) area of interstitial cells (IC) has been studied extensively in bladder, but is rather unexplored in the rest of the urinary tract. This cell layer is intriguing because of the localization directly underneath the urothelium, the intercellular contacts and the close relationship with nerve endings and capillaries. In this study, we examine the ULP layer of IC in human renal pelvis, ureter and urethra, and we make a comparison with ULP IC in bladder. Tissue was obtained from normal areas in nephrectomy, cystectomy and prostatectomy specimens, and processed for morphology, immunohistochemistry and electron microscopy. A morphological and immunohistochemical phenotype for the ULP IC was assessed and region-dependent differences were looked for. The ULP IC in renal pelvis, ureter and urethra had a similar ultrastructural phenotype, which differed somehow from that of bladder IC, that is, thinner and longer cytoplasmic processes, no peripheral actin filaments and presence of dense core granules and microtubules. Together with their immunohistochemical profile, these features are most compatible with the phenotype of telocytes, a recently discovered group of stromal cells. Based on their global ultrastructural and immunohistochemical phenotype, ULP IC in human bladder should also be classified as telocytes. The most striking immunohistochemical finding was the variable expression of oestrogen receptor (ER) and progesterone receptor (PR). The functional relevance of ULP telocytes in the urinary tract remains to be elucidated, and ER and PR might therefore be promising pharmacological research targets.

Survival after surgical treatment using competing-risk analysis has been previously examined in patients with prostate cancer (PCa). However, the combined effect of age and comorbidities has not been assessed in patients with high-risk PCa who might have heterogeneous rates of competing mortality despite the presence of aggressive disease.To examine the risk of 10-yr cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathologic characteristics of patients treated with radical prostatectomy (RP) for high-risk PCa.Within a multi-institutional cohort, 3828 men treated with RP for high-risk PCa (defined as the presence of at least one of these risk factors: prostate-specific antigen >20 ng/ml, biopsy Gleason score 8-10, clinical stage ≥ T3) were identified.All patients underwent RP and pelvic lymph node dissection.Competing-risk Poisson regression analyses were performed to simultaneously assess the 10-yr CSM and OCM rates after RP. The same analyses were also conducted after stratification of patients according to age at surgery, comorbidity status assessed by the Charlson Comorbidity Index (CCI), and number of risk factors (one vs two or more).Overall, 229 patients (5.9%) died from PCa; 549 (14.3%) died from other causes. The 10-yr CSM and OCM rates ranged from 5.1% to 12.8% and from 4.3% to 37.4%, respectively. Age and CCI were the major determinants of OCM; their impact on CSM was minimal. OCM was the leading cause of death in all patient groups except in young men (≤ 59 yr) with no comorbidities, regardless of the number of risk factors (10-yr CSM and OCM 6.9-12.8% and 5.5-6.3%, respectively). The main limitation was the lack of patients managed conservatively.Even in the context of high-risk PCa, long-term CSM after RP is modest and represents the leading cause of death only in young, healthy patients. Conversely, older and sicker patients with multiple risk factors are at the highest risk of dying from OCM while sharing very low CSM rates.

Early salvage radiation therapy (eSRT) represents a treatment option for patients who experience a prostate-specific antigen (PSA) rise after radical prostatectomy (RP); however, the optimal PSA level for eSRT administration is still unclear. To test the impact of PSA level on cancer control after eSRT according to pathologic tumour characteristics. The study included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after RP. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at PSA ≤0.5 ng/ml. Biochemical recurrence (BCR) after eSRT was defined as two consecutive PSA values ≥0.2 ng/ml. Multivariable Cox regression analysis tested the association between pre-eSRT PSA level and BCR after eSRT. Covariates consisted of pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), and surgical margin status (negative vs positive). We tested an interaction with PSA level and baseline pathologic risk for the hypothesis that BCR-free survival differed by pre-eSRT PSA level. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score ≥8, and negative surgical margins. Median follow-up among patients who did not experience BCR after eSRT was 57 mo (interquartile range: 27–105). At 5 yr after eSRT, BCR-free survival rate was 82% (95% confidence interval [CI], 78–85). At multivariable Cox regression analysis, pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio: 4.89; 95% CI, 1.40–22.9; p < 0.0001). When patients were stratified according to the number of risk factors at final pathology, patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR as high as 10% per 0.1 ng/ml of PSA level compared with only 1.5% in patients with one or no pathologic risk factors. In this retrospective study, cancer control after eSRT greatly depended on pretreatment PSA. The absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. In patients with more adverse pathologic features, eSRT conferred better cancer control when administered at the very first sign of PSA rise. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP. In this retrospective study, cancer control after early salvage radiation therapy (eSRT) was influenced by pretreatment prostate-specific antigen (PSA) level. This effect was highest in men with at least two of the following pathologic features: pT3b/pT4 disease, pathologic Gleason score ≥8, and negative surgical margins. In these patients, eSRT conferred better cancer control when administered at the very first sign of PSA rise.

The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era.To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC.Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25-82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC.Metastasis resection from various anatomic sites with the aim of completely removing detected lesions.Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan-Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The α error for statistical significance was set at 0.05.Multivariable analysis revealed that primary tumour T stage ≥ 3 (hazard ratio [HR]: 2.8; p<0.01), primary tumour Fuhrman grade ≥ 3 (HR: 2.3; p<0.03), nonpulmonary metastases (HR: 3.1; p<0.03), disease-free interval ≤ 12 mo (HR: 2.3; p<0.058), and multiorgan metastases (HR: 2.5; p<0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log-rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% (p<0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites.LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC.

The efficacy of preoperative pelvic floor muscle training (PFMT) for urinary incontinence (UI) after open radical prostatectomy (ORP) and robot-assisted laparoscopic radical prostatectomy (RARP) is still unclear.To determine whether patients with additional preoperative PFMT regain urinary continence earlier than patients with only postoperative PFMT after ORP and RARP.A randomized controlled trial enrolled 180 men who planned to undergo ORP/RARP.The experimental group (E, n=91) started PFMT 3 wk before surgery and continued after surgery. The control group (C, n=89) started PFMT after catheter removal.The primary end point was time to continence. Patients measured urine loss daily (24-h pad test) until total continence (three consecutive days of 0 g of urine loss) was achieved. Secondary end points were 1-h pad test, visual analog scale (VAS), International Prostate Symptom Score (IPSS), and quality of life (King's Health Questionnaire [KHQ]). Kaplan-Meier analysis and Cox regression with correction for two strata (age and type of surgery) compared time and continence. The Fisher exact test was applied for the 1-h pad test and VAS; the Mann-Whitney U test was applied for IPSS and KHQ.Patients with additional preoperative PFMT had no shorter duration of postoperative UI compared with patients with only postoperative PFMT (p=0.878). Median time to continence was 30 and 31 d, and median amount of first-day incontinence was 108 g and 124 g for groups E and C, respectively. Cox regression did not indicate a significant difference between groups E and C (p=0.773; hazard ratio: 1.047 [0.768-1.425]). The 1-h pad test, VAS, and IPSS were comparable between both groups. However, "incontinence impact" (KHQ) was in favor of group E at 3 mo and 6 mo after surgery.Three preoperative sessions of PFMT did not improve postoperative duration of incontinence.Netherlands Trial Register No. NTR 1953.

Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT).To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT.Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml.We compared aRT versus observation followed by esRT.The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis).Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population.At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.

The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in patients with nonmetastatic prostate cancer (PCa) relapse after primary curative therapy are controversial.To assess the effectiveness of HT for nonmetastatic PCa relapse, prognostic factors for treatment outcome, timing of treatment, and the most effective treatment strategy to provide guidance for clinical practice.A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library (search ended March 2015). Studies were critically appraised for risk of bias. The outcomes included overall and cancer-specific survival, metastasis-free survival, symptom-free survival, progression to castrate resistance, adverse events, and quality of life.Of 9687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomised comparative studies, and 17 case series). The results suggest that only a subgroup of patients, especially those with high-risk disease, may benefit from early HT. The main predictors for unfavourable outcomes were shorter PSA doubling time (<6-12 mo) and higher Gleason score (>7). Early HT may be warranted for patients with high-risk disease. An intermittent HT strategy appears feasible. Most studies had a moderate to high risks of bias.HT for PCa relapse after primary therapy with curative intent should be reserved for patients at highest risk of progression and with a long life expectancy. The potential benefits of starting HT should be judiciously balanced against the associated harms.This article summarises the evidence on the benefits and harms of hormonal treatment in prostate cancer (PCa) patients in whom the disease has recurred following earlier curative treatment. We found that only a select group of patients with aggressive PCa and a fast rising prostate-specific antigen may benefit from early hormonal treatment (HT), whereas in others HT may be more harmful than beneficial.

Abstract Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR. Mol Cancer Ther; 15(7); 1702–12. ©2016 AACR.

