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Introduction: Most men diagnosed with very-low and low-risk prostate cancer are candidates for active surveillance; however, there is still a misclassification risk. We examined whether PI-RADS category 4 or 5 combined with ISUP 1 on prostate biopsy predicts upgrading and/or adverse pathology at radical prostatectomy., Materials and Methods: A total of 127 patients had ISUP 1 cancer on biopsy after multiparametric MRI (mpMRI) and then underwent radical prostatectomy. We then evaluated them for ISUP upgrading and/or adverse pathology on radical prostatectomy., Results: Eight-nine patients (70%) were diagnosed with PI-RADS 4 or 5 lesions. ISUP upgrading was significantly higher among patients with PI-RADS 4-5 lesions (84%) compared to patients with equivocal or non-suspicious mpMRI findings (26%, p < 0.001). Both PI-RADS 4-5 lesions (OR 24.3, 95% CI 7.3, 80.5, p < 0.001) and stage T2 on DRE (OR 5.9, 95% CI 1.2, 29.4, p = 0.03) were independent predictors of upgrading on multivariate logistic regression analysis. Men with PI-RADS 4-5 lesions also had significantly more extra-prostatic extension (51% vs. 3%, p < 0.001) and positive surgical margins (16% vs. 3%. p = 0.03). The only independent predictor of adverse pathology was PI-RADS 4-5 (OR 21.7, 95% CI 4.8, 99, p < 0.001)., Conclusion: PI-RADS 4 or 5 lesions on mpMRI were strong independent predictors of upgrading and adverse pathology. Incorporating mpMRI findings when selecting patients for active surveillance must be further evaluated in future studies.

Introduction:   Prostate cancer screening with PSA is associated with low specificity; furthermore, little is known about the optimal timing of biopsy.  We aimed to evaluate whether a risk classification system combining PSA density (PSAD) and mpMRI can predict clinically significant cancer and determine biopsy timing., Materials and Methods:  We reviewed the medical records of 256 men with a PI-RADS ≥ 3 lesion on mpMRI who underwent transperineal targeted and systematic biopsies of the prostate between 2017-2019.  Patients were stratified into three risk groups based on PSAD and mpMRI findings. The study endpoint was clinically significant prostate cancer (CSPC).  The association between the risk groups and CSPC was evaluated., Results:  Based on the proposed risk stratification system 42/256 men (16%) were high-risk (mpMRI finding of extra-prostatic extension and/or seminal vesicle invasion and/or a PI-RADS 5 lesion with a PSAD > 0.15 ng/mL²), 164/256 (64%) intermediate-risk (PI-RADS 4-5 lesions and/or PSAD > 0.15ng/mL² with no high-risk features) and 50/256 (20%) low-risk (PI-RADS 3 lesions and PSAD ≤ 0.15 ng/mL²).  High-risk patients had significantly higher rates of CSPC (76%) when compared to intermediate-risk (26%) and low-risk (4%).  On multivariable logistic regression analysis adjusted for age, previous biopsy, and clinical T-stage we found an association between intermediate-risk (OR = 4.84, p = 0.038) and high-risk (OR = 40.13, p < 0.001) features and CSPC.  High-risk patients had a shorter median biopsy delay time (110 days) compared to intermediate- and low-risk patients (141 and 147 days, respectively).  We did not find an association between biopsy delay and CSPC., Conclusions:   Our findings suggest that a three-tier risk classification system based on mpMRI and PSAD can identify patients at high-risk for CSPC who may benefit from earlier biopsy.

The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol ® -Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% ( n = 33) had a durable long-term response, with 62% ( n = 24) showing decreased/stable PSA, 90% ( n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

