The Rho-kinase inhibitor Y27632 promotes ureteral relaxation in an in vivo rat model for partial ureteral obstruction.

PURPOSE: Aim of this study was to evaluate the effect of intravenous Y27632 (a ROK inhibitor) on intra-ureteral pressures and on blood pressure in an in vivo rat model for unilateral partial ureteral obstruction (PUO). METHODS: 15 Male Sprague Dawley rats were used. Under isofluran anesthesia, saline was continuously infused via polyethylene (PE)-10 catheters inserted in the ureters beneath the kidney pelvis. Left psoas muscle was sutured around the distal left ureter to create a partial obstruction. Carotid artery and femoral vein were cannulated with PE catheters for registration of mean arterial blood pressure (MAP) and for administration of drugs. Left and right ureter pressures and MAP were simultaneously recorded. Y27632 (0.03 and 0.1 mg/kg each n = 6-7) was given intravenously. T-test was used for comparisons. RESULTS: Spontaneous peristaltic pressure waves were recorded at baseline for both ureters. After the obstruction, Y27632 reduced maximum pressure (MaxP) by 10.5 ± 1.9% (0.03 mg/kg; p = 0.004) and 29.1 ± 4.8% (0.1 mg/kg; p < 0.001), minimum pressure (MinP) by 5.2 ± 2.3% (0.03 mg/kg; p = 0.02) and 12.2 ± 3.4% (0.1 mg/kg; p = 0.009), the area under the curve (AUC) by 7.8 ± 2.4% (0.03 mg/kg; p = 0.008) and 16.5 ± 3.7% (0.1 mg/kg;p = 0.007), the waves amplitude by 23.4 ± 11.3% (0.03 mg/kg; p = 0.098) and 38.7 ± 7.5% (0.1 mg/kg; p < 0.001), with no effect on contraction frequency. During simultaneous recordings from the normal ureter at the investigated doses, Y27632 reduced MaxP, MinP, AUC and waves amplitude by 1-7%. The MAP was reduced by 12.5 ± 5.3% (0.03 mg/kg; p = 0.07) and 15.8 ± 1.8% (0.1 mg/kg; p < 0.001). CONCLUSIONS: Y27632 decreased intra-ureteral pressures of a partially obstructed ureter with limited effect on blood pressure in an animal model of unilateral PUO.

The effect of androgen deprivation treatment on subsequent risk of bladder cancer diagnosis in male patients treated for prostate cancer.

INTRODUCTION: Bladder cancer (BCa) is three-to-four times more common in men than in women. To explain this gender gap, several theories have been proposed, including the impact of androgen hormones. The aim of this study was to investigate the differential impact of androgen deprivation therapy (ADT) on subsequent risk of developing BCa in men with prostate cancer (PCa). METHODS: A total of 196,914 patients diagnosed with histologically confirmed localized PCa between 2000 and 2009 were identified in the SEER-Medicare insurance program-linked database. Competing-risk regression analyses were performed to assess the risk of developing BCa adjusting for the risk of all-cause mortality. Univariable and multivariable competing-risk regression analyses were performed to test the effect of ADT on BCa incidence for each PCa treatment modality. RESULTS: Of the 196,914 individuals included in the study, 68,421 (34.7%) received ADT. Median (IQR) follow-up was 59 (29-95) months. Overall, a total of 2495 (1.3%) individuals developed BCa during follow-up. After stratification according to ADT, the 10-year cumulative incidence rate was 1.75% (95% CI 1.65-1.85). In the untreated group, the 10-year cumulative incidence rate was 1.99% (95% CI 1.83-2.15). In multivariable competing-risk regression, the use of ADT was not associated with BCa, after accounting for the risk of dying from any cause (p = 0.1). CONCLUSION: We failed to identify any impact of ADT on the risk of developing a subsequent BCa even after stratifying according to the type of treatment. Further studies are required to explain the gender gap in BCa incidence and outcomes.

Inverse stage migration patterns in North American patients undergoing local prostate cancer treatment: a contemporary population-based update in light of the 2012 USPSTF recommendations.