<h2>Abstract</h2><h3>Background</h3> Penile cancer (PeCa) represents a diagnostic and therapeutic challenge given the low patient volume, which may result in inadequate physician expertise and poor guideline adherence. Since 2015, we have developed a specific care pathway for PeCa in our tertiary referral center. <h3>Objective</h3> To evaluate the impact of a dedicated PeCa care pathway on patient management, the adequacy of pathological reporting, and oncological outcomes. <h3>Design, setting, and participants</h3> We retrospectively queried our institutional registry (S-66482) to identify patients who were surgically treated for PeCa between January 1989 and April 2022. The patient numbers were evaluated within a broader national context. <h3>Outcome measurements and statistical analysis</h3> We compared patient, surgery, tumor, and pathological data before and after 2015. Kaplan-Meier analysis was used to compare local and regional recurrence rates and cancer-specific survival (CSS). <h3>Results and limitations</h3> Overall, 313 patients were included, of whom 204 (65.1%) were surgically treated after 2015. The median number of patients treated yearly was significantly higher after 2015 (26 vs 5; <i>p</i> < 0.01). Patients treated after 2015 more frequently had no palpable lymph nodes at diagnosis, despite similar primary tumor stage. After adoption of the PeCa care pathway, organ-sparing surgery (OSS) was more commonly performed (79.9% vs 57.8%; <i>p</i> < 0.01) despite local staging being similar and without observing a significant increase in positive margins. Surgical staging in patients with European Association of Urology intermediate- or high-risk tumors was conducted more frequently after 2015 (90% vs 41%; <i>p</i> < 0.01). Pathology reporting was standardized, and there was more frequent reporting of p16 staining status (81.4% vs 8.3%; <i>p</i> < 0.01), lymphovascular invasion (93.8% vs 44.3%; <i>p</i> < 0.01), and perineural invasion (92.4% vs 44.3%; <i>p</i> < 0.01) following implementation. <h3>Conclusions</h3> Implementation of a standardized care pathway for PeCa resulted in higher rates of OSS and pathological nodal staging and more complete pathology reports. Considering that these changes were associated with an increase in the number of patients treated, academic-driven centralization may play a role in optimizing the management of these patients. <h3>Patient summary</h3> We evaluated the impact of a care pathway for patients with penile cancer on patient management, the completeness of pathology reporting, and cancer control. We found that implementation of this pathway was associated with an increase in the number of patients treated, higher rates of organ-sparing surgery and lymph node staging, and more complete pathology reports. Centralization of care may play a role in optimizing the management of penile cancer.

Abstract Many human epithelial cancers, particularly those with a poor prognosis, express high levels of fatty acid synthase (FAS), a key metabolic enzyme linked to the synthesis of membrane phospholipids in cancer cells. In view of the recent finding that in the human prostate cancer cell line LNCaP, overexpression of FAS can be largely attributed to constitutive activation of the phosphatidylinositol‐3 (PI3) kinase/Akt kinase pathway, the activation status of the Akt pathway, and whether this activation coincides with increased FAS expression, was examined in clinical prostate cancer tissues. Using well‐preserved frozen prostatic needle biopsies and a sensitive Envision detection technique, S473‐phosphorylated Akt (pAkt) was found in 11/23 low‐grade prostatic intraepithelial neoplasia (PIN) lesions, in all (36/36) high‐grade PINs, and in all (86/86) invasive carcinomas. Non‐neoplastic tissues were negative. Interestingly, in low‐grade PINs and low‐grade carcinomas, pAkt was mainly cytoplasmic or membrane‐bound and was associated with moderate elevation of FAS expression. In 24/36 high‐grade PINs and 82/88 invasive carcinomas, pAkt was found at least partly in the nucleus. Greater nuclear pAkt staining, and higher FAS expression, correlated with a higher Gleason score. In the light of previous findings that pAkt plays a causative role in the overexpression of FAS in cancer cells in culture, these data strongly suggest that high‐level expression of FAS in prostate cancer tissues is linked to phosphorylation and nuclear accumulation of Akt. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.

To clarify the role of radical prostatectomy (RP) in the treatment of locally advanced and high-grade prostate cancer.Literature search of Medline publications on surgery for locally advanced and high-grade prostate cancer.In patients with locally advanced disease, the cancer-specific survival rate after RP at 5- and 10-yr follow-up was 85-100% and 57-91.6%, respectively. The overall survival rate at 5 and 10 yr was>75% and 60%, respectively. In patients with high-grade prostate cancer (Gleason score> or =8), the biochemical recurrence-free survival after RP at 5 and 10 yr of follow-up was 51% and 39%, respectively. Nomograms and modern imaging techniques are useful in predicting pathologic stage, presence of positive lymph nodes, or seminal vesicle involvement. These allow physicians to recognise those patients with locally advanced disease who are most likely to benefit from surgical treatment. Downgraded and organ- or specimen-confined high-grade tumours can have a good prognosis after surgery. The prostate-specific antigen value and the percent positive biopsy cores can be helpful in identifying men with high-grade prostate cancer most likely to benefit from RP.It is likely that surgery has a role in the treatment of locally advanced and high-grade tumours. However, it is necessary and urgent to have randomised trials assessing survival and quality of life when RP is and is not included in the multimodality treatment.

The incidence of prostate cancer increases with age, with a median age at diagnosis of 68 years. Owing to increased life expectancy, the management of prostate cancer in senior adult men (i.e., aged 70 years or older) represents an important public health concern and a major challenge for the future. No specific guidelines have previously been published on the management of prostate cancer in older men. The SIOG has developed a proposal of recommendations in this setting.A systematic bibliographical search focused on screening, diagnostic procedures, treatment options for localised, locally advanced and metastatic prostate cancer in senior adults was performed. Specific aspects of the geriatric approach were emphasised, including evaluation of health status (nutritional, cognitive, thymic, physical and psycho-social) and screening for vulnerability and frailty. Attention was drawn to the consequences of androgen deprivation and complications of local treatment, mainly incontinence. The collected material has been reviewed and discussed by a scientific panel including urologists, radiation oncologists, medical oncologists and geriatricians from both Europe and North America.The consensus is to use either European Association of Urology or National Comprehensive Cancer Network clinical recommendations for prostate cancer treatment and to adapt them to health status based on instrumental activities of daily living (IADL) and activities daily living (ADL), comorbidity evaluation by Cumulative Illness Scoring Rating-Geriatrics and screening for malnutrition. Patients in Group 1 (no abnormality) are 'fit' and should receive the same treatment as younger patients; patients in Group 2 (one impairment in IADL or one uncontrolled comorbidity or at risk of malnutrition) are 'vulnerable' and should receive standard treatment after medical intervention; patients in Group 3 (one impairment in ADL or more than one uncontrolled comorbidity or severe malnutrition) are 'frail' and should receive adapted treatment; patients in Group 4 (dependent) should receive only symptomatic palliative treatment.Treatment of prostate cancer in senior adults should be adapted to health status. Specific prospective studies in this setting are warranted.

The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact.We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples.Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.

To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib.We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS).A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP >5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74-3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20-4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP >5 mg/L (difference = 29%, 95% CI 15-42). When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03-1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16-1.43; P < 0.001). Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59-0.68) to 0.69 (0.65-0.73), and the c-statistic of OS at 5 years from 0.65 (0.60-0.69) to 0.70 (0.66-0.74). Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome.Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

Accurate staging modalities to diagnose lymph node involvement in patients with prostate cancer (PCa) are lacking. We wanted to prospectively assess sensitivity, specificity, and positive predictive value (PPV) and negative predictive value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for nodal staging in patients with PCa at high risk for lymph node involvement.In total, 75 patients with a risk≥10% but<35% for lymph node (LN) metastases (Partin tables) who had N0 lesions based on the findings of contrast-enhanced CT scans were included. Patients underwent (11)C-choline PET-CT and DW MRI before surgery, which consisted of a superextended lymph node dissection followed by radical prostatectomy. LNs were serially sectioned and histopathologically examined after pankeratin staining. These results were used as the gold standard to compare with the imaging results.Of 1,665 resected LNs (median = 21, range: 7-49), 106 affected LNs (median = 2, range: 1-10) were found in 37 of 75 patients (49%). On a region-based analysis, we found a low sensitivity of 8.2% and 9.5% and a PPV of 50.0% and 40.0% for (11)C-choline PET-CT and DW MRI, respectively. The patient-based analysis showed a sensitivity of 18.9% and 36.1% for and a PPV of 63.6% and 86.7% (11)C-choline PET-CT and DW MRI, respectively. Even when both imaging modalities were combined, sensitivity values remained too low to be clinically useful.Because of the low sensitivity, there is no indication for routine clinical use of either (11)C-choline PET-CT or DW MRI for LN staging in patients with PCa, in whom CT scan findings were normal.

^99mTc-trofolastat (^99mTc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen, shows high potential to detect prostate cancer (PCa) noninvasively using SPECT. We therefore wanted to assess the performance of ^99mTc-trofolastat SPECT/CT in a phase 2 multicenter, multireader prospective study in patients with intermediate- and high-grade PCa, before radical prostatectomy and extended pelvic lymph node (LN) dissection, with histopathology as the gold standard. <b>Methods:</b> PCa patients (<i>n</i> = 105) with an increased risk of LN involvement (LNI) underwent pelvic ^99mTc-trofolastat SPECT/CT before radical prostatectomy with extended pelvic LN dissection. The sensitivity of ^99mTc-trofolastat for detection of PCa on a patient and lobe basis, using visual and semiquantitative (tumor-to-background ratio [TBR]) scores, and of LNI was evaluated as well as the correlation of uptake within the gland to Gleason scores (GS) and assessment of the predictive potential of ^99mTc-trofolastat uptake for LNI. <b>Results:</b> PCa was detected in 98 patients (94%) with acceptable variability between readers. There was a significantly higher visual score and TBR in positive lobes compared with tumor-negative lobes. Receiver-operating characteristic analysis showed that visual scores more accurately discriminated lobes with GS ≤ 3 + 3 from ≥ 3 + 4, whereas TBRs discriminated high-grade disease from normal lobes better. Visual scores and TBRs correlated significantly with GS. ^99mTc-trofolastat SPECT/CT detected LNI with a sensitivity of 50% and specificity of 87%, and TBR values significantly predicted LNI with a sensitivity of 90%. <b>Conclusion:</b>^99mTc-trofolastat SPECT/CT detects PCa with high sensitivity in patients with intermediate- and high-risk PCa compared with histology. It has the potential to be used as a surrogate marker for GS and predict LNI.

Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. We aimed to identify the optimal candidates for early SRT after RP. The study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. The primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. At a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.06, p < 0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. We developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. In patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified.

The current standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) plus either docetaxel or abiraterone. Growing evidence suggests that metastasis-directed therapy (MDT) and/or local therapy targeted to the primary tumour (ie, prostate) may be of benefit in the setting of oligometastatic disease. Several prospective studies are underway; however, until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with oligometastases.This comprehensive review aims to collate the available evidence to date for a role of MDT and/or prostate-targeted therapy in the setting of oligometastatic PCa, as well as discuss ongoing trials in this setting.We searched PubMed for the combination of "prostate cancer" and "oligometastatic", "oligometastases", "oligometastasis", "solitary metastases", "stereotactic body radiotherapy", "SBRT", "stereotactic ablative radiotherapy", "SABR", "salvage lymphadenectomy", or "metastasectomy" in publications over the last 20yr. We also searched ClinicalTrials.gov to identify relevant ongoing trials.The studies were divided according to the timing of metastasis into synchronous (ie, detected at the time of primary PCa diagnosis) and metachronous (ie, detected after treatment of the primary tumour), and according to treatment modality into MDT (including salvage lymph node dissection [sLND]) and prostate-targeted treatment. For MDT of synchronous/metachronous metastases, we included 16 completed studies and 11 ongoing prospective studies. In the case of sLND for nodal-only recurrence after primary treatment with curative intent, we included 11 completed studies. Finally, for prostate-targeted treatment of synchronous metastatic PCa, we included 25 completed studies and 11 ongoing prospective studies. In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions (surgery or radiotherapy) appears to be a feasible strategy and may delay the use of systemic therapies. MDT is a promising option in oligometastatic PCa patients, but more robust data are needed. In the setting of synchronous oligometastatic disease, aggressive cytoreductive treatment needs further data to confirm the benefits.In this review, we provide a comprehensive overview of the current literature on the treatment of patients with oligometastatic PCa. The data suggest that although ADT plus either docetaxel or abiraterone remains the mainstay of treatment for mPCa, in oligometastatic PCa, improved outcomes may be achieved with metastasis- and prostate-targeted therapies. The studies included in this review are mainly retrospective in nature, limiting the strength of the evidence they provide. Prospective studies are ongoing, and their results are eagerly awaited.We reviewed the treatment of patients with prostate cancer that has spread to five sites or fewer. We conclude that while androgen deprivation plus either docetaxel or abiraterone should remain the standard of care, there is evidence that treatment targeted at the metastases and the primary tumour may improve the outcome for the patient and potentially delay the use of systemic treatment.

To describe the anatomical patterns of prostate cancer (PCa) recurrence after primary therapy and to investigate if patients with low-volume disease have a better prognosis as compared with their counterparts.Patients eligible for an 18-F choline positron-emission tomography (PET)-computed tomography (CT) were enrolled in a prospective cohort study. Eligible patients had asymptomatic biochemical recurrence after primary PCa treatment and testosterone levels >50 ng/mL. The number of lesions was counted per scan. Patients with isolated local recurrence (LR) or with ≤3 metastases (with or without LR) were considered to have low-volume disease and patients with >3 metastases to have high-volume disease. Descriptive statistics were used to report recurrences. Cox regression analysis was used to investigate the influence of prognostic variables on the time to developing castration-resistant PCa (CRPC).In 208 patients, 625 sites of recurrence were detected in the lymph nodes (N1/M1a: 30%), the bone (18%), the prostate (bed; 11%), viscera (4%), or a combination of any of the previous (37%). In total, 153 patients (74%) had low-volume recurrence and 55 patients (26%) had high-volume recurrence. The 3-year CRPC-free survival rate for the whole cohort was 79% (95% confidence interval 43-55), 88% for low-volume recurrences and 50% for high-volume recurrences (P < 0.001). Longer PSA doubling time at time of recurrence and low-volume disease were associated with a longer time to CRPC.Three out of four patients with PCa with a 18-F choline PET-CT-detected recurrence have low-volume disease, potentially amenable to local therapy. Patients with low-volume disease have a better prognosis as compared with their counterparts. Lymph node recurrence was the most dominant failure pattern.

Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non–muscle-invasive bladder cancer patients. Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20–1.82; P<0.001). With maintenance, TICE was more effective than Connaught for the time to first recurrence (HR = 0.66; 95% CI: 0.47–0.93; P = 0.019) with a trend for cancer specific survival (HR = 0.36; 95% CI: 0.14–0.92; P = 0.033). For time to progression and overall survival, Connaught and TICE had a similar efficacy. Compared to no maintenance therapy, maintenance BCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given.

Despite the diverse physiological activities of androgens and glucocorticoids, the corresponding receptors are very close members of the nuclear-receptor super family. Their action mechanisms show striking similarities, since both receptors recognize very similar DNA-response elements and recruit the same coactivators to their target genes. The specificity of the responses lies mainly in the tissue-specific expression of the receptors and in their ligand specificity. In cells, where both receptors are expressed, the mechanisms leading to the difference in target genes are less obvious. They lie in part in subtle variations of the DNA-binding sites, in cooperativity with other transcription factors and in differential allosteric signals from the DNA and ligand to other receptor domains. We will highlight the different suggestions that might explain the DNA sequence selectivity and will compare the possible allosteric routes between the response elements and the different functions in the transactivation process. The interplay of androgen and glucocorticoid receptors is also highly relevant in clinical settings, where both receptors are therapeutically targeted. We will discuss the possibility that the glucocorticoid and androgen receptors can play partially redundant roles in castration-resistant prostate cancer.

Metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC) as an alternative to systemic therapy. In the absence of randomized trials, the benefit and best way of patient selection remain unclear. Earlier, we described four molecular ccRCC-subtypes (ccrcc1-4) that have a prognostic and predictive value upon first-line sunitinib or pazopanib.Assess the prognostic value of ccrcc1-4 subtypes after complete metastasectomy. (1) Compare outcomes of good-prognosis ccrccc2&3-tumors with intermediate/poor-prognosis ccrcc1&4-tumors. (2) Compare outcomes of the four subtypes separately.Single-center retrospective study (1995-2017), assessing 43 ccRCC patients undergoing complete metastasectomy without systemic treatment.Molecular subtype determined with established 35-gene expression classifier.Median disease-free survival (DFS), time to systemic therapy, cancer-specific (CSS) and overall survival (OS) from metastasectomy, estimated with Kaplan-Meier method and tested against other predictors with multivariable Cox regression.Median DFS was 23 mo for ccrcc2&3-tumors versus 9 mo for ccrcc1&4-tumors (p=0.011, hazard ratio [HR]=2.6). Median time to systemic therapy was 92 mo versus 28 mo (p=0.003, HR=3.3). Median CSS was 133 mo versus 50 mo (p<0.001, HR=2.7). Median OS was 127 mo versus 50 mo (p=0.011, HR=2.5). The classification remained independent upon multivariable analysis. Outcomes remained significantly different when comparing four subtypes separately. The intrinsic heterogeneity of expression profiles is a limitation of this approach.Even after clinical patient selection, patients with a ccrcc1- or ccrcc4-tumor are at a higher risk of relapse after complete metastasectomy. Patients with a ccrcc2- or ccrcc3-tumor usually experience a long DFS. These results need validation in a larger cohort to establish the subtypes as prognostic marker.Metastasectomy is recommended for some patients with metastatic clear-cell kidney cancer; however, we do not know who will benefit the most. We show that molecular subtypes increase the possibility to predict which patients are at risk for early relapse after metastasectomy and who may benefit more from other treatment options.

In metastatic castration-refractory prostate cancer (mCRPC), state-of-the-art treatment consists of androgen biosynthesis inhibition (abiraterone), inhibition of the androgen receptor (enzalutamide), chemotherapy, or radium-223 in combination with androgen deprivation therapy (ADT). A subgroup of these patients show oligoprogression, with the progression of only a limited number of metastatic spots, while all other metastases remain controlled by ongoing systemic therapy. In a bi-institutional retrospective study, we tested the hypothesis that progression-directed therapy (PDT) targeting oligoprogressive lesions might defer the initiation of next-line systemic treatment (NEST). A total of 30 patients were diagnosed with mCRPC and experienced oligoprogression, defined as a total of three or fewer progressive lesions either at known metastatic sites and/or the appearance of new metastasis and/or local recurrence. All patients were under active ADT with or without second-line systemic treatment. All patients received PDT targeting the oligoprogressive lesions, while ongoing systemic treatment was maintained. There was median NEST-free survival of 16mo (95% confidence interval [CI] 10-22) and progression-free survival of 10mo (95% CI 6-15) with only minor radiotherapy- or surgery-related toxicity. These findings encourage further prospective trials. PATIENT SUMMARY: In patients with metastatic castration-refractory prostate cancer, surgical treatment or high-dose radiation therapy directed to only the limited number of progressive metastatic spots, while all other metastases remained controlled by ongoing systemic therapy, led to substantial postponement of next-line systemic treatment in our study.