Objective: Multiparametric magnetic resonance imaging (mpMRI) is central to diagnosing prostate cancer; however, not all imaged lesions represent clinically significant tumors. We aimed to evaluate the association between the relative tumor volume on mpMRI and clinically significant prostate cancer on biopsy., Materials and Methods: We retrospectively reviewed the medical records of 340 patients who underwent combined transperineal targeted and systematic prostate biopsies between 2017 and 2021. Tumor volume was estimated based on the mpMRI diameter of suspected lesions. Relative tumor volume (tumor density) was calculated by dividing the tumor and prostate volumes. The study outcome was clinically significant cancer on biopsy. Logistic regression analyses were used to evaluate the association between tumor density and the outcome. The cutoff for tumor density was determined with ROC curves., Results: Median estimated prostate and peripheral zone tumor volumes were 55cm 3 and 0.61cm 3 , respectively. Median PSA density was 0.13 and peripheral zone tumor density was 0.01. Overall, 231 patients (68%) had any cancer and 130 (38%) had clinically significant cancer. On multivariable logistic regression age, PSA, previous biopsy, maximal PI-RADS score, prostate volume, and peripheral zone tumor density were significant predictors of outcome. Using a threshold of 0.006, the sensitivity, specificity, positive and negative predictive values of peripheral zone tumor density were 0.9, 0.51, 0.57, and 0.88, respectively., Conclusion: Peripheral zone tumor density is associated with clinically significant prostate cancer in patients with PI-RADS 4 and 5 mpMRI lesions. Future studies are required to validate our findings and evaluate the role of tumor density in avoiding unnecessary biopsies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although prostate-specific membrane antigen (PSMA) PET/CT has been shown valuable for staging biopsy-proven [B(+)] high-risk prostate cancer, elderly patients are occasionally referred for PSMA PET/CT without a preimaging confirming biopsy [B(-)]. The current study evaluated the rate, clinical characteristics, and PET-based stage of elderly B(-) patients and explored whether biopsy status affects therapeutic approach. Methods: One hundred consecutive patients at least 80 y old who underwent staging 68 Ga-PSMA-11 PET/CT were included. For each patient, we documented whether preimaging biopsy was performed, the clinical parameters, the PET-based staging parameters, and the primary therapy received. Results: Thirty-four (34%) of the elderly patients included in the study had no preimaging biopsy. Compared with B(+) patients, B(-) patients were older (median age, 87 vs. 82 y; P < 0.01), with worse performance status ( P < 0.01) and higher prostate-specific antigen (PSA) levels (median, 57 vs. 15.4 ng/mL; P < 0.01). On 68 Ga-PSMA-11 PET/CT, all B(-) patients had avid disease, with trends toward higher rates of bone metastases (47.1% vs. 28.8%) and overall advanced disease (50% vs. 33.3%) than in B(+) patients. Among patients with localized ( n = 36) or locally advanced ( n = 25) disease, B(-) patients were less commonly referred than B(+) patients for definitive therapies ( P < 0.01). However, higher age, Eastern Cooperative Oncology Group performance status, and PSA were other probable factors determining their therapeutic approach. Among 39 patients with advanced disease, 38 received hormonal therapy irrespective of their biopsy status. Among B(-) patients with advanced disease who were referred for hormonal therapy, 12 of 13 with follow-up data showed a biochemical or imaging-based response. Conclusion: Real-life experience with 68 Ga-PSMA-11 PET/CT indicates that around one third of elderly patients are referred for imaging without a preimaging confirming biopsy. These patients are likely to be older, with a worse clinical status and higher PSA levels. Advanced disease might be more likely to be identified on their 68 Ga-PSMA-11 PET/CT images, and if it is, their biopsy status does not preclude them from receiving hormonal therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The aim of the study was to elaborate the incidence and type of skeletal involvement in a large cohort of patients with newly diagnosed prostate cancer (PCa) referred for Ga-68 PSMA-11 PET/CT staging in a single center., Methods: Study cohort included 963 consecutive patients with newly diagnosed PCa referred for Ga-68 PSMA-11 PET/CT study for staging. The incidence of bone involvement, type of bone metastases, and extent of disease were determined and correlated with the ISUP Grade Group (GG) criteria and PSA levels., Results: Bone metastases were found in 188 (19.5%) of 963 patients. Bone metastases were found in 10.7% of patients with PSA < 10 ng/dL and in 27.4% of patients with PSA > 10 ng/dL and in 6.1% of patients with GG ≤ 2/3 and in 8.9% of patients with GG 4/5. In 7.6% of the patients, skeletal involvement was extensive, while 11.9% of patients had oligometastatic disease. Osteoblastic type metastases were the most common type of bone metastases presented in 133 of the patients with malignant bone involvement (70.7%). More than half of them had only osteoblastic lesions (72 patients (38.3%)), while the other (61 patients (32.5%)) had also intramedullary and/or osteolytic type lesions. Intramedullary metastases were found in 97 patients (51.6%), while 41 (21.8%) of them were only intramedullary lesions. Osteolytic metastases were detected in 36 patients (19.2%), of which 8 were only osteolytic lesions., Conclusion: Although traditionally bone metastases of PCa are considered osteoblastic, osteolytic and intramedullary metastases are common, as identified on PET with labeled PSMA. Skeletal spread may be present also in patients with GG ≤ 2/3 and PSA < 10 ng/dL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Concurrent systematic biopsies during image-guided targeted biopsies of the prostate were found to improve the detection rate of clinically significant prostate cancer (CSPC). However, these biopsies do not routinely include anterior or apical sampling. We aimed to evaluate the significance of anterior and apical samplings during combined biopsies., Methods: After obtaining institutional review board approval we identified 303 consecutive patients who underwent transperineal combined biopsies of the prostate between 2017-2020. Systematic biopsies were obtained from the peripheral zone, anterior zone, and apex. Study outcomes included CSPC and any cancer on anterior or apical biopsies. Logistic regression analyses were used to evaluate the association between pre-biopsy characteristics and study outcomes., Results: Median prostatic-specific-antigen value was 6.8 ng/dL. Most patients had stage T1c disease (77%). Overall, combined biopsies detected CSPC in 87 patients (29%). Any cancer and CSPC in the anterior zone were found in 54 (18%) and 19 (6%) patients, respectively. Any cancer and CSPC in the apex were found in 54 (18%) and 16 (5%) patients, respectively. Anterior/apical samplings upgraded the pathological result in 19 patients (6%). Logistic regression analyses demonstrated that PI-RADS 5 lesions predicted the presence of CSPC in both the anterior zone (OR = 8, 95%CI = 3-22, P <0.001) and apex (OR = 4, 95%CI = 1-10, P = 0.01)., Conclusions: Avoiding anterior and apical samplings during prostate biopsy does not result in substantial under-diagnosis of significant cancer. However, these areas are easily accessible using the transperineal approach and should be sampled in selected patients, particularly those with PI-RADS 5 lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Optimal therapy of biochemically relapsed prostate cancer (BRPC) after local treatment is elusive. An established modified citrus pectin (PectaSol ® , P-MCP), a dietary polysaccharide, is an established antagonist of galectin-3, a carbohydrate-binding protein involved in cancer pathogenesis. Based on PSA dynamics, we report on the safety and the primary outcome analysis of a prospective phase II study of P-MCP in non-metastatic BRPC based. Sixty patients were enrolled, and one patient withdrew after a month. Patients ( n = 59) were given P-MCP, 4.8 grams X 3/day, for six months. The primary endpoint was the rate without PSA progression and improved PSA doubling time (PSADT). Secondary endpoints were the rate without radiologic progression and toxicity. Patients that did not progress by PSA and radiologically at six months continued for an additional twelve months. After six months, 78% ( n = 46) responded to therapy, with a decreased/stable PSA in 58% ( n = 34), or improvement of PSADT in 75% ( n = 44), and with negative scans, and entered the second twelve months treatment phase. Median PSADT improved significantly ( p = 0.003). Disease progression during the first 6 months was noted in only 22% ( n = 13), with PSA progression in 17% ( n = 10), and PSA and radiologic progression in 5% (n = 3). No patients developed grade 3 or 4 toxicity.