PURPOSE: Recent studies demonstrated ongoing inverse stage migration in prostate cancer (PCa) patients towards more advanced and unfavorable tumors. The USPSTF grade D recommendation may impact this trend in North American patients. We assessed contemporary stage migration and treatment trends in a large North American cohort diagnosed with PCa 2009-2014. METHODS: Time-trend analyses were performed in patients within the Surveillance, Epidemiology, and End Results database, with complete data of clinical tumor stage, biopsy Gleason score, and validated PSA values, resulting in 211,645 assessable patients. Patients were stratified according to their different treatment methods [radical prostatectomy (RP), radiotherapy (RT), and no local treatment (NLT)] and according to clinical and pathological risk stratification (D'Amico and CAPRA-S score). RESULTS: Over time, proportions of D'Amico low-risk (LR) decreased, with an increase in intermediate-to-high-risk (IR/HR) patients. These trends were more distinct in men ≥ 70 years. NLT proportions increased, most notably in D'Amico LR and/or older patients. Conversely, RP proportions remained stable in younger HR and increased in older HR patients. Similar patterns were demonstrated in the RP-treated subgroup: D'Amico HR, pT3, and/or lymph-node invasion or CAPRA-S HR proportions increased from 23.5 to 30.8, 24.3 to 32.9, and 10.7 to 16.3% (each p ≤ 0.015). CONCLUSIONS: Inverse stage migration with increase of unfavorable PCa continues in most contemporary North American patients. However, a paradigm shift to treat LR patients with less invasive methods (NLT) was demonstrated. Contrary, HR patients increasingly undergo LT. Future studies with long-term follow-up might answer if inverse stage migration vs. treatment trends translate into different PCa metastases/mortality rates vs. proposed NLT benefits, particularly related to USPSTF-recommended reduced PSA screening.

Impact of multiparametric MRI and MRI-targeted biopsy on pre-therapeutic risk assessment in prostate cancer patients candidate for radical prostatectomy.

PURPOSE: To assess the current status and future potential of multiparametric MRI (mpMRI) and MRI-targeted biopsy (MRI-TBx) on the pretherapeutic risk assessment in prostate cancer patients' candidates for radical prostatectomy. METHODS: A literature search of the MEDLINE/PubMed and Scopus database was performed. English-language original and review articles were analyzed and summarized after an interactive peer-review process of the panel. RESULTS: Pretherapeutic risk assessment tools should be based on target plus systematic biopsies, where the addition of systematic biopsy (TRUS-Bx) to the mpMRI-target cores is associated with a lower rate of upgrading at final pathology. The combination of mpMRI findings with clinical parameters outperforms models based on clinical parameters alone in the prediction of adverse pathological outcomes and oncological results. This is particularly true when a specialized radiologist is present. CONCLUSION: The combination of mpMRI findings and clinical parameters should be considered to improve patient stratification in the pretherapeutic risk assessment. There is an urgent need to develop or include MRI data and MRI-TBx findings in available preoperative risk tools. This will allow improving the pretherapeutic risk assessment, providing important additional information for patient-tailored treatment planning and optimizing outcomes.

Efficacy and safety of artificial urinary sphincter (AUS): Results of a large multi-institutional cohort of patients with mid-term follow-up.

AIMS: To assess efficacy and safety as well as predictive factors of dry rate and freedom from surgical revision in patients underwent AUS placement. The artificial urinary sphincter (AUS) is still considered the standard for the treatment of moderate to severe post-prostatectomy stress urinary incontinence (SUI). However, data reporting efficacy and safety from large series are lacking. METHODS: A multicenter, retrospective study was conducted in 16 centers in Europe and USA. Only primary cases of AUS implantation in non-neurogenic SUI after prostate surgery, with a follow-up of at least 1 year were included. Efficacy data (continence rate, based on pad usage) and safety data (revision rate in case of infection and erosion, as well as atrophy or mechanical failure) were collected. Multivariable analyses were performed in order to investigate possible predictors of the aforementioned outcomes. RESULTS: Eight hundred ninety-two men had primary AUS implantation. At 32 months mean follow-up overall dry rate and surgical revision were 58% and 30.7%, respectively. Logistic regression analysis showed that patients without previous incontinence surgery had a higher probability to be dry after AUS implantation (OR: 0.51, P = 0.03). Moreover institutional case-load was positively associated with dry rate (OR: 1.18; P = 0.005) and freedom from revision (OR: 1.51; P = 0.00). CONCLUSIONS: The results of this study showed that AUS is an effective option for the treatment of SUI after prostate surgery. Moreover previous incontinence surgery and low institutional case-load are negatively associated to efficacy and safety outcomes.