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson’s χ2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.

In the current era, minimally invasive surgery using ablative techniques for the treatment of small renal tumours has become a more common and feasible treatment option. In this review, we present recent data regarding the utility of needle ablative techniques in the experimental and clinical settings.We performed a comprehensive evaluation of available published data from 1997 to 2006 that were identified with PubMed. Official proceedings of internationally known scientific societies held in the same time period were also assessed.Two main thermoablative techniques, cryoablation (CA) and radiofrequency ablation (RFA), represent the current available minimally invasive treatments for renal cell carcinoma (RCC). CA has been more extensively studied and has gained acceptance from patients and physicians. The procedure is well tolerated by patients even with serious concomitant diseases. RFA is delivered with a monopolar alternating current. Morbidity rates for this modality remain slightly higher than those for cryotherapy. Both techniques are associated with highly successful cancer control rates at short-to-medium follow-up in patients with tumour size <3 cm. Multiple lesions can be treated simultaneously and the procedures can be repeated. However, long-term follow-up data are still lacking.Minimally invasive ablative approaches seem to represent an attractive alternative to extirpative surgery for the treatment of small renal neoplasms in select patients. Potential developments include concepts to improve the accuracy of thermal ablation using novel imaging modalities with reduction in side-effects and optimised selection and follow-up of patients to provide at least equivalent cancer control to conventional surgery.

To present a summary of the 2007 version of the European Association of Urology (EAU) guidelines on prostate cancer (PCa).A literature review of the new data emerging from 2004 to 2007 was performed by the working panel. The guidelines have been updated, and the level of evidence/grade of recommendation was added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.A full version is available at the EAU Office or at www.uroweb.org. Systemic prostate biopsy under ultrasound guidance is the preferred diagnostic method. Active treatment is mostly recommended for patients with localized disease and a long life expectancy, with radical prostatectomy being shown to be superior to watchful waiting in a prospective randomized trial. Nerve-sparing radical prostatectomy represents the approach of choice in organ-confined disease; neoadjuvant androgen deprivation demonstrates no improvement of outcome variables. Radiation therapy should be performed with at least 72 and 78 Gy in low-risk and intermediate- to high-risk PCa, respectively. Monotherapeutic androgen deprivation is the standard of care in metastatic PCa; intermittent androgen deprivation might be an alternative treatment option for selected patients. Follow-up is largely based on prostate-specific antigen and a disease-specific history with imaging only indicated when symptoms occur. Cytotoxic therapy with docetaxel has emerged as the reference treatment for metastatic hormone-refractory PCa.The knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice.

Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration. To examine the current status of vaccine therapy for RCC and to provide information on relevant clinical studies. We reviewed recent literature on Medline (2003–2008, using the keywords renal cell carcinoma, cancer vaccines, active immunotherapy, and dendritic cells). Subsequent references were identified from reference list of retrieved articles. Quality assessment included prospective phase 1–3 trials and critical evaluations with low numbers of patients. Therapeutic vaccines can be divided in autologous tumour cell–based vaccines, genetically modified tumour cell–based and dendritic cell (DC)–based vaccines, and peptide-based vaccines. To date, only two randomised, adjuvant, phase 3 studies investigating RCC vaccines have been published. Autologous tumour cell vaccine (Reniale) improved the 5-yr progression-free survival (PFS) for high-risk nonmetastatic RCC patients at all tumour stages when administered after nephrectomy. The benefit was clearer in the T3 group. A per-protocol analysis revealed a statistically significant PFS and overall survival (OS) in favour of the vaccine. Autologous tumour-derived heat shock protein peptide complex (HSPPC-96; vitespen) could not significantly improve recurrence-free survival in RCC patients at high risk for recurrence after nephrectomy, but did so in intermediate risk patients. DC vaccination in metastatic RCC (mRCC) patients is safe and can induce antigen-specific immune response and obtain tumour regression in a subset of patients. RCC vaccines have much less toxicity than other current therapies and remain an important area for further research. Reniale has shown significant benefit as an adjuvant RCC vaccine. Vitespen seems promising as an adjuvant treatment in earlier stage disease. A possible area of research is the use of RCC vaccines with immune-enhancing or antiangiogenic agents in the adjuvant setting.

No AccessJournal of UrologyInvestigative Urology1 May 2013A Possible Role for MicroRNA-141 Down-Regulation in Sunitinib Resistant Metastatic Clear Cell Renal Cell Carcinoma Through Induction of Epithelial-to-Mesenchymal Transition and Hypoxia Resistance Joost Berkers, Olivier Govaere, Pascal Wolter, Benoit Beuselinck, Patrick Schöffski, Léon C. van Kempen, Maarten Albersen, Joost Van den Oord, Tania Roskams, Johan Swinnen, Steven Joniau, Hendrik Van Poppel, and Evelyne Lerut Joost BerkersJoost Berkers Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author , Olivier GovaereOlivier Govaere Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium More articles by this author , Pascal WolterPascal Wolter Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium Financial interest and/or other relationship with Pfizer. More articles by this author , Benoit BeuselinckBenoit Beuselinck Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium More articles by this author , Patrick SchöffskiPatrick Schöffski Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium More articles by this author , Léon C. van KempenLéon C. van Kempen Department of Pathology, McGill University/Jewish General Hospital, Montreal, Quebec, Canada More articles by this author , Maarten AlbersenMaarten Albersen Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author , Joost Van den OordJoost Van den Oord Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author , Tania RoskamsTania Roskams Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author , Johan SwinnenJohan Swinnen Department of Oncology, Catholic University Leuven, Leuven, Belgium More articles by this author , Steven JoniauSteven Joniau Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author , Hendrik Van PoppelHendrik Van Poppel Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author , and Evelyne LerutEvelyne Lerut Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.11.133AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib. Materials and Methods: We performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay. Results: Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions. Conclusions: In our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment. References 1 : Epidemiology and risk factors for kidney cancer. Nat Rev Urol2010; 7: 245. 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Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byLaguna M (2020) Re: Development and Validation of a Robust Multigene Signature as an Aid to Predict Early Relapse in Stage I-III Clear Cell and Papillary Renal Cell CancerJournal of Urology, VOL. 204, NO. 4, (875-875), Online publication date: 1-Oct-2020.Laguna M (2017) Re: A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients with Metastatic Renal Cell CarcinomaJournal of Urology, VOL. 199, NO. 1, (23-25), Online publication date: 1-Jan-2018.Laguna M (2014) Re: Tivozanib versus Sorafenib as Initial Targeted Therapy for Patients with Metastatic Renal Cell Carcinoma: Results from a Phase III TrialJournal of Urology, VOL. 192, NO. 4, (1079-1079), Online publication date: 1-Oct-2014.Ishihara T, Seki N, Inoguchi S, Yoshino H, Tatarano S, Yamada Y, Itesako T, Goto Y, Nishikawa R, Nakagawa M and Enokida H (2014) Expression of the Tumor Suppressive miRNA-23b/27b Cluster is a Good Prognostic Marker in Clear Cell Renal Cell CarcinomaJournal of Urology, VOL. 192, NO. 6, (1822-1830), Online publication date: 1-Dec-2014. Volume 189Issue 5May 2013Page: 1930-1938 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Keywordsepithelial-mesenchymal transitioncarcinoma, renal cellMIRN141 microRNA, humansunitinibkidneyMetricsAuthor Information Joost Berkers Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author Olivier Govaere Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium More articles by this author Pascal Wolter Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium Financial interest and/or other relationship with Pfizer. More articles by this author Benoit Beuselinck Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium More articles by this author Patrick Schöffski Department of General Medical Oncology, Leuven Cancer Institute Leuven, University Hospitals Leuven, Leuven, Belgium More articles by this author Léon C. van Kempen Department of Pathology, McGill University/Jewish General Hospital, Montreal, Quebec, Canada More articles by this author Maarten Albersen Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author Joost Van den Oord Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author Tania Roskams Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author Johan Swinnen Department of Oncology, Catholic University Leuven, Leuven, Belgium More articles by this author Steven Joniau Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author Hendrik Van Poppel Department of Urology, University Hospitals Leuven, Leuven, Belgium More articles by this author Evelyne Lerut Laboratory of Translational Cell and Tissue Research, Catholic University Leuven, Leuven, Belgium Department of Pathology, University Hospitals Leuven, Leuven, Belgium More articles by this author Expand All Advertisement PDF downloadLoading ...