Background: High-risk prostate cancer is associated with adverse pathology and unfavorable outcomes after radical prostatectomy. 68 Ga-PSMA PET/CT is more accurate than conventional imaging for preoperative staging. We aimed to evaluate whether lymph node involvement on 68 Ga-PSMA PET/CT prior to radical prostatectomy in patients with high-risk prostate cancer is associated with worse short-term oncologic outcomes., Methods: We retrospectively reviewed 149 patients with high-risk localized or locoregional prostate cancer who underwent 68 Ga-PSMA PET/CT prior to radical prostatectomy between 2015 and 2020. None of the patients received neoadjuvant or adjuvant treatment. The study endpoints were PSA persistence and biochemical recurrence. Logistic regression models were used to identify preoperative predictors of PSA persistence. Kaplan-Meier analyses were used to estimate biochemical recurrence-free survival., Results: Of 149 identified patients, 19 (13%) were found to have lymph node involvement on preoperative 68 Ga-PSMA PET/CT. The sensitivity, specificity, and accuracy of 68 Ga-PSMA PET/CT for identifying pathologic lymph node involvement were 68%, 95%, and 92%, respectively. PSA persistence rate was lower among patients with PET-negative lymph nodes than those with PET-positive nodes (15 vs. 84%, p < 0.001). Positive nodes on imaging (OR = 41.03, p < 0.001) and clinical T2c-T3 stage (OR = 6.96, p = 0.002) were associated with PSA persistence on multivariable analysis. Among patients with PET-negative nodes the 1- and 2-year biochemical recurrence-free survival rates were 87% and 76%, respectively., Conclusions: Preoperative staging with 68 Ga-PSMA PET/CT may identify a subgroup of high-risk prostate cancer patients with favorable short-term outcomes after radical prostatectomy without adjuvant treatment. Future studies will evaluate whether these results are sustained during long-term follow-up., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

18 F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)-based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18 F-PSMA-1007 with 68 Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent 18 F-PSMA-1007 and 68 Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen κ-coefficient was used to assess the concordance between 18 F-PSMA-1007 and 68 Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUV max was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers (κ ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18 F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18 F-PSMA-1007 and 68 Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. 18 F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Data on the accuracy of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in patients with intermediate/high-risk prostate cancer are being accumulated. Its role in assessing the extent of local disease has not been fully elaborated., Aim: To determine the performance characteristics of 68Ga-PSMA PET/CT in identifying local disease extension in patients with intermediate/high risk prostate cancer., Methods: 68Ga-PSMA PET/CT studies of 61 consecutive patients with intermediate/high-risk prostate cancer who underwent radical prostatectomy were reviewed by nuclear medicine specialists. Tumor location, extraprostatic extension (EPE), seminal vesicle invasion (SVI), and lymph nodes involvement (LNI) were compared to pathological findings. The incremental value of 68Ga-PSMA PET/CT to established nomograms was determined., Results: Two patients without pathologic uptake of 68Ga-PSMA were excluded. Seventeen patients were diagnosed with EPE (29%), 12(20%) had SVI and 3(5%) LNI. The concordance between tumor location and 68Ga-PSMA PET/CT findings was 48%, and EPE was not indicated by PET in any of the patients. The sensitivity, specificity, positive, and negative predictive value for SVI were 58%, 96%, 78%, 90%, respectively (area under the receiver operating characteristic curve = 0.77) and for LNI 67%, 98%, 67%, 98%, respectively (area under the receiver operating characteristic curve = 0.82). Incorporating imaging findings into the MSKCC-SVI nomogram enhanced the diagnostic accuracy from 0.84 to 0.95 (Integrated Discrimination Increment 0.24, P = 0.004)., Conclusion: In patients with intermediate/high-risk prostate cancer, 68Ga-PSMA PET/CT provides information regarding intraprostatic tumor location, SVI and LNI but has no role in assessment for EPE. This information might be useful for pretreatment counseling, decision-making and possibly preoperative planning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The multiple pathways that are involved in neuroendocrine differentiation (NED) in prostate cancer (PCa) are poorly elucidated. Evidence suggests that several environmental triggers induce NED leading to the adaptation of PCa to its close environment to maintain cell proliferation. Nevertheless, there is conflicting evidence regarding the prognostic role of NED in PCa., Methods: In this review, we aimed to summarize all available data about NED and to assess the prognostic role of NED in disease progression and therapy resistance, and its role in routine clinical practice. This review was based on articles found through a PubMed literature search between 1993 and 2013. The study outcome measure was the effect of NED on oncologic outcomes at each PCa stage., Results: In total, 59 articles reporting on the effect of NED on oncologic outcomes have been selected. In clinical practice, immunostaining for NED markers could have interesting predictive value for assessing the oncologic outcomes in patients receiving androgen-deprivation therapy. Thus, patients with high NED burden may be candidates for more aggressive treatment strategies targeting NED pathways. Conversely, strong evidence is lacking concerning its potential independent prognostic value in hormone-naïve PCa., Conclusions: Current published data are not sufficient to recommend the use of NE markers in routine practice, particularly at early PCa stage., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer., Methods: A review of the literature was performed in April 2014 using the Medline/PubMed database. Studies were identified using the search terms "prostate cancer," "metastatic," "metastasis," "high risk," "radiation therapy," "radiotherapy" and "prostatectomy" from 1990 until April, 2014. Articles were also identified through searches of references of these articles., Results: Retrospective series and population-based data suggest that the use of local treatment of the prostate in patients with primary metastatic prostate cancer may improve cancer-specific survival and overall survival compared with treating these patients with androgen deprivation therapy alone. The clinical outcome in metastatic prostate cancer is largely determined by the extent of lymph node involvement and overall metastatic burden. Contemporary data are lacking to recommend one alternative of local therapy (radiotherapy or radical prostatectomy) over the other. The primary limitation of this literature review is the lack of published randomized trial assessing the role of local treatment in addition to systemic therapy., Conclusions: Local treatment appears to improve oncologic outcomes in metastatic prostate cancer patients. Nevertheless, due to the lack of high-quality evidence, its role needs to be confirmed in future prospective trials. The selection of ideal candidates and optimal treatment alternative (radiotherapy, radical prostatectomy or other) warrants further investigation.