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

Prediction of Complications in Radical Prostatectomy Prostate Cancer Patients: Simulated Annealing versus Co-Morbidity Indexes.

BACKGROUND: The Deyo/Charlson co-morbidity index (CCI) and Klabunde co-morbidity index (KCI) co-morbidity indexes represent outdated indexes when the endpoint of complications after radical prostatectomy (RP) is considered. A novel group of co-morbidities derived from International Classification of Diseases-9 diagnostic codes in a contemporary RP database could provide better accuracy. Research Design, Subjects and Measures: We relied on 20,484 patients with clinically localized non-metastatic prostate cancer treated with RP between 2000 and 2009 in the Surveillance, Epidemiology, and End Results-Medicare linked database. We examined 2 endpoints, namely, 90-day medical complication rate and 90-day surgical complication rate after RP. Simulated annealing (SA) was used to develop a novel co-morbidity index. Finally, the newly identified groups of co-morbid conditions were compared with the CCI and Klabunde indexes. RESULTS: Our SA identified 10 and 7 individual co-morbid conditions able to predict 90-day medical and surgical complications respectively. This novel model showed improved predictive accuracy over CCI and KCI for the 2 endpoints considered (respectively: 59.4 vs. 58.1 and 58.0% for medical complications, 58.0 vs. 56.8 and 56.7% for surgical complications). CONCLUSIONS: The newly defined groupings of co-morbid conditions resulted in better ability to predict the 2 endpoints of interest compared to CCI and KCI. However, the gain was marginal. This implies that better tools should be defined to more accurately predict these outcomes.

Identifying candidates for super-extended staging pelvic lymph node dissection among patients with high-risk prostate cancer.

OBJECTIVES: To assess if the preoperative lymph node invasion (LNI) risk could be used to tailor the extent of pelvic lymph node dissection (PLND) according to individual profile in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), and to identify those who would benefit from the removal of the common iliac and pre-sacral nodes. PATIENTS AND METHODS: A total of 471 patients with high-risk PCa treated with RP and a super-extended PLND that included the removal of the pre-sacral and common iliac nodes between 2006 and 2016 were identified. The risk of LNI was calculated according to the Briganti nomogram. Multivariable logistic regression analyses assessed the association between LNI risk and involvement of the common iliac and pre-sacral regions. The risk of positive common iliac and pre-sacral nodes was plotted over the LNI risk using the LOWESS-smoothed fit curve. RESULTS: The median preoperative LNI risk was 25.5%. The median number of nodes removed was 23, and 171 (36.3%) patients had LNI. Overall, 61 (13.0%) and 28 patients (5.9%), respectively, had positive common iliac and pre-sacral nodes alone or in combination with other sites. The LNI risk was associated with the involvement of the common iliac and pre-sacral regions (all P < 0.001). The proportion of patients with positive common iliac and pre-sacral nodes progressively increased according to the LNI risk. The adoption of a 30% threshold would result in avoiding the removal of the common iliac and pre-sacral nodes in >60% cases, with a risk of missing LNI in these regions of <5%. CONCLUSIONS: Fewer than 5% of patients with an LNI risk of <30% harbour positive common iliac and pre-sacral nodes. A super-extended PLND that includes the dissection of these regions should be considered exclusively in patients with an LNI risk ≥30%.

How can we expand active surveillance criteria in patients with low- and intermediate-risk prostate cancer without increasing the risk of misclassification? Development of a novel risk calculator.

OBJECTIVE: To develop a novel tool to increase the number of patients with prostate cancer eligible for active surveillance (AS) without increasing the risk of unfavourable pathological features (i.e., misclassification) at radical prostatectomy (RP). PATIENTS AND METHODS: Overall, 16 049 patients with low- or intermediate-risk prostate cancer treated with RP were identified. Misclassification was defined as non-organ confined or grade group ≥3 disease at RP. The coefficients of a logistic regression model predicting misclassification were used to develop a risk score. We then performed a systematic analysis of different thresholds to discriminate between patients with or without unfavourable disease and we compared it to available AS criteria. RESULTS: Overall, 5289 (33.0%) patients had unfavourable disease. At multivariable analyses, PSA level, clinical stage, biopsy grade group, the number of positive cores, and PSA density were associated with the risk of unfavourable disease (all P < 0.001). The Prostate Cancer Research International: Active Surveillance (PRIAS) criteria were associated with a lower risk of misclassification (13%) compared to other criteria. Overall, 3303 (20.6%) patients were eligible according to the PRIAS protocol. The adoption of an 18% threshold according to the risk score increased the proportion of eligible patients from 20.6% to 29.4% without increasing the risk of misclassification as compared to the PRIAS criteria. CONCLUSIONS: The use of a novel risk score for AS selection would result in an absolute increase of 10% in the number of patients eligible for this approach without increasing the risk of misclassification.