To evaluate the use of semi-quantitative dynamic contrast-enhanced MRI (DCE-MRI) parameters for the detection of prostatic carcinoma in correlation to whole-mount histopathology.Fifty-three patients with biopsy-proven prostate cancer were examined by DCE-MRI at 1.5-T. Cancerous and benign prostatic tissue regions of interest were delineated based on the histopathology of whole-mount sections and several semi-quantitative parameters were calculated: time to peak (TTP), maximal contrast enhancement (Cpeak), speed of contrast uptake (Wash-in) and clearance rate of the contrast agent (Wash-out). The area under the ROC curve was determined for each parameter.Within individual patients, a consistently higher Cpeak and faster Wash-in were present in cancerous compared to benign prostatic tissue. Both the TTP and the Wash-out occurred more rapidly in tumour tissue than in normal prostatic tissue. Despite a considerable inter-patient overlap of parameter values between tumour and normal prostatic tissue, area under the ROC curve analysis demonstrated that the Wash-in was a good discriminator for cancer and benign tissue (AUC 0.82). Combination of the Wash-in and the Wash-out proved to be even more accurate (AUC 0.87) to discriminate between cancerous and benign prostatic regions.The Wash-in is a useful parameter for prostate cancer detection by DCE-MRI.

Objective To compare functional outcomes, i.e. urinary incontinence ( UI ), voiding symptoms and quality of life, after open ( ORP ) and robot‐assisted radical prostatectomy ( RARP ). Patients and Methods Between S eptember 2009 and J uly 2011, 180 consecutive patients underwent radical prostatectomy; of these, 116 underwent ORP and 64 underwent RARP . We prospectively assessed the functional outcomes of each group during the first year of follow‐up. We measured UI on the 3 days before surgery (24‐h pad test) and daily after surgery until total continence, defined as 3 consecutive days of 0 g urine leak, was achieved. Additionally, all patients were assessed before surgery and at 1, 3, 6 and 12 months after surgery using the I nternational P rostate S ymptom S core ( IPSS ) and the K ing's H ealth Q uestionnaire ( KHQ ). All patients received pelvic floor muscle training until continence was achieved. K aplan– M eier analyses and C ox regression with correction for covariates were used to compare time to continence. A M ann– W hitney U ‐test was used to assess IPSS and KHQ . Results Patients in the RARP group had a significantly lower D ' A mico risk group allocation and underwent more nerve‐sparing surgery. Other characteristics were similar. Patients in the RARP group regained continence sooner than those in the ORP group ( P = 0.007). In the RARP group, the median time to continence (16 vs 46 days, P = 0.026) was significantly shorter and the median amount of first day UI (44 vs 186 g, P &lt; 0.01) was significantly smaller than in the ORP group. After correction for all covariates, the difference remained significant ( P = 0.036, hazard ratio [ HR ] 1.522 (1.027–2.255). In addition, younger men, men with positive surgical margins and men without preoperative incontinence achieved continence sooner. A comparison of time to continence between groups with a sufficient number of patients (intermediate risk and/or bilateral nerve‐sparing) still showed a faster return of continence after RARP , but the effect decreased in size and was nonsignificant ( HR &gt;1.2, P &gt; 0.05). Only six patients (two in the RARP and four in the ORP group) still had UI after 1 year. Patients in the RARP group had significantly better IPSS scores at 1 ( P = 0.013) and 3 ( P = 0.038) months, and scored better in almost all KHQ aspects. Conclusion In this prospective trial, patients treated with RARP tended to regain urinary continence sooner than patients treated with ORP , but in subgroup analyses statistical significance disappeared and effect size decreased dramatically, indicating that the results must be interpreted with caution.

Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC).The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.

A medical treatment for urethral stricture (US) is not yet available.To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US.Male rats were divided into three groups: sham, US, and hADSC (n=12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-β1 in the urethral wall.One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses.Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot.US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p<0.05). By ultrasound, US rats had hyperechogenic and thick urethral walls with narrowed lumen compared with sham rats, whereas hADSC rats displayed less extensive urethral changes. Isolated detrusor from US rats exhibited 34-55% smaller contractions than detrusor from sham rats (p<0.05). Corresponding values were 11-35% for isolated detrusors from hADSC rats. Collagen and elastin protein expression were increased in the penile urethras of US rats compared with sham and hADSC groups (p<0.05). Endothelial and inducible nitric oxide synthase expressions were higher (p<0.05) in the hADSC group. Compared with US rats, hADSC rats demonstrated decreased expression of several fibrosis-related genes. Administration of hADSCs was performed at an early stage of US development, which we consider a limitation of the study.Local injection of hADSCs prevents stricture formation and urodynamic complications in a new rat model for US.Stem cell therapy is effective for preventing urethral stricture in an experimental setting.

To investigate predictive pathological factors for local recurrence (LR) after glansectomy for penile squamous cell carcinoma (SCC) and to develop a risk score for prediction of LR after glansectomy. In this retrospective study, we analyzed 117 patients operated between February 2005 and January 2016 in a supraregional penile cancer center in the UK for LR after glansectomy and glans reconstruction. Univariate and multivariate Cox proportional hazards regression was used to identify 4 prognostic indicators for LR. The hazard ratio (HR) of LR was estimated in Kaplan-Meier analysis, and based on these data, we designed a postoperative model for prediction of LR based on 3 risk groups. Median follow-up period was 33.7 (95% CI: 26.8–40.3) months; 12.8% of the patients experienced LR. Univariate Cox proportional hazards regression revealed that the risk factors for recurrence were the presence of perineural invasion, carcinoma in situ, positive margin on definitive pathology, and high-grade disease. Based on Kaplan-Meier analysis stratified by number of factors present, we defined 3 risk groups for LR: low (0,1 risk factors) as reference, intermediate (2,3 risk factors) with HR of 13.9 (95% CI: 1.81–107.04, P = 0.0115), or high risk (all 4 risk factors present) with a HR of 34.2 (95% CI: 3.07–381.81, P = 0,0041). Limitations include the retrospective design and low number of events inherent to the rare nature of penile SCC. Perineural invasion, carcinoma in situ, positive definitive margins, and the presence of high-grade SCC predict LR following glansectomy. These factors can be used to stratify patients into low-, intermediate-, and high-risk groups for recurrence which may be used to tailor follow-up.

We previously described 4 molecular subtypes of metastatic clear cell renal cell carcinoma (mccRCC), named ccrcc1-4 (Beuselinck et al, 2015). These have both prognostic and predictive value for patients treated with first-line sunitinib, with distinctive objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The ccrcc2 and ccrcc3 tumors have the best outcomes, followed by ccrcc1 and then ccrcc4. We hypothesized that these molecular subtypes would show similar outcomes with first-line pazopanib treatment.We classified 28 mccRCC tumors treated with pazopanib as first-line therapy, as described previously. The primary endpoints were PFS and OS from the start of pazopanib. A secondary endpoint was ORR. Because there were only 2 ccrcc3 tumors, they were pooled with the ccrcc2 tumors for outcome analysis.PFS was 9 months for the ccrcc2 and ccrcc3 tumors, 5 months for ccrcc1 tumors, and 3 months for the ccrcc4 tumors (P = .011). The corresponding OS duration was 69, 19, and 5 months (P = .003). The corresponding ORR was 50%, 33%, and 0%. The corresponding mean tumor size decreased by 34%, 6%, and 2% (P = .032). The ccrcc1-4 classification was a stronger predictor of outcome than the International Metastatic Renal Cell Carcinoma Database Consortium score on univariate analysis (P = .011 vs. P = .094 for PFS and P = .003 vs. .013 for OS). Both remained independent on bivariate analysis.The molecular subtypes of mccRCC are associated with outcome on pazopanib as first-line therapy. The prognostic and predictive value of the ccrcc1-4 molecular classification requires validation in prospective trials.

Complete transurethral resection of bladder tumor (TURBT) is the initial procedure of choice for non–muscle-invasive bladder cancer, but its quality is far from optimal in clinical practice. We evaluated the existing body of evidence substantiating current quality control indicators (QCIs) for TURBT. A literature search was performed using PubMed and Embase, and selected articles were reviewed according to their level of evidence. Disease recurrence and progression were used as the primary end points. No hard evidence supports complete resection as a QCI, but rationally, it is the most important indicator for TURBT. A repeat resection is an important QCI in high-risk disease patients, but evidence suggests that it may not be necessary when detrusor muscle is present in the initial resection specimen. The presence of detrusor muscle in the resection specimen is a validated QCI for TURBT. Adjuvant intravesical instillation is a scientifically proven QCI. Bladder perforation is a controversial QCI in the existing literature. No evidence indicates the ideal time frame for the initial TURBT; thus, initial therapy in the first 6 weeks after diagnosis is not a good QCI. Three of the 6 proposed QCIs for TURBT are supported by evidence. Our literature analysis indicated the use of complete resection, repeat resection, the presence of detrusor muscle, and intravesical instillation are QCIs to minimize recurrence and progression, and increase beneficial outcomes.