Objectives: Prostate biopsy (PB) is the gold standard for the diagnosis of prostate cancer (PCa). However, the optimal number of biopsy cores remains debatable. We sought to compare contemporary standard (10-12 cores) vs. saturation (=18 cores) schemes on initial as well as repeat PB., Methods: A non-systematic review of the literature was performed from 2000 through 2013. Studies of highest evidence (randomized controlled trials, prospective non-randomized studies, and retrospective reports of high quality) comparing standard vs saturation schemes on initial and repeat PB were evaluated. Outcome measures were overall PCa detection rate, detection rate of insignificant PCa, and procedure-associated morbidity., Results: On initial PB, there is growing evidence that a saturation scheme is associated with a higher PCa detection rate compared to a standard one in men with lower PSA levels (<10 ng/ml), larger prostates (>40 cc), or lower PSA density values (<0.25 ng/ml/cc). However, these cut-offs are not uniform and differ among studies. Detection rates of insignificant PCa do not differ in a significant fashion between standard and saturation biopsies. On repeat PB, PCa detection rate is likewise higher with saturation protocols. Estimates of insignificant PCa vary widely due to differing definitions of insignificant disease. However, the rates of insignificant PCa appear to be comparable for the schemes in patients with only one prior negative biopsy, while saturation biopsy seems to detect more cases of insignificant PCa compared to standard biopsy in men with two or more prior negative biopsies. Very extensive sampling is associated with a high rate of acute urinary retention, whereas other severe adverse events, such as sepsis, appear not to occur more frequently with saturation schemes., Discussion: Current evidence suggests that saturation schemes are associated with a higher PCa detection rate compared to standard ones on initial PB in men with lower PSA levels or larger prostates, and on repeat PB. Since most data are derived from retrospective studies, other endpoints such as detection rate of insignificant disease - especially on repeat PB - show broad variations throughout the literature and must, thus, be interpreted with caution. Future prospective controlled trials should be conducted to compare extended templates with newer techniques, such as image-guided sampling, in order to optimize PCa diagnostic strategy.

Objective: To explore preferences in the management of patients with newly diagnosed high-risk prostate cancer (PCa) among urologists in Europe through a web-based survey., Materials and Methods: A web-based survey was conducted between 15 August and 15 September 2013 by members of the Prostate Cancer Working Group of the Young Academic Urologists Working Party of the European Association of Urology (EAU). A specific, 29-item multiple-choice questionnaire covering the whole spectrum of diagnosis, staging and treatment of high-risk PCa was e-mailed to all urologists included in the mailing list of EAU members. Europe was divided into four geographical regions: Central-Eastern Europe (CEE), Northern Europe (NE), Southern Europe (SE) and Western Europe (WE). Descriptive statistics were used. Differences among sample segments were obtained from a z-test compared with the total sample., Results: Of the 12,850 invited EAU members, 585 urologists practising in Europe completed the survey. High-risk PCa was defined as serum PSA ≥20 ng/mL or clinical stage ≥ T3 or biopsy Gleason score ≥ 8 by 67% of responders, without significant geographical variations. The preferred single-imaging examinations for staging were bone scan (74%, 81% in WE and 70% in SE; P = 0.02 for both), magnetic resonance imaging (53%, 72% in WE and 40% in SE; P = 0.02 and P = 0.01, respectively) and computed tomography (45%, 60% in SE and 23% in WE; P = 0.01 for both). Pre-treatment predictive tools were routinely used by 62% of the urologists, without significant geographical variations. The preferred treatment was radical prostatectomy as the initial step of a multiple-treatment approach (60%, 40% in NE and 70% in CEE; P = 0.02 and P < 0.01, respectively), followed by external beam radiation therapy with androgen deprivation therapy (29%, 45% in NE and 20% in CEE; P = 0.01 and P = 0.02, respectively), and radical prostatectomy as monotherapy (4%, 7% in WE; P = 0.04). When surgery was performed, the open retropubic approach was the most popular (58%, 74% in CEE, 37% in NE; P < 0.01 for both). Pelvic lymph node dissection was performed by 96% of urologists, equally split between a standard and extended template. There was no consensus on the definition of disease recurrence after primary treatment, and much heterogeneity in the administration of adjuvant and salvage treatments., Conclusion: With the limitation of a low response rate, the present study is the first survey evaluating preferences in the management of high-risk PCa among urologists in Europe. Although the definition of high-risk PCa was fairly uniform, wide variations in patterns of primary and adjuvant/salvage treatments were observed. These differences might translate into variations in quality of care with a possible impact on ultimate oncological outcome., (© 2014 The Authors. BJU International © 2014 BJU International.)

Objective: To test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort., Materials and Methods: We performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4)., Results: The final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤ 10 ng/ml, PSAD ≤ 0.15 ng/ml/g, T1c, and ≤ 2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers., Conclusions: Approximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Prostate cancer screening among the general population is highly debatable. Nevertheless, screening among high-risk groups is appealing. Prior data suggests that men carrying mutations in the BRCA1& 2 genes may be at increased risk of developing prostate cancer. Additionally, they appear to develop prostate cancer at a younger age and with a more aggressive course. However, prior studies did not systematically perform prostate biopsies and thus cannot determine the true prevalence of prostate cancer in this population., Methods: This will be a prospective diagnostic trial of screening for prostate cancer among men with genetic predisposition. The target population is males (40-70 year old) carrying a BRCA1 and/or BRCA2 germ line mutation. They will be identified via our Genetic counseling unit. All men after signing an informed consent will undergo the following tests: PSA, free to total PSA, MRI of prostate and prostate biopsy. The primary endpoint will be to estimate the prevalence, stage and grade of prostate cancer in this population. Additionally, the study aims to estimate the impact of these germ line mutations on benign prostatic hyperplasia. Furthermore, this study aims to create a bio-bank of tissue, urine and serum of this unique cohort for future investigations. Finally, this study will identify an inception cohort for future interventional studies of primary and secondary prevention., Discussion: The proposed research is highly translational and focuses not only on the clinical results, but on the future specimens that will be used to advance our understanding of prostate cancer patho-physiology. Most importantly, these high-risk germ-line mutation carriers are ideal candidates for primary and secondary prevention initiatives., Trial Registration: ClinicalTrials.gov: NCT02053805.