Surgical treatment for clinical node-positive bladder cancer patients treated with radical cystectomy without neoadjuvant chemotherapy.

OBJECTIVE: Growing literature supports good survival expectancies in bladder cancer (BCa) patients affected by clinical node metastases (cN+) treated with multimodal therapy. We evaluated the role of adjuvant chemotherapy in cN+BCa patients treated with radical cystectomy (RC) and pelvic lymph node dissection (PLND) without neoadjuvant chemotherapy (NAC). METHODS: We evaluated a total of 192 patients with BCa and cN+. All patients were treated with RC and PLND without NAC between 2001 and 2013. Kaplan-Meier analyses and Cox regression analyses were used to assess the impact of adjuvant chemotherapy (ACT) on recurrence, cancer-specific mortality (CSM) and overall mortality (OM) after surgery. RESULTS: Overall, 99 patients (51.6%) were found without node metastases at RC, while 18 (9.4%), 58 (30.2%) and 17 (8.9%) patients were found pN1, pN2 and pN3, respectively. With a median follow-up of 48 months, in cN+ patients we recorded 5-year recurrence, CSM and OM of 55, 53 and 51%, respectively. Overall, 36 (18.8%) patients were treated with adjuvant chemotherapy. At univariable analyses, ACT was associated with improved overall survival [Hazard ratio (HR): 0.42, confidence interval (CI) 0.20-0.86, p = 0.02) in pN+ subgroup only. These results were confirmed at multivariable analyses, where ACT was associated with improved CSS (HR: 0.45, CI 0.21-0.89, p = 0.03) and OS (HR: 0.37, CI 0.17-0.81, p = 0.01). CONCLUSIONS: We report good survival outcomes in cN+ patients treated with RC. The use of ACT after surgery increases survival expectancies, especially in those patients with pathological node disease. Our data need to be further evaluated in prospective setting.

Effect of pathological high-risk features on cancer-specific mortality in non-metastatic clear cell renal cell carcinoma: a tool for optimizing patient selection for adjuvant therapy.

PURPOSE: Adjuvant therapies for non-metastatic renal cell carcinoma (nmRCC) are being tested to improve outcomes in patients with high-risk (hR) nmRCC. The objective of the current study is to test the ability of three hR features to identify patients who are at the highest risk of cancer-specific mortality (CSM) after partial or radical nephrectomy. METHODS: Within the Surveillance Epidemiology and End Results (SEER) database (1988-2013), we identified 23,632 nm "clear cell" RCC partial or radical nephrectomy patients with hR features: Fuhrman grade (FG) 3 or 4 or pathological classifications T3a or T3b or lymph node invasion (LNI), or combination of these. Kaplan-Meier analyses (KM) and multivariable Cox's regression models (CRM) evaluated the effect of hR features on CSM. RESULTS: Overall 11,568 (48.9%) patients harbored FG3-4, 5575 (23.6%) pT3a/b, 140 (0.6%) LNI, 5366 (22.7%) FG3-4 and pT3a/b, 183 (0.8%) LNI and pT3a/b, 203 (0.9%) LNI and FG3-4 and 597 (2.5%) LNI, FG3-4 and pT3a/b. Median CSM-free survival was 51, 58 and 22 months for LNI and pT3a/b, for LNI and FG3-4 and for LNI, FG3-4 and pT3a/b and was not reached for the other groups. These results remained unchanged in multivariable CRMs, where all hR features represented independent predictors. CONCLUSIONS: Individuals with combination of LNI with FG3-4 or pT3a/b and patients with all three hR features are at highest risk of CSM. In consequence, these patients may represent ideal candidates for adjuvant therapy either in clinical practice or future prospective trials.

Survival after radical prostatectomy or radiotherapy for locally advanced (cT3) prostate cancer.