Presence of lymph node metastases (LNM) is an important prognostic factor for cancer-specific survival (CSS) in patients with upper tract urothelial carcinoma (UTUC). In various neoplasms, 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) is an established modality for preoperative lymph node (LN) staging. In UTUC, the diagnostic value of FDG-PET/CT for LN staging is unknown. To determine the diagnostic value of FDG-PET/CT for LN staging in patients with UTUC. Data of 152 patients with UTUC who underwent FDG-PET/CT followed by surgical treatment in eight centers between 2007 and 2017 were retrospectively collected. Patients receiving neoadjuvant chemotherapy were excluded. FDG-PET/CT results were compared with histopathology after lymph node dissection (LND). Recurrence-free survival (RFS), CSS, and overall survival (OS) were analyzed using Kaplan-Meier estimates, and compared for patients with and without suspicious LNs on FDG-PET/CT. We included 117 patients, of whom 62 underwent LND. Seventeen patients had LNM at histopathological evaluation. Sensitivity and specificity of FDG-PET/CT for diagnosis of LNM were 82% (95% confidence interval [CI]: 57–96) and 84% (95% CI: 71–94), respectively. RFS was significantly worse in patients with LN-positive FDG-PET/CT than in those with LN-negative FDG-PET/CT (p = 0.03). CSS (p = 0.11) and OS (p = 0.5) were similar between groups. This study is limited by its retrospective design and by its sample size. Our results warrant further validation. FDG-PET/CT has 82% sensitivity and 84% specificity for the detection of LNM in patients with UTUC. Presence of suspicious LNs on FDG-PET/CT is associated with worse RFS. In patients with upper tract urothelial cancer, positron emission tomography with computed tomography (PET/CT) scans can detect lymph node metastases with noteworthy accuracy. Presence of suspicious lymph nodes on 18F-fluorodeoxyglucose PET/CT is associated with worse recurrence-free survival.

Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases. To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting. Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified. Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools. Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation. Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population. Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

<h2>Abstract</h2> Advanced and metastatic renal cell cancer (RCC) is resistant to conventional chemotherapy. Only a very small number of patients survive long term after immunotherapy. However, any effect of interleukin-2 (IL-2) and/or interferon on median overall survival is small, and treatment-associated toxicities may be severe. The disease is therefore an area of high unmet medical need. Activation of the VEGF and EGF/RAS/RAF/MAP kinase pathways is frequent in solid tumours such as RCC. Such activation is implicated in tumour angiogenesis and proliferation. VEGF and EGF receptors and molecules (such as RAF kinase) involved in downstream signalling are therefore potential appropriate targets for drug therapy. Several antibodies and low molecular weight tyrosine kinase inhibitors (TKIs) have completed phase II clinical trials. Phase II studies of multitargeted agents, which include inhibition of VEGFR tyrosine kinase in their repertoire (sorafenib, sunitinib and AG 013736), show clear second-line activity in metastatic RCC. The same is true of the anti-VEGF antibody, bevacizumab. In a randomised phase III comparison against placebo in pretreated patients, sorafenib doubled median progression free survival (24 versus 12 weeks). Studies now in progress will determine whether benefits seen second-line will also be evident first-line, and whether the activity of novel agents can be increased by combining them with each other, with cytokines, or with chemotherapy.

To review the natural history and biological potential of small renal masses in order to evaluate whether surveillance is an option for treatment of small renal masses.Literature search of MEDLINE and additional references from non-MEDLINE-indexed publications concerning surveillance of small renal masses.Because approximately 26-33% of observed small renal masses do not show radiographic growth, it has been suggested that a brief period of active surveillance may be feasible for selected renal masses, with treatment limited to tumours showing growth. Even though tumour growth might be absent or slow, a proportion of these tumours will express significant malignant behaviour. The biological behaviour of a tumour cannot be unambiguously predicted at present. Surveillance of small renal masses should only be considered in elderly and/or infirm patients with competing health risks, in those with limited life expectancy, and in those for whom surgery is not an option. In all other patients, active surveillance can be considered in the context of a study protocol only. In the majority of the patients, nephron-sparing surgery remains the gold standard treatment.Surveillance should only be considered as an alternative to surgery for the treatment of small renal masses in selected patients. It should always be combined with close follow-up imaging and should be allowed only when the patient and the urologist accept the calculated risk. Long-term, prospective studies are needed to provide a more accurate assessment of the natural history and metastastic potential of small renal masses.

Partin tables are the most widely used tool to predict histopathologic stage after radical prostatectomy (RP) in organ-confined tumors. Such a predictive table in clinical T3 disease is still lacking. Our objective was to create a reference table for clinical unilateral T3a prostate cancer. Between 1987 and 2004, 200 patients with clinical unilateral T3a disease underwent a RP and bilateral pelvic lymphadenectomy at our institution. No patient had received neoadjuvant treatment. Patients were divided into three prostate-specific antigen (PSA) subgroups (≤10 ng/ml, >10–20 ng/ml, and >20 ng/ml) and two biopsy Gleason sum (GS) subgroups (≤7 [3+4] and ≥7 [4+3]). These parameters were used in the table as predictors for final histopathology. Margin and nodal status were also recorded. The multinomial log-linear regression analysis was used to construct the table. The table stratifies patients into six demarcated risk groups. In the first group, consisting of patients with PSA ≤10 and GS ≤7 (3+4), understaging was only 6% (5% pT3b and 1% pT4). The risk for understaging cT3a prostate cancer increases further with increasing PSA and GS. In the sixth group, consisting of patients with PSA >20 and GS ≥7 (4+3), understaging was as high as 68% (44% pT3b and 22% pT4). Receiver operating characteristic analyses showed good accurate predictive ability of the table for seminal vesicle involvement and adjacent structure involvement, with moderate predictive ability for extraprostatic extension only. We present a table combining preoperative serum PSA and biopsy GS to predict histopathologic results in clinical unilateral T3a prostate cancer. The table may provide a basis for decision-making and patient counseling before treating this cancer.

OBJECTIVE To present our experience with nephron‐sparing surgery (NSS) for T1b renal cell carcinoma (RCC) in a high‐volume tertiary referral centre. NSS for RCC of &lt;4 cm (T1a) is increasingly accepted, although its role for RCC of 4–7 cm (T1b) remains controversial. PATIENTS AND METHODS The records of 67 consecutive patients who had NSS for RCC of 4–7 cm at our institution were reviewed retrospectively. Data were collected on surgical indications, tumour characteristics, complications, changes in serum creatinine level, time to recurrence and time to death. Clinical progression‐free survival (CPFS), overall survival (OS), cancer‐specific survival (CSS) rates were estimated statistically. RESULTS The mean patient age was 62 years. Surgical indications were absolute in 26 (39%) patients, relative in 11 (16%) and elective in 30 (45%). Two patients (3%) required postoperative embolization, and none developed a urinary fistula. Four patients (6%) had positive resection margins; none of these developed tumour recurrence. After a median (range) follow‐up of 40.1 (1–98.3) months, 10 patients (15%) had died, of whom only one death was related to NSS (postoperative hypovolaemic shock). The tumour recurred in seven patients (10%) all of whom were alive at the last follow‐up. Three patients (4%) developed a local recurrence and four (6%) developed locoregional or distant disease. The projected 5‐year CPFS, CSS and OS rates were 84%, 99% and 72%, respectively. Seven (10%) patients developed de novo renal insufficiency. Elective and relative indications were not associated with a significant change in serum creatinine level ( P = 0.22 and 0.10, respectively); in the absolute category this difference was statistically significant ( P = 0.005). The main limitation is that the study was uncontrolled and retrospective, with a medium‐term follow‐up. CONCLUSIONS This study showed the excellent surgical feasibility and CSS for NSS in T1b RCC. Local cancer control was achieved in the large majority of patients, with preservation of renal function in those with elective indications. Absolute indications significantly correlated with loss of renal function.

Urinary diversion is performed on a regular basis in urological practice. Surgeons tend to underestimate the metabolic effects of any type of diversion. From the patient's perspective, diarrhea is the most bothersome complaint after urinary diversion. This might be accompanied by malabsorption syndromes, such as vitamin B12 deficiency. Electrolyte abnormalities can occur frequently such as hyperchloremic metabolic acidosis, or less frequently such as hypokalemia, hypocalcaemia, and hypomagnesaemia. Bone health is at risk in patients with urinary diversion. Some patients might benefit from vitamin D and calcium supplementation. Many patients are also subject to urinary calculus formation, both at the level of the upper urinary tract as in intestinal reservoirs. Urinary diversion can affect hepatic metabolism, certainly in the presence of urea-splitting bacteria. The kidney function has to be monitored prior to and lifelong after urinary diversion. Screening for reversible causes of renal deterioration is an integral part of the followup.

Resumen Objetivo Presentar un resumen de la version del 2007 de la guia de la Asociacion Europea de Urologia (EAU) para el cancer de prostata (CaP). Metodos Se realizo por un grupo de trabajo una revision de los nuevos datos presentes desde 2004 hasta 2007 en la literatura. Las guias han sido actualizadas y el nivel de evidencia/grado de recomendacion ha sido anadido al texto basandose en una revision sistematica de la literatura, que incluia una busqueda de las bases de datos online y revisiones bibliograficas. Resultados Una version completa esta disponible en la EAU Office o en www.uroweb.org. El metodo diagnostico de eleccion es la biopsia sistematizada de la prostata bajo control ecografico. El tratamiento activo es el recomendado en la mayoria de los pacientes con enfermedad localizada y una larga esperanza de vida, siendo la prostatectomia radical superior a la vigilancia (“watchful waiting”) en un ensayo randomizado prospectivo. La prostatectomia radical con preservacion de bandeletas es la tecnica de eleccion en la enfermedad organo-confinada; el bloqueo androgenico neoadyuvante no ha demostrado una mejoria en las variables de resultados. La radioterapia debe realizarse con al menos 72 Gy en el CaP de bajo riesgo y con 78 Gy en el de intermedio - alto riesgo. El bloqueo androgenico en monoterapia es el estandar del tratamiento en el CaP metastasico; el bloqueo androgenico intermitente podria ser un tratamiento alternativo en pacientes seleccionados. El seguimiento se basa principalmente en los niveles de PSA y en la anamnesis especifica de la enfermedad, estando las pruebas de imagen solo indicadas cuando aparecen los sintomas. La quimioterapia con docetaxel ha surgido como el tratamiento de referencia para el CaP metastasico hormonorefractario. Conclusiones El conocimiento en el campo del CaP esta rapidamente cambiando. Estas guias de la EAU resumen los hallazgos mas recientes y los aplican a la practica clinica.