Context: The clinical significance of positive surgical margins (PSMs) in radical prostatectomy (RP) specimens and the management of affected patients remain unclear., Objective: To address pitfalls in the pathologic interpretation of margin status; provide an update on the incidence, predictors, and long-term oncologic implications of PSMs in the era of robot-assisted laparoscopic RP (RALRP); and suggest a practical evidence-based approach to patient management., Evidence Acquisition: A systematic review of the literature was performed in April 2013 using Medline/PubMed, Web of Science, and Scopus databases and the Cochrane Database of Systematic Reviews. Studies focusing on PSMs in RP pertinent to the objectives of this review were included. Particular attention was paid to publications within the last 5 yr and those concerning RALRP., Evidence Synthesis: A total of 74 publications were retrieved. Standardized measures to overcome variability in the pathologic interpretation of surgical margins have recently been established by the International Society of Urological Pathology. The average rate of PSMs in contemporary RALRP series is 15% (range: 6.5-32%), which is higher in men with a more advanced pathologic stage and equivalent to the rate reported in prior open and laparoscopic prostatectomy series. The likelihood of PSMs is strongly influenced by the surgeon's experience irrespective of the surgical approach. Technical modifications using the robotic platform and the role of frozen-section analysis to reduce the margin positivity rate continue to evolve. Positive margins are associated with a twofold increased hazard of biochemical relapse, but their association with more robust clinical end points is controversial. Level 1 evidence suggests that adjuvant radiation therapy (RT) may favorably affect prostate-specific antigen recurrence rates, but whether the therapy also affects systemic progression, prostate cancer-specific mortality, and overall survival remains debatable., Conclusions: Although positive margins in prostate cancer are considered an adverse oncologic outcome, their long-term impact on survival is highly variable and largely influenced by other risk modifiers. Adjuvant RT appears to be effective, but further study is required to determine whether early salvage RT is an equivalent alternative., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: High-risk prostate cancer often represents a lethal disease requiring timely diagnosis and effective therapy. Standardized criteria that define high-risk prostate cancer have yet to be established, rendering the discrimination of high-risk from nonhigh-risk patients a challenge. This review summarizes the contemporary definitions of high-risk prostate cancer and their clinical utility., Recent Findings: As currently defined, high-risk prostate cancer constitutes a heterogeneous group of tumors with varying pathological features and inconsistent outcomes. Some high-risk patients may harbor systemic disease and relapse after local definitive therapy, whereas a substantial proportion have localized cancers and may be cured by surgery alone. If properly identified, these high-risk patients should be deemed candidates for curative treatment and spared the morbidity of systemic therapy. Additional information derived from systematic prostate biopsy, magnetic resonance findings, and, possibly, pretreatment prostate-specific antigen kinetics may be incorporated into the currently available models to yield a better prediction and to allow more informed decision-making., Summary: The quandary of how to define high-risk prostate cancer is pertinent. Various contemporary definitions of high-risk prostate cancer are available, most of which lack adequate sensitivity and specificity. Patients with high-risk clinically localized prostate cancer, by any of the current definitions, should not be uniformly disqualified from local definitive therapy with curative intent.

Context: The Second International Consultation on Bladder Cancer recommendations on urothelial carcinoma (UC) of the prostate were presented at the 2011 European Association of Urology Congress in Vienna, Austria, on March 18, 2011., Objective: Our aim is to summarize the Second International Consultation on Bladder Cancer recommendations on UC of the prostate to help clinicians assess the current evidence-based management., Evidence Acquisition: The committee performed a thorough review of new data and updated previous recommendations. Levels of evidence and grades of recommendation were assigned based on a systematic review of the literature that included a search of online databases and review articles., Evidence Synthesis: Once a non-muscle-invasive high-grade tumor or carcinoma in situ (CIS) of the bladder has been diagnosed, careful follow-up of the prostatic urethra is necessary. Noninvasive UC including CIS of the prostate should be treated with intravesical bacillus Calmette-Guérin (BCG) following endoscopic resection. A transurethral resection of the prostate may improve contact of BCG with the prostatic urethra, and it appears that response rates to BCG are increased (level of evidence: 3). Transurethral biopsy of the prostatic urethra is effective in identifying prostatic involvement but may not accurately reveal the extent of involvement, particularly with stromal invasion. Stromal invasion by UC of the prostate carries a poor prognosis. Radical cystoprostatectomy is the treatment of choice for locoregional control in patients with prostatic stromal invasion., Conclusions: These recommendations contain updated information on the diagnosis and treatment of UC of the prostate. However, prospective trials are needed to further elucidate the best management of these patients., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess whether radiation therapy for prostate cancer (PCa) increases the risk of metachronous rectal cancer (RCa) and compare outcomes of RCa after radiation therapy and surgery., Patients and Methods: The Israel Cancer Registry was queried to identify patients with PCa and RCa diagnosed between 1982 and 2005. The age adjusted standardized incidence ratio (SIR) of RCa was defined as the ratio between the observed and expected (calculated) RCa cases and compared among the following: overall Israeli male population, patients with PCa treated with radiation therapy, patients with PCa treated surgically. The medical records of men diagnosed with RCa were reviewed and clinical characteristics retrieved., Results: Of 29,593 men diagnosed with PCa, 2163 were treated with radiation therapy, 6762 were treated surgically and 20,068 patients were treated with either primary androgen deprivation therapy or offered watchful waiting. Of the entire study cohort, 194 (0.65%) patients were diagnosed with subsequent RCa. Compared to the overall male population and stratified by treatment modality, the risk of developing RCa after radiation therapy was significantly increased (SIR = 1.81, 95% CI 1.2-2.5), whereas it was not increased in those managed by surgery (SIR = 1.22, 95% CI 0.85-1.65). RCa after radiation therapy was diagnosed at a more advanced stage, translating into inferior disease specific survival., Conclusions: Compared to men diagnosed with PCa managed by surgery, we observed an increased risk of RCa in patients treated with radiation therapy. Further studies are needed to validate these findings and assess whether routine colonoscopic surveillance is warranted after pelvic radiation.

Objective: • 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., Methods: • 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., Results: • 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%), Conclusions: • 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., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Purpose: Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making., Materials and Methods: Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively., Results: The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer., Conclusions: Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The long-term risk of prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread prostate-specific antigen (PSA) screening. Models that predict the risk of PCSM are needed for patient counseling and clinical trial design., Methods: A multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM. Patient clinical information and treatment outcome was modeled using Fine and Gray competing risk regression analysis to predict PCSM., Results: Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM ranged from 5% to 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM. A nomogram predicting the 15-year risk of PCSM was developed, and the externally validated concordance index was 0.82. Neither preoperative PSA velocity nor body mass index improved the model's accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%., Conclusion: Few patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screen-detected cancers. Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.