PURPOSE: No prospective data examined the effect of radical prostatectomy (RP) vs. external beam radiotherapy (EBRT) in locally advanced prostate cancer (PCa). We aimed to compare survival outcomes of RP and EBRT in patients harboring cT3N0-1 PCa. METHODS: Within the SEER database (2004-2014), we identified 5500 cT3N0-1 PCa patients. Cumulative incidence plots and competing-risks regression models (CRRs) tested cancer-specific mortality (CSM) and other cause of mortality (OCM) according to treatment type. The multivariable relationship between baseline prostate-specific antigen (PSA) values and 10-year CSM after either RP or EBRT was graphically depicted using the LOESS smoothing method. Sensitivity analyses were performed in cT3N0-only patients, after OCM propensity score matching, and through landmark analyses. RESULTS: Ten-year CSM and OCM rates were significantly higher after EBRT (15.8 and 28.2%) than RP (8.1 and 10.4%) (all p < 0.0001). In multivariable CRRs, RP yielded lower CSM [hazard ratio (HR): 0.64] than EBRT. Significantly lower 10-year CSM rate was recorded after RP vs. EBRT through the entire range of baseline PSA values. The same results were recorded in cT3N0 subgroup, as well as after OCM propensity score matching. Finally, landmark analyses at 6, 12, 24, and 36 months rejected the effect of favorable survival bias after RP. CONCLUSIONS: CSM was significantly lower after RP than EBRT in cT3N0-1 PCa. A lower CSM was recorded throughout the entire range of baseline PSA and even in cT3N0 subgroup, as well as after OCM propensity score matching and landmark analyses.

Contemporary rates of adherence to international guidelines for pelvic lymph node dissection in radical cystectomy: a population-based study.

OBJECTIVE: To examine the rates of adherence to guidelines for pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and to identify predictors of omitting PLND. MATERIALS AND METHODS: We relied on 66,208 patients treated with RC between 2004 and 2013 within the National Inpatients Sample (NIS) database. We examined the rates of PLND according to year of surgery, patient and hospital characteristics. Univariate and multivariate logistic regression analyses assessed the probability of PLND use, after adjusting for year of surgery, age, gender, race, comorbidities, hospital location, teaching status and hospital surgical volume. RESULTS: Overall, PLND was performed on 54,223 (81.9%) RC patients. The rates PLND at RC significantly increased over the study period from 72.3% in 2004 to 85.9% in 2013, (p < 0.001). Barriers to PLND at RC consisted of female gender (OR: 1.31; 95% CI 1.25-1.38; p < 0.001), African American race (OR: 1.21; 95% CI 1.10-1.32; p < 0.001), intermediate (OR: 1.78; 95% CI 1.68-1.88; p < 0.001) or low surgical volume institutions (OR: 2.59; 95% CI 2.44-2.74; p < 0.001), non-teaching institution status (OR: 1.21; 95% CI 1.15-1.27; p < 0.001) and rural hospital location (OR: 1.13; 95% CI 1.01-1.25; p = 0.03). CONCLUSIONS: It is encouraging to note increasing rates of PLND at RC over time. Both patients and hospital characteristics influence PLND rates. More efforts should be aimed at reducing inequalities in PLND at RC due to these highly modifiable variables.

The New Prostate Cancer Grading System Does Not Improve Prediction of Clinical Recurrence After Radical Prostatectomy: Results of a Large, Two-Center Validation Study.