Prostate cancer (PCa) is a major health care problem because of its high prevalence, health-related costs, and mortality. Epidemiological studies have suggested an important role of genetics in PCa development. Because of this, an increasing number of single nucleotide polymorphisms (SNPs) had been suggested to be implicated in the development and progression of PCa. While individual SNPs are only moderately associated with PCa risk, in combination, they have a stronger, dose-dependent association, currently explaining 30% of PCa familial risk. This review aims to give a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. We will highlight the major research questions in the translation of SNP identification into clinical practice.

To investigate the additional value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) to T2-weighted (T2w) magnetic resonance imaging (MRI) for localization of intraprostatic tumor nodules.Forty-nine prostate cancer patients underwent T2w MRI and (11)C-choline PET-CT before radical prostatectomy and extended lymphadenectomy. Tumor regions were outlined on the whole-mount histopathology sections and on the T2w MR images. Tumor localization was recorded in the basal, middle, and apical part of the prostate by means of an octant grid. To analyze (11)C-choline PET-CT images, the same grid was used to calculate the standardized uptake values (SUV) per octant, after rigid registration with the T2w MR images for anatomic reference.In total, 1,176 octants were analyzed. Sensitivity, specificity, and accuracy of T2w MRI were 33.5%, 94.6%, and 70.2%, respectively. For (11)C-choline PET-CT, the mean SUV(max) of malignant octants was significantly higher than the mean SUV(max) of benign octants (3.69 ± 1.29 vs. 3.06 ± 0.97, p < 0.0001) which was also true for mean SUV(mean) values (2.39 ± 0.77 vs. 1.94 ± 0.61, p < 0.0001). A positive correlation was observed between SUV(mean) and absolute tumor volume (Spearman r = 0.3003, p = 0.0362). No correlation was found between SUVs and prostate-specific antigen, T-stage or Gleason score. The highest accuracy (61.1%) was obtained with a SUV(max) cutoff of 2.70, resulting in a sensitivity of 77.4% and a specificity of 44.9%. When both modalities were combined (PET-CT or MRI positive), sensitivity levels increased as a function of SUV(max) but at the cost of specificity. When only considering suspect octants on (11)C-choline PET-CT (SUV(max) ≥ 2.70) and T2w MRI, 84.7% of these segments were in agreement with the gold standard, compared with 80.5% for T2w MRI alone.The additional value of (11)C-choline PET-CT next to T2w MRI in detecting tumor nodules within the prostate is limited.

<h3>Objective</h3> Evaluation of surgical outcomes, survival, and morbidity associated with pelvic exenteration (PE) performed for gynecologic malignancies. <h3>Methods</h3> Review of 36 consecutive patients who underwent PE between June 1999 and April 2010. <h3>Results</h3> Pelvic exenteration was performed for cancer of the cervix (n = 18), endometrium (n = 9), vagina/vulva (n = 8), and ovary (n = 1). Four patients underwent PE as primary treatment and 32 patients for recurrent disease after pelvic radiotherapy. Median age was 57 years (range, 35–81 years). Bricker (n = 17), Mainz pouch (n = 10), and augmentation after bladder resection (n = 6) were used as urinary derivations. J-pouch coloanal anastomosis was performed in 14, colostomy in 13, and side-to-end anastomosis in 4 patients. There was no operative mortality. The most important postoperative complications were rectovaginal fistula (5), urinary leakage (2), vesicovaginal fistula (1), and sepsis (3). One of the 6 patients with a partial cystectomy developed a vesicovaginal fistula, which was successfully treated with a Martius flap. With a median follow-up of 78 months (range, 2–131) months, the 5-year overall and disease-specific survival (DSS) rates were 44% and 52%, respectively. Five-year DSS for cervical, endometrial, and vaginal/vulvar cancer was 44%, 80%, and 57%, respectively. Combined operative and radiotherapeutic treatment (CORT) was performed in 3 patients with pelvic side wall relapse. Of the 15 patients 65 years or older, a 5-year DSS of 71% was observed in comparison with 42% in the younger subgroup, and their complication rates were similar to the younger patient group. Thirteen patients (36%) reported to have psychological disturbances associated with stoma-related problems. Only 3 patients requested a vaginal reconstruction during follow-up. <h3>Conclusions</h3> Pelvic exenteration offers a sustained survival with an acceptable morbidity in patients with advanced or recurrent gynecologic cancer. Older age was not associated with higher morbidity/mortality in this series.

The clinical heterogeneity of prostate cancer (PCa) makes it difficult to identify those patients that could benefit from more aggressive treatments.As a contribution to a better understanding of the genomic changes in the primary tumor that are associated with the development of high-risk disease, we performed exome sequencing and copy number determination of a clinically homogeneous cohort of 47 high-risk PCas.We confirmed recurrent mutations in SPOP, PTEN and TP53 among the 850 point mutations we detected.In seven cases, we discovered genomic aberrations in the TET1 (Ten-Eleven Translocation 1) gene which encodes a DNA hydroxymethylase than can modify methylated cytosines in genomic DNA and thus is linked with gene expression changes.TET1 protein levels were reduced in tumor versus non-tumor prostate tissue in 39 of 40 cases.The clinical relevance of changes in TET1 levels was demonstrated in an independent PCa cohort, in which low TET1 mRNA levels were significantly associated with worse metastases-free survival.We also demonstrate a strong reduction in hydroxymethylated DNA in tumor tissue in 27 of 41 cases.Furthermore, we report the first exploratory (h)MeDIP-Seq analyses of eight high-risk PCa samples.This reveals a large heterogeneity in hydroxymethylation changes in tumor versus non-tumor genomes which can be linked with cell polarity.

Hormonal manipulation concomitant to salvage radiotherapy (SRT) given for biochemical recurrence (BCR) after radical prostatectomy (RP) improved outcomes in two randomized trials. However, neither of these studies focused on men treated at low prostate-specific antigen (PSA) levels. To test if the impact of androgen deprivation therapy (ADT) on metastasis in patients undergoing early SRT varies according to prostate cancer (PCa) features. A total of 525 patients received SRT at PSA levels ≤2 ng/ml. Multivariable Cox regression analyses assessed factors associated with metastasis. We tested the hypothesis that the impact of ADT varied according to the risk of metastasis. An interaction with groups (concomitant ADT vs no ADT) and the probability of distant metastasis according to a newly developed model was tested. A nonparametric curve explored the relationship between the risk of metastasis and 10-yr metastasis rates according to ADT. Median PSA and radiotherapy dose were 0.42 ng/ml and 66 Gy, respectively. Overall, 178 (34%) patients received ADT. At a median follow-up of 104 mo, 71 patients experienced metastasis. Grade group ≥4 (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.01–3.30), pT3b/4 (HR: 2.61; 95% CI: 1.51–4.52), and dose (HR: 0.82; 95% CI: 0.76–0.89) were associated with metastasis. The impact of ADT differed according to the risk of metastasis calculated using a multivariable model (p = 0.01). This was confirmed when considering patients treated with early SRT (p = 0.046), where ADT was associated with a reduction in the rate of metastasis only in eSRT; patients with more aggressive characteristics (ie, pT3b/4 and grade group ≥4, or pT3b/4 and PSA at eSRT ≥0.4 ng/ml). The beneficial effect of ADT concomitant to eSRT varied significantly according to disease characteristics, such that only men with more aggressive PCa features benefit from ADT in the eSRT setting for BCR after RP. The oncological benefits of concomitant androgen deprivation therapy (ADT) in patients undergoing salvage radiotherapy (SRT) vary according to pathological characteristics. Only patients with more aggressive disease characteristics seemed to benefit from the use of hormonal manipulation at the time of early SRT. Conversely, the potential side effects of ADT could be spared in patients with low prostate-specific antigen levels and favorable pathological features.

(1) Background: Secondary lymphedema is a chronic, progressive, and debilitating condition with an important impact on quality of life. Lymphedema is a frequently reported complication in oncological surgery but has not been systematically studied in the setting of prostate cancer. (2) Methods: Pubmed/MEDLINE and Embase were systematically searched to identify articles reporting on lower limb or genital lymphedema after primary treatment (surgery of radiation therapy) of the prostate and the pelvic lymph nodes in men with prostate cancer. Primary outcome was the prevalence of lower limb and genital lymphedema. (3) Results: Eighteen articles were eligible for qualitative synthesis. Risk of bias was high in all included studies, with only one study providing a prespecified definition of secondary lymphedema. Eleven studies report the prevalence of lower limb (0-14%) and genital (0-1%) lymphedema after radical prostatectomy with pelvic lymph node dissection (PLND) Seven studies report a low prevalence of lower limb (0-9%) and genital (0-8%) lymphedema after irradiation of the pelvic lymph nodes. However, in the patient subgroups that underwent pelvic irradiation after staging pelvic lymph node dissections, the prevalence of lower limb (18-29%) and genital (2-22%) lymphedema is substantially elevated. (4) Conclusion: Prostate cancer patients undergoing surgery or irradiation of the pelvic lymph nodes are at risk of developing secondary lymphedema in the lower limbs and the genital region. Patients receiving pelvic radiation after pelvic lymph node dissection have the highest prevalence of lymphedema. The lack of a uniform definition and standardized diagnostic criteria for lower limb and genital lymphedema hampers the accurate estimation of their true prevalence. Future clinicals trials are needed to specifically evaluate secondary lymphedema in patients undergoing prostate cancer treatments, to identify potential risk factors and to determine the impact on quality of life.