Context: This review focuses on positive surgical margins (PSM) in radical prostatectomy (RP)., Objective: To address the etiology, incidence, and oncologic impact of PSM and discuss technical points to help surgeons minimize their positive margin rate. An evidence-based approach to assist clinicians in counseling patients with a PSM is provided., Evidence Acquisition: A literature search in English was performed using the National Library of Medicine database and the following key words: prostate cancer, surgical margins, and radical prostatectomy. Seven hundred sixty-eight references were scrutinized, and 73 were selected for rigorous review based on their pertinence, study size, and overall contribution to the field., Evidence Synthesis: In contemporary series, PSM are reported in 11-38% of patients undergoing RP. Although variability exists in the pathologic interpretation of surgical margins, PSM are associated with an increased hazard of biochemical recurrence (BCR) and local disease recurrence as well as the need for secondary cancer treatment. A posterolateral PSM appears to confer the greatest risk of recurrence, whereas the prognostic significance of positive apical margins remains controversial. The role of preoperative imaging and intraoperative frozen section analysis are being investigated to reduce margin positivity rates. Level-1 evidence indicates that adjuvant radiotherapy (RT) in men with PSM reduces BCR rates and clinical progression and possibly improves overall survival (OS)., Conclusions: PSM in RP specimens are uniformly considered an adverse outcome. Regardless of approach (open or laparoscopic), attention to surgical detail is essential to minimize rates. For patients with a PSM destined to experience a cancer recurrence, RT is the only established treatment with curative potential. A randomized trial in patients with PSM comparing immediate postoperative RT to salvage RT is critically needed before definitive recommendations can be made.

Objectives: Consensus recommendations for the identification and treatment of men whose apparent organ confined prostate cancer has high risk features are lacking. Despite ongoing refinements in surgical technique and improvements in morbidity and functional outcomes, the tradition of steering high-risk patients away from radical prostatectomy (RP) remains steadfast., Methods: We performed a medical literature search in English using MEDLINE/PubMed that addressed high risk prostate cancer. We analyzed the literature with respect to the historical evolution of this concept, current risk stratification schemes and treatment guidelines and related short and long term outcomes following RP., Results: Contemporary evidence suggest that patients classified with high-risk prostate cancer by commonly used definitions do not have a uniformly poor prognosis after RP. Many cancers categorized clinically as high risk are actually pathologically confined to the prostate, and most men with such cancers who undergo RP are alive and free of additional therapy long after surgery. RP in the high-risk setting appears to be associated with a similar morbidity as in lower-risk patients., Conclusion: Men with clinically localized high-risk prostate cancer should not be categorically disqualified from local definitive therapy with RP. With careful attention to surgical technique, cancer control rates should improve further, and adverse effects on quality of life after RP should continue to decrease.

Objectives: For prostate cancer screening, the role of prostate-specific antigen (PSA) velocity (PSAV) in conjunction with total PSA is controversial. We evaluated the relationship of PSAV to histologic findings on biopsy and assessed whether PSAV provides independent predictive information., Methods: From a community-based cohort of 25,276 men screened from 1991 to 2001, 1851 underwent a first biopsy for an elevated PSA and nonsuspicious digital rectal examination with a PSAV available from the year before biopsy. We analyzed the association between PSAV and biopsy histology., Results: The histologic findings on biopsy were cancer in 468 (25%), prostatic inflammation in 135 (7%), and benign prostate tissue in 1248 (68%). The cancer detection rate was associated with PSAV and, depending on PSAV, ranged from 13% to 36% (P <0.001). Among men with a PSAV less than 0.5 ng/mL per year, the cancer rate ranged from 27% to 36%, at a PSAV of 0.5 to 3.0 ng/mL per year was 24% to 28%, and at a PSAV greater than 3.0 ng/mL per year was 13% to 18%. On multivariable analysis adjusting for age and PSA, PSAV was independently associated with risk of cancer on biopsy (P <0.0005). The rate of prostatic inflammation was directly associated with PSAV (PSAV of 3.0 ng/mL per year or less: 5% to 9%; PSAV greater than 3.0 ng/mL per year: 11% to 13%, P = 0.01)., Conclusions: In screened men with an elevated PSA undergoing biopsy, PSAV provides independent predictive information for estimating prostate cancer risk. Modest increases in PSA are associated with an increased risk of cancer, whereas more dramatic PSA rises are associated with a diminishing risk of cancer and higher rate of inflammation.

Controversy remains regarding the preferred therapy for high-risk, clinically localized prostate cancer. High-risk prostate cancer represents a diverse disease entity for which accurate risk assessment is critical to informed counseling and clinical decision making. For men with high-risk features, electing surgery as a local definitive therapy should be based on the best available evidence rather than a surgeon's bias and experience. Patients classified with high-risk prostate cancer by common definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers that are clinically categorized as high risk are actually pathologically confined to the prostate, and most of these men do not require additional long-term therapy after surgery. For some high-risk patients, an integrated approach combining local and systemic therapy may be advantageous. Available studies using adjuvant and neoadjuvant strategies have their individual strengths and weaknesses; unfortunately, none has provided persuasive evidence to dictate the standard of care in the high-risk setting. Therefore, results are eagerly anticipated from ongoing randomized trials exploring the merits of perioperative chemohormonal therapy in high-risk patients. This review discusses current limitations and challenges in accurately identifying high-risk patients and focuses on radical prostatectomy alone or as part of multimodal therapy for men with high-risk prostate cancer.

Objectives: Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer., Materials and Methods: Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4-40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer-specific mortality (PCSM) were estimated with competing risk analysis., Results: Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR=1.3-5.2, p<0.05) and metastatic progression (HR=2.1-6.9, p<0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR=3.2-10.4, p<0.0005)., Conclusions: Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease.

Purpose: Transurethral bladder tumor resection is associated with imperfect clinical staging and incomplete tumor removal. Transurethral prostate resection may be complicated by inadvertent damage to the urinary sphincter, bladder neck and trigone. We performed a multicenter pilot and feasibility study of a novel working element for resectoscopes designed to improve the efficacy and safety of transurethral endoscopic surgery., Materials and Methods: An innovative working element for resectoscopes was developed to convert the standard in/out linear/axial movement at the handgrip into a side-to-side, bidirectional, lateral rotating motion. The device is compatible with current optical technology and conventional electrocautery generators, and it has been granted marketing approval. It consists of variably sized cutting loops designed for transurethral resection of bladder tumors and the prostate. To date 80 patients with bladder cancer (38) or benign prostatic hyperplasia (42) have undergone surgery with this instrument at our 3 clinical sites., Results: No safety concerns were evident. When used during transurethral bladder tumor resection, lateral resection at the base of the tumor enabled accurate depth of penetration into the bladder wall, which may decrease the risk of bladder perforation and improve pathological assessment of tumor invasion. During transurethral prostate resection this novel tool facilitated dissection of adenoma adjacent to the verumontanum and prostatovesical junction, which may decrease the risk of sphincteric damage and bladder neck injury., Conclusions: A novel resectoscope is currently under prospective clinical investigation to establish its surgical and pathological efficacy, ease of use and side effect profile. Current data suggest that the learning curve is mild, its use is safe and it provides distinct advantages when used for transurethral resection of bladder tumors and the prostate.