BACKGROUND: A new prostate cancer (PCa) grading system (namely, Gleason score-GS- ≤6 vs. 3 + 4 vs. 4 + 3 vs. 8 vs. ≥9) was recently proposed and assessed on biochemical recurrence (BCR) showing improved predictive abilities compared to the commonly used three-tier system (GS ≤6 vs. 7 vs. ≥8). We assessed the predictive ability of the five-tier grade group (GG) system on harder clinical endpoint, namely clinical recurrence (CR). METHODS: Between 2005 and 2014, 9,728 clinically localized PCa patients were treated with radical prostatectomy (RP) at two tertiary referral centers. Kaplan-Meier curves, multivariable Cox regression analyses, and concordance index (C-index) were used to assess CR after treatment according to four Gleason grade classifications at biopsy and RP: Group 1: ≤6 versus 7 versus ≥8; Group 2: ≤6 versus 3 + 4 vs. 4 + 3 versus ≥8; Group 3: ≤6 versus 7 versus 8 versus ≥9; Group 4: ≤6 versus 3 + 4 versus 4 + 3 versus 8 versus ≥9. Same analyses were repeated in patients who had BCR (n = 1,624). Decision curve analyses were performed to evaluate and compare the net benefit associated with the use of the four Gleason grade classifications. RESULTS: Overall, 443 (4.6%) patients had CR. The hazard ratio of the GS 3 + 4, 4 + 3, 8, and ≥9 relative to GS ≤6 were 3.63, 5.93, 11.44, 18.08 and 4.93, 9.99, 15.31 and 25.12 in the pre- and post-treatment models, respectively. The C-index of the five-tier GG system was slightly higher relative to the other 3 Gleason grade classifications both in the pre- (range: 0.001-0.006) and post-treatment models (range: 0-0.008). Similar findings were observed when we focused our analyses in patients with BCR after RP. The use of the five-tier GG system did not result into higher net-benefit relative to the other three Gleason grade classifications. CONCLUSIONS: The difference in accuracy between the five-tier GG system and the other Gleason grade classifications, using CR as an endpoint, is clinically negligible. Current evidence suggests that the five-tier GG system represents a simplified user-friendly scheme available for patient counseling rather than a new histopathological diagnostic system that improves the prediction of CR. Prostate 77:263-273, 2017. © 2016 Wiley Periodicals, Inc.

Population-Based Validation of the 2014 ISUP Gleason Grade Groups in Patients Treated With Radical Prostatectomy, Brachytherapy, External Beam Radiation, or no Local Treatment.

BACKGROUND: To test discriminant ability of the 2014 ISUP Gleason grade groups (GGG) for prediction of prostate cancer specific mortality (PCSM) after radical prostatectomy (RP), brachytherapy (BT), external beam radiation (EBRT) or no local treatment (NLT) relative to traditional Gleason grading (TGG). METHODS: In the Surveillance, Epidemiology, and End Results (SEER)-database (2004-2009), 2,42,531 non-metastatic prostate cancer (PCa) patients were identified, who underwent local treatment (RP, BT, EBRT only) or NLT. Follow-up endpoint was PCSM. Biopsy and/or pathological Gleason score (GS) were categorized as TGG ≤6, 7, 8-10 or GGG: I (≤6), II (3 + 4), III (4 + 3), IV (8), and V (9-10). Kaplan-Meier plots, multivariable Cox regression analyses and receiver operating characteristics (ROC) area under the curve analyses (AUC) were used. RESULTS: Median follow-up was 76 months (IQR: 59-94). For the four examined treatment modalities, all five GGG strata and all three TGG strata independently predicted PCSM. GGG yielded 1.5-fold or greater HR differences between GGG II and GGG III, and twofold or greater HR differences between GGG IV and GGG V. Relative to TGG, GGG added 0.4-1.1% to AUC. CONCLUSIONS: This large population-based cohort study confirms the added discriminant properties of the novel GGG strata and confirms a modest gain in predictive accuracy. Prostate 77: 686-693, 2017. © 2017 Wiley Periodicals, Inc.

North American Population-Based Validation of the National Comprehensive Cancer Network Practice Guideline Recommendation of Pelvic Lymphadenectomy in Contemporary Prostate Cancer.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend a pelvic lymph node dissection (PLND) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) if a nomogram predicted risk of lymph node invasion (LNI) is ≥2%. We examined this and other thresholds, including nomogram validation. METHODS: We examined records of 26,713 patients treated with RP and PLND between 2010 and 2013, within the Surveillance, Epidemiology, and End Results database. Nomogram thresholds of 2-5% were tested and external validation was performed. RESULTS: LNI was recorded in 4.7% of patients. Nomogram accuracy was 80.4% and maintained minimum accuracy of 75.6% in subgroup analyses, according to age, race, and nodal yield >10. With the NCCN recommended 2% nomogram threshold, PLND could be avoided in 22.3% of patients at the expense of missing 3.0% of individuals with LNI. Alternative thresholds of 3%, 4%, and 5% yielded respective PLND avoidance rates of 60.4%, 71.0%, and 79.8% at the expense of missing 17.8%, 27.2%, and 36.6% of patients with LNI. NCCN cut-off recommendation was best satisfied with a threshold of <2.6%, at which PLND could be avoided in 13,234 patients (49.5%) versus missing 141 patients with LNI (11.2%). CONCLUSION: NCCN LNI nomogram remains accurate in contemporary patients. However, the 2% threshold appears to be too strict, since only 22.3% of PLNDs can be avoided, instead of the stipulated 47.7%. The optimal 2.6% threshold allows a higher rate of PLND avoidance (49.5%), at the cost of 11.2% missed instances of LNI, as recommended by NCCN guidelines. PATIENT SUMMARY. External validation in contemporary SEER prostate cancer patients showed that the NCCN nomogram remains accurate for predicting lymph node invasion and seems to be optimal at an alternative 2.6% threshold, with best ratio of avoided pelvic lymph node dissections (49.5%) and missed LNIs (11.2%), as recommended by NCCN guideline. Prostate 77:542-548, 2017. © 2017 Wiley Periodicals, Inc.