•Synchronous metastatic CSPC is associated with lower AR activity than metachronous disease.•Patients with synchronous metastatic CSPC derive a greater benefit to combination AR plus non AR-based therapy.•Clinical and biologic differences between synchronous and metachronous metastasis are most prominent in low-volume disease. BackgroundMetastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy.Patients and methodsWe performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann–Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan–Meier method and multivariable Cox regression.ResultsA total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05).ConclusionsWe have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease. Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann–Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan–Meier method and multivariable Cox regression. A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

Prostate cancer encompasses a biological continuum from a slow-growing indolent tumour to a highly aggressive and potentially fatal form. A major challenge faced daily by physicians is to identify men with localized prostate cancer who are at high risk of dying from the disease, in order to maximize disease control and survival, without overtreating men who are likely to die from comorbidities. Treatment selection in patients with localized prostate cancer should be guided not only by patient-related factors (e.g. age and comorbidities), but also by cancer-related parameters (clinical stage, biopsy grade and preoperative prostate-specific antigen [PSA]) that enable patients to be classified as low, intermediate, or high risk for unfavourable outcomes. Surgery alone will only cure a fraction of high-risk patients. Instead these patients typically need a pro-active multimodal approach comprising a combination of surgery, radiotherapy and/or hormonal deprivation. The place of chemotherapy in the adjuvant or neoadjuvant setting in this patient group needs to be evaluated in clinical trials.

Segmental testicular infarction is a rare cause of acute scrotum. Its aetiology is not well defined and it can be clinically confused with a testicular tumour. Because the differential diagnosis between segmental testicular infarction and testicular tumour can be difficult, most authors in the past recommended surgery. Imaging plays an important role in the preoperative diagnosis, with a colour Doppler ultrasonography as the investigation of choice although magnetic resonance imaging (MRI) can be useful in doubtful cases. The objective of this retrospective study was to describe the radiologic findings and the outcome of conservative management in a single-centre experience of 19 cases of segmental testicular infarction.

The objective of this study was to present the long-term outcomes and determine outcome predictors in very high-risk (cT3b-T4) prostate cancer (PCa) after radical prostatectomy (RP).Between January 1989 and December 2004, 51 patients with cT3b-T4 PCa underwent RP. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS) and overall survival (OS) rate. Multivariate Cox proportional hazard models were used to determine the predictive power of clinical and pathological variables in BPFS and CPFS.Median follow-up was 108 months [interquartile range (IQR) 73.5-144.5]. The median serum prostate-specific antigen (PSA) was 16.9 ng/ml (IQR 7-37.2). Median biopsy and pathological Gleason (pGS) score were both scored as 7 (range 4-10 and 5-9, respectively). Overstaging was frequent (37.2%); four patients (7.8%) had organ-confined stage pT2, while 15 (29.4%) had extracapsular extension only (pT3a). Another 23 (45.1%) were confirmed with seminal vesicle invasion (pT3b) and nine (17.7%) had adjacent structure invasion (pT4). Eleven patients (21.6%) had lymph-node involvement. Thirty-two patients (62.7%) had positive surgical margins. The BPFS, CPFS, CSS and OS at 5 and 10 years were 52.7%, 45.8%;78.0%, 72.5%; 91.9%, 91.9% and 88.0%, 70.7%. In the multivariate Cox proportional hazard models, pathological stage was an independent predictor of BPFS while preoperative PSA and pGS was an independent predictor of CPFS.The management of cT3b-T4 PCa typically consists of a multimodality treatment in which RP is a valuable first step. Overstaging was frequent (37.2%), and almost one-quarter of the patients remained free of additional treatments. Long-term cancer-related outcomes were very satisfactory.

The LNCaP and C4-2B cell lines form an excellent preclinical model to study the development of metastatic castration-resistant prostate cancer, since C4-2B cells were derived from a bone metastasis that grew in nude mice after inoculation with the LNCaP-derived, castration-resistant C4-2 cells. Exome sequencing detected 2188 and 3840 mutations in LNCaP and C4-2B cells, respectively, of which 1784 were found in both cell lines. Surprisingly, the parental LNCaP cells have over 400 mutations that were not found in the C4-2B genome. More than half of the mutations found in the exomes were confirmed by analyzing the RNA-seq data, and we observed that the expressed genes are more prone to mutations than non-expressed genes. The transcriptomes also revealed that 457 genes show increased expression and 246 genes show decreased expression in C4-2B compared to LNCaP cells. By combining the list of C4-2B-specific mutations with the list of differentially expressed genes, we detected important changes in the focal adhesion and ECM-receptor interaction pathways. Integration of these pathways converges on the myosin light chain kinase gene (MLCK) which might contribute to the metastatic potential of C4-2B cells. In conclusion, we provide extensive databases for mutated genes and differentially expressed genes in the LNCaP and C4-2B prostate cancer cell lines. These can be useful for other researchers using these cell models.

The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa.Consider effectiveness and safety of vaccination strategies in the treatment of PCa.We searched three bibliographic databases (January 1995 through October 2010) for randomised phase 2 and 3 studies of vaccination strategies for PCa based on predetermined relevant Medical Subject Heading terms and free text terms.Data from 3 randomised phase 3 and 10 randomised phase 2 vaccination trials are discussed with respect to clinical outcome in terms of progression-free survival and OS, toxicity, prostate-specific antigen (PSA) response, and immunologic response. Three phase 3 trials (D9901, D9902A, and D9902B) that enrolled a total of 737 patients, all controlled and double-blinded, tested the efficacy of sipuleucel-T. The largest of these three trials, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), has demonstrated safety and effectiveness of sipuleucel-T (now marketed as Provenge) as measured by prolonged survival of 512 asymptomatic patients with metastatic castration-resistant PCa (mCRPC). The study showed a 4.1-mo median survival benefit in the sipuleucel-T vaccine-treated group compared with the control group (25.8 vs 21.7 mo; hazard ratio [HR]: 0.78; 95% confidence interval [CI], 0.62-0.98; p=0.032) and extended 3-yr survival (31.7% vs 23.0%). In contrast, two phase 3 vaccination trials with a whole-tumour-cell mixture of two PCa cell lines (GVAX) and testing GVAX either alone or in combination with chemotherapy versus chemotherapy alone (VITAL1 and 2) were terminated prematurely based on futility and increased deaths. Other phase 2 vaccination trials testing different types of vaccines in castration-resistant PCa patients have been reported with variable outcomes. Notably, a controlled, double-blind, randomised phase 2 vaccine trial of PROSTVAC-VF, a recombinant viral vector containing complementary DNA encoding PSA, in 125 patients with chemotherapy-naïve, minimally symptomatic mCRPC also demonstrated safety but no significant effect on the time to disease progression. In comparison with controls (n=40), PROSTVAC-VF-treated patients (n=82) experienced longer median survival of 8.5 mo (25.1 vs 16.6 mo; HR: 0.56; 95% CI, 0.37-0.85; p=0.0061) and extended 3-yr survival (30% vs 17%). In general, PCa vaccines are perceived to have less toxicity compared with current cytotoxic or targeted therapies. Evaluation of clinical efficacy of different vaccination strategies (eg, protein-, peptide- and DNA-based vaccines) in the context of properly designed and controlled phase 3 studies is warranted.Cancer vaccines represent a new paradigm in the treatment of PCa. The IMPACT trial showed improved survival but no difference in time to disease progression in mCRPC patients with minimal tumour burden. Observations in phase 2 and 3 trials pave the way for other vaccination approaches for this disease, raise questions regarding the most appropriate clinical trial designs, and underscore the importance of identifying biomarkers for antitumour effect to better implement such therapies.

Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients.A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation.Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95% CI, 1.03 to 17.72) as well as in the combined cohort (HR, 2.74; 95% CI, 1.42 to 5.27) in multivariate analysis.Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.

To review recently published literature presenting an overview of the current insights and (clinical and technical) developments on pelvic exenterative surgery for gynecological malignancies.Lateral recurrences, positive pelvic node status, age and high body mass index should be abandoned as contraindications for pelvic exenteration. F-fluorodeoxyglucose positron emission tomography-computed tomography is a valuable imaging tool, especially for the detection of enlarged lymph nodes and for distinguishing fibrosis from recurrence. Combined omental plus vertical rectus abdominis myocutaenous flaps give significant reduction in complications, whereas fascia sparing (myo)cutaneous flaps seem promising in decreasing donor-site complications.Pelvic exenteration is indicated when curative alternatives are inferior or exhausted for advanced primary or locally gynecological recurrent cancer confined to the pelvis. Palliative pelvic exenteration should only be considered when disease-related morbidity is uncontrollable with other therapeutic modalities. Modifications in different surgical steps are still evolving to decrease the pelvic exenteration associated high morbidity. A complete resection and lymph node invasion free status are directly related to a better prognosis.