The management of low risk prostate cancer, defined as Gleason's sum

Purpose: Oxidative damage has been linked to prostate carcinogenesis but its role in disease development and progression remains elusive. We investigated associations between indexes of oxidative stress with localized and advanced prostate cancer. Specifically we assessed the susceptibility of serum lipids to copper induced peroxidation (oxidizability)., Materials and Methods: Serum oxidizability, and levels of alpha-tocopherol, malonyldialdehyde and uric acid were assessed in samples from 79 patients with prostate cancer, including 42 with localized and 37 with metastatic disease receiving androgen deprivation therapy, and 25 control subjects. Oxidizability was assayed by continuous spectroscopic monitoring of the accumulation of peroxidation products. The lag preceding oxidation, that is the delay between the induction and propagation of the reaction, served as a measure of the resistance of serum lipids to oxidation., Results: Compared to control subjects patients with localized prostate cancer had no difference in oxidative stress indexes, whereas those with metastatic disease had a shorter lag preceding oxidation and increased malonyldialdehyde (p <0.05), each reflecting a state of high oxidative stress. In patients with prostate cancer the probability of disease progression from localized to advanced state increased with a shorter lag preceding oxidation (p <0.001), increased malonyldialdehyde (p <0.03) and decreased uric acid (p <0.04). Localized and metastatic disease was associated with increased rather than decreased alpha-tocopherol (p <0.008 and <0.005, respectively)., Conclusions: Patients with advanced prostate cancer are subject to high oxidative stress, as determined by increased susceptibility of serum lipids to peroxidation. This association was not detected in patients with localized cancer and it is not attributable to altered levels of alpha-tocopherol.

Purpose: Standardized criteria are lacking to define high risk, clinically localized prostate cancer before definitive treatment. Reliance on simple risk stratification schemes to define high risk cancers has led many physicians and patients toward therapeutic nihilism, inappropriately selecting androgen deprivation instead of definitive local therapy. Of patients undergoing radical prostatectomy we identified those at high risk based on 8 previously described definitions. We examined pathological characteristics and prostate specific antigen outcomes., Materials and Methods: The study population included 4,708 men treated with radical prostatectomy alone between 1985 and 2004. Estimates of prostate specific antigen relapse for patients at high risk were generated with the Kaplan-Meier method. Cox proportional hazards regression was used to estimate the HR for recurrence in high risk vs nonhigh risk cohorts., Results: Depending on the definition used patients at high risk composed 3% to 38% of the study population. The proportion of patients with extracapsular extension, seminal vesicle invasion and lymph node metastasis among men with high risk cancer was 35% to 71%, 10% to 33% and 7% to 23%, respectively. Of the high risk tumors 22% to 63% proved to be confined to the prostate pathologically. While patients at high risk had a 1.8 to 4.8-fold increased hazard of prostate specific antigen relapse, their 5-year relapse-free probability after radical prostatectomy alone was 49% (95% CI 39 to 58) to 80% (95% CI 77 to 83). Of patients at high risk who had relapse 25% across all definitions experienced relapse more than 2 years after surgery and in 26% to 39% prostate specific antigen doubling time at recurrence was 10 months or greater., Conclusions: Patients diagnosed with high risk cancer by currently available definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers classified clinically as high risk are actually confined to the prostate pathologically. The risk of extraprostatic disease and prostate specific antigen relapse varies greatly depending on the definition used.

Objectives: To examine whether radical prostatectomy (RP) conducted before 4 or 6 weeks after prostate biopsy is associated with surgical difficulty or efficacy. Many urologists recommend an interval of at least 4 to 6 weeks between prostate biopsy and RP., Methods: Using our surgical database, we identified 2996 men undergoing open RP and compared the outcomes after surgery stratified by the interval from biopsy, analyzed as a dichotomous variable with cutpoints of either 4 or 6 weeks. The estimated blood loss and operating room time were considered surrogates for surgical difficulty, and surgical margin status and postoperative urinary and erectile function surrogates for surgical efficacy. We used regression models to assess whether the time to RP affected these surgical outcomes after controlling for the surgeon, surgeon experience, and various clinical and pathologic disease features., Results: The interval between biopsy and RP was 4 weeks or less for 168 men (6%) and 6 weeks or less for 416 men (14%). Using an interval of 4 weeks or less or 6 weeks or less, multivariate mixed effects regression analyses did not show a significant association between early surgery and operating room time, estimated blood loss, surgical margin status, urinary continence, or erectile function (all P > or = 0.18). Our results were sufficiently precise to exclude an important effect of early surgery., Conclusions: The results of our study have shown that performing radical prostatectomy shortly after prostate biopsy, within 4 to 6 weeks, does not adversely influence surgical difficulty or efficacy.

Objectives: To characterise the natural history of metastatic prostate cancer after radical prostatectomy (RP) in patients followed expectantly for rising prostate-specific antigen (PSA) (noncastrate metastases)., Methods: Cox proportional hazards analyses were used to assess predictors of survival among 95 patients who developed clinically detectable noncastrate metastases after RP. The initial metastatic phenotype was characterised as minimal (nodal or axial skeletal involvement) or extensive (appendicular skeletal involvement or visceral metastases). Estimates of survival after diagnosis of metastases were generated with the Kaplan-Meier method., Results: Median disease-specific survival from diagnosis of noncastrate metastases was 6.6 yr (95% confidence interval [CI], 5.2, 7.9). The initial site of metastatic disease was bone, lymph node, and viscera in 63%, 36%, and 6% of patients, respectively. Thirteen patients (14%) had extensive disease at their first metastatic manifestation. Longer PSA doubling time in the rising PSA state (hazard ratio [HR] 0.8 for each month increase in doubling time; 95%CI, 0.67-0.94) and the initial metastatic phenotype (HR 0.3 for minimal vs. extensive disease; 95%CI, 0.1-0.6) were associated with improved survival. The prostatectomy Gleason score, lymph node status at RP, PSA level at diagnosis of metastases, and interval from surgery to diagnosis of metastases did not correlate with outcome., Conclusion: Men who develop noncastrate metastases after RP may have a durable survival. Favourable prognostic indicators include longer PSA doubling time preceding diagnosis of metastases and initial involvement of axial skeleton or lymph nodes.