Population-Based External Validation of the Updated 2012 Partin Tables in Contemporary North American Prostate Cancer Patients.

OBJECTIVE: To externally validate the updated 2012 Partin Tables in contemporary North American patients treated with radical prostatectomy (RP) for localized prostate cancer (PCa) at community institutions. MATERIALS AND METHODS: We examined records of 25,254 patients treated with RP and pelvic lymph node dissection (PLND) between 2010 and 2013, within the surveillance, epidemiology, and end results database. The ROC derived AUC assessed discriminant properties of the updated 2012 Partin Tables of organ confined disease (OC), extracapsular extension (ECE), seminal vesical invasion (SVI), and lymph node invasion (LNI). Calibration plots focused on calibration between predicted and observed rates. RESULTS: Proportions of OC, ECE, SVI, and LNI at RP were 69.8%, 18.4%, 7.4%, and 4.4%, respectively. Accuracy for prediction of OC, ECE, SVI, and LNI was 70.4%, 59.9%, 72.9%, and 77.1%, respectively. In subgroup analyses in patients with nodal yield >10, accuracy for LNI prediction was 76.0%. Subgroup analyses in elderly patients and in African American patients revealed decreased accuracy for prediction of all four endpoints. Last but not least, SVI and LNI calibration plots showed excellent agreement, versus good agreement for OC (maximum underestimation of 10%) and poor agreement for ECE (maximum overestimation of 12%). CONCLUSION: Taken together, the updated 2012 Partin Tables can be unequivocally endorsed for prediction of OC, SVI, and LNI in community-based patients with localized PCa. Conversely, ECE predictions failed to reach the minimum accuracy requirements of 70%. Prostate 77:105-113, 2017. © 2016 Wiley Periodicals, Inc.

Early Postoperative Radiotherapy is Associated with Worse Functional Outcomes in Patients with Prostate Cancer.

PURPOSE: The effect of time between radical prostatectomy and radiation therapy on postoperative functional outcomes is still unclear in patients with surgically managed prostate cancer. We hypothesized that a shorter time between radical prostatectomy and radiotherapy might be associated with worse functional recovery rates after radical prostatectomy. MATERIALS AND METHODS: We retrospectively evaluated 2,190 patients treated with radical prostatectomy and stratified according to radiotherapy schedule (adjuvant radiotherapy, salvage radiotherapy, no radiotherapy). We examined recovery rates for erectile function and urinary function according to adjuvant radiotherapy, salvage radiotherapy and no radiotherapy, and according to time from surgery to radiotherapy. Cox regression analyses were used to evaluate the impact of these predictors on functional outcomes. RESULTS: Median followup was 48 months. The 3-year erectile function recovery rates were 35.0%, 29.0% and 11.6% in patients who received no radiotherapy, salvage radiotherapy and adjuvant radiotherapy, respectively (p <0.001), and differed significantly according to time to radiotherapy (11.7% vs 34.7% for less than 1 year vs 1 year or more, respectively, p <0.001). The 3-year urinary continence recovery rates were 70.7%, 59.0% and 42.2% in patients who received no radiotherapy, salvage radiotherapy and adjuvant radiotherapy, respectively (p <0.001), and differed according to time to radiotherapy (43.5% vs 62.7% for less than 1 year vs 1 year or more, respectively, p <0.001). Cox regression analyses confirmed the negative impact of early radiotherapy on recovery rates for erectile function and urinary continence. CONCLUSIONS: Time from radical prostatectomy to radiotherapy has an important role in the recovery of erectile function and urinary continence. Delayed radiotherapy is preferred to improve functional outcomes after surgery.

Long-term utility of adjuvant hormonal and radiation therapy for patients with seminal vesicle invasion at radical prostatectomy.

OBJECTIVE: To investigate the long-term utility of adjuvant therapy after radical prostatectomy (RP) for prostate cancer with seminal vesicle invasion (SVI; pT3b), as the published data are conflicting. PATIENTS AND METHODS: Patients with SVI during RP and pelvic lymph node dissection at two major referral centres from 1986 to 2014 were included. Kaplan-Meier analyses and multivariable Cox regressions were used to determine if adjuvant radiotherapy (aRT) and adjuvant hormonal therapy (aHT) were predictors of biochemical recurrence (BCR), cancer-specific mortality (CSM) and overall mortality (OM). Subset analyses were performed for pN0 patients and pN+ patients. RESULTS: Overall, 3 279 patients with prostate cancer and SVI were included with a median follow-up of 148 months. Considering the whole SVI population, 1 387 (42%) received no adjuvant therapy, 1 179 (36%) received aHT, 461 (14.1%) received aRT, while 252 (7.7%) received both aHT and aRT. The 10-year BCR, CSM, and OM rates were 64%, 14%, and 27%, respectively. In the overall population, aRT and aHT were predictors of BCR, CSM and OM (all P < 0.04). When only pT3bN0 patients were considered, aHT was a significant multivariate predictor of BCR [hazard ratio (HR) 0.50, P < 0.001), CSM (HR 0.62, P = 0.01) and OM (HR 0.75, P = 0.004). Conversely, aRT was not associated with survival outcomes (all P > 0.05). When only the subgroup pT3bN+ was considered, the use of aRT was related to an improvement in CSM (HR 0.65, P = 0.03) and OM (HR 0.78, P = 0.03). CONCLUSIONS: aHT + aRT seems to be effective in pT3b patients. However, when stratified according to the presence of nodal metastases, aHT remains effective only in the node-negative subgroup, while aRT remains effective only in the node-positive subgroup. Further data including prospective trials are warranted to study the utility of adjuvant therapies in this setting.

External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer.

BACKGROUND: Previous studies have examined testosterone levels after external beam radiation (EBRT) monotherapy, but since 2002 only sparse contemporary data have been reported. AIM: To examine testosterone kinetics in a large series of contemporary patients after EBRT. METHODS: The study was conducted in 425 patients who underwent definitive EBRT for localized prostate cancer from 2002 through 2014. Patients were enrolled in several phase II and III trials. Exclusion criteria were neoadjuvant or adjuvant androgen-deprivation therapy or missing data. Testosterone was recorded at baseline and then according to each study protocol (not mandatory in all protocols). Statistical analyses consisted of means and proportions, Kaplan-Meier plots, and logistic and Cox regression analyses. OUTCOMES: Testosterone kinetics after EBRT monotherapy and their influence on biochemical recurrence. RESULTS: Median follow-up of 248 assessable patients was 72 months. One hundred eighty-six patients (75.0%) showed a decrease in testosterone. Median time to first decrease was 6.4 months. Median percentage of decrease to the nadir was 30% and 112 (45.2%) developed biochemical hypogonadism (serum testosterone < 8 nmol/L). Of all patients with testosterone decrease, 117 (62.9%) recovered to at least 90% of baseline levels. Advanced age, increased body mass index, higher baseline testosterone level, and lower nadir level were associated with a lower chance of testosterone recovery. Subgroup analyses of 166 patients treated with intensity-modulated radiotherapy confirmed the results recorded for the entire cohort. In survival analyses, neither testosterone decrease nor recovery was predictive for biochemical recurrence. CLINICAL IMPLICATIONS: EBRT monotherapy influences testosterone kinetics, and although most patients will recover, approximately 45% will have biochemical hypogonadism. STRENGTHS AND LIMITATIONS: We report on the largest contemporary series of patients treated with EBRT monotherapy in whom testosterone kinetics were ascertained. Limitations are that testosterone follow-up was not uniform and the study lacked information on health-related quality-of-life data. CONCLUSION: Our findings indicate that up to 75% of patients will have a profound testosterone decrease, with up to a 40% increase in rates of biochemical hypogonadism, although the latter events will leave biochemical recurrence unaffected. Pompe RS, Karakrewicz PI, Zaffuto E, et al. External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer. J Sex Med 2017;14:876-882.