Purpose: Prostate specific antigen velocity 2.0 ng/ml per year or greater in the year before prostate cancer diagnosis is associated with cancer specific survival following radical prostatectomy and radiation therapy. We evaluated the relationship between prediagnosis prostate specific antigen velocity and cancer progression following primary radiation therapy., Materials and Methods: We analyzed the records of 24,893 men from a community based prostate cancer screening study and identified 237 with clinically localized prostate cancer who elected primary radiation therapy. Our final cohort consisted of 130 men, including 83 treated with external beam radiation and 47 treated with brachytherapy. Patient specific variables at diagnosis were analyzed for their value in predicting biochemical progression using American Society for Therapeutic and Radiation Oncology criteria., Results: Mean followup +/- SD was 64 +/- 35 months. Prostate specific antigen at diagnosis, family history of prostate cancer and prediagnosis prostate specific antigen velocity 2.0 ng/ml per year or greater were associated with cancer progression following brachytherapy or external beam radiation. Of men with prostate specific antigen velocity 2.0 ng/ml per year or greater 38% had cancer progression compared to 12% with prostate specific antigen velocity less than 2.0 ng/ml per year (OR 4.3, p = 0.003). The 6-year progression-free survival estimate was 57% in men with prostate specific antigen velocity 2.0 ng/ml per year or greater and 82% in men with prostate specific antigen velocity less than 2.0 ng/ml per year (p < 0.001). On multivariate analysis absolute prostate specific antigen at diagnosis and prostate specific antigen velocity 2.0 ng/ml per year or greater were independently associated with cancer progression in men treated with external beam radiation therapy or brachytherapy., Conclusions: Men with a prediagnosis prostate specific antigen velocity of 2.0 ng/ml per year or greater are at increased risk for cancer progression following brachytherapy or external beam radiation compared to men with a prostate specific antigen velocity of less than 2.0 ng/ml per year.

Purpose: Bladder neck invasion by prostate cancer in radical prostatectomy specimens is uncommon and, thus, its influence on disease recurrence has not been well defined. Consequently the classification of bladder neck invasion in the TNM staging system is controversial. We studied our cohort of patients with stage pT4 disease and bladder neck invasion to clarify the true clinical behavior and prognostic significance of bladder neck invasion in radical prostatectomy specimens., Materials and Methods: The study group consisted of 4,090 consecutive patients treated with radical prostatectomy at one of our institutions between 1983 and 2001. Median followup was 53.1 months (range 1 to 189). After excluding from analysis patients treated with neoadjuvant androgen withdrawal or preoperative irradiation 72 of the remaining 2,571 (2.8%) with bladder neck invasion were classified with stage pT4 disease and their specimens were reviewed. Progression-free probability was determined by Kaplan-Meier analysis. Using the Cox proportional hazards model the independent prognostic significance of bladder neck invasion was assessed after controlling for pretreatment prostate specific antigen, final Gleason sum, extracapsular extension, surgical margins status, seminal vesicle invasion and lymph node involvement., Results: Of the 72 patients categorized with stage pT4 disease 14 (19%) had poorly differentiated Gleason sum 8 to 10 cancer, 38 (53%) had established extracapsular extension, 24 (33%) had seminal vesicle invasion and 8 (11%) had lymph node involvement. However, 26 patients (36%) had cancer confined to the prostate and 28 (39%) had negative surgical margins except for the bladder neck site. The mean 5-year progression-free probability plus or minus SD in all stage pT4 cases was 68% +/- 7%, which was better than in cases of seminal vesicle invasion (52% +/- 5%, log rank test p = 0.0156) but worse than in those of extracapsular extension (84% +/- 4.1%). Univariate analysis of the stage pT4 cohort revealed that higher prostatectomy Gleason sum, more extensive extracapsular extension and seminal vesicle invasion were significantly associated with an adverse prognosis. However, in a multivariate model that included all radical prostatectomy cases the finding of bladder neck invasion or stage pT4 disease did not independently predict prostate specific antigen recurrence., Conclusions: Stage pT4 disease comprises a heterogeneous group of tumors with various pathological features and inconsistent outcomes. Assigning the pT4 stage to cases of microscopic bladder neck invasion provides no independent ability for predicting disease progression after adjusting for other adverse disease features. Due to this and previously reported data the definition of stage pT4 disease should be modified in the next version of the TNM staging system.

When applying nomograms to a clinical setting it is essential to know how their predictions compare with clinicians'. Comparisons exist outside of the prostate cancer literature. We reviewed these comparisons and conducted 2 experiments comparing predictions of clinicians with prostate cancer nomograms. By using Medline, we searched studies from January 1966 to July 1999 that compared human predictions with nomogram predictions. Next, we conducted 2 experiments: (1) 17 urologists were presented with 10 case vignettes and asked to predict the 5-year recurrence-free probabilities for each patient; (2) case presentations of 63 prostate cancer patients (including full clinical histories with complete diagnostic data and surgical findings) were made to a group of 25 clinicians who were asked to predict organ-confined disease. We found 22 published studies comparing human experts with nomograms, greater than half (13 of 22) showed the nomogram performing above the level of the human expert. Our first experiment showed urologist modification of 165 nomogram predictions led to a decrease in prediction accuracy (c-index decreased from.67 to.55, P <.05). In our second experiment, clinician predictions of organ-confined disease were comparable to the nomogram (area under the receiver operating characteristic curve [AUC] 0.78 and 0.79, respectively). A mixed-model suggests the nomogram did not augment clinician prediction accuracy (doctor excess error 1.4%, P =.75, 95% confidence interval [CI]: -10.9% to 8.2%). Our data suggest that nomograms do not seem to diminish predictive accuracy and they may be of significant benefit in certain clinical decision making settings., (Copyright 2002, Elsevier Science (USA). All rights reserved.)