Abstract 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.
Abstract Background Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, ...8–10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3 + 4 = 7 and 4 + 3 = 7 are often considered the same prognostic group. Objective To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. Design, setting, and participants Between 2005 and 2014, 20 845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. Outcome measurements and statistical analysis Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. Results and limitations In the surgery cohort, we found large differences in recurrence rates between both Gleason 3 + 4 versus 4 + 3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3 + 4, 4 + 3, 8, and 9–10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five–grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. Conclusions The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. Patient summary We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.
To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human ...tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer.
•Assembly of cross-species regulatory networks supports genome-wide interrogation•Cross-species interrogation identifies conserved master regulators of malignancy•FOXM1 and CENPF interact synergistically to drive malignant prostate cancer•Co-expression of FOXM1 and CENPF is prognostic for prostate cancer outcome
Aytes et al. assembled human and mouse prostate cancer gene regulatory networks and applied cross-species computational analyses to find master regulators. They identified FOXM1 and CENPF, which cooperate to coordinate an expression program that promotes prostate cancer malignancy, illustrating the strategy’s utility.
Abstract Background Although the initial robot-assisted radical prostatectomy (RARP) series showed 12-mo potency rates ranging from 70% to 80%, the few available comparative studies did not permit ...any definitive conclusion about the superiority of this technique when compared with retropubic radical prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP). Objectives The aims of this systematic review were (1) to evaluate the current prevalence and the potential risk factors of erectile dysfunction after RARP, (2) to identify surgical techniques able to improve the rate of potency recovery after RARP, and (3) to perform a cumulative analysis of all available studies comparing RARP versus RRP or LRP. Evidence acquisition A literature search was performed in August 2011 using the Medline, Embase, and Web of Science databases. Only comparative studies or clinical series including >100 cases reporting potency recovery outcomes were included in this review. Cumulative analysis was conducted using Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). Evidence synthesis We analyzed 15 case series, 6 studies comparing different techniques in the context of RARP, 6 studies comparing RARP with RRP, and 4 studies comparing RARP with LRP. The 12- and 24-mo potency rates ranged from 54% to 90% and from 63% to 94%, respectively. Age, baseline potency status, comorbidities index, and extension of the nerve-sparing procedure represent the most relevant preoperative and intraoperative predictors of potency recovery after RARP. Available data seem to support the use of cautery-free dissection or the use of pinpointed low-energy cauterization. Cumulative analyses showed better 12-mo potency rates after RARP in comparison with RRP (odds ratio OR: 2.84; 95% confidence interval CI: 1.46–5.43; p = 0.002). Only a nonstatistically significant trend in favor of RARP was reported after comparison with LRP (OR: 1.89; p = 0.21). Conclusions The incidence of potency recovery after RARP is influenced by numerous factors. Data coming from the present systematic review support the use of a cautery-free technique. This update of previous systematic reviews of the literature showed, for the first time, a significant advantage in favor of RARP in comparison with RRP in terms of 12-mo potency rates.
The last decade has seen several advances in radical prostatectomy (RP) technique and post-RP care that are relevant to erectile function (EF) recovery.
We examined whether these practice changes ...have led to observed improvements in EF rates over time.
We identified 2364 patients treated with either open or minimally-invasive RP at a single academic center in 2008–2015. To mitigate confounding by the surgical learning curve, only patients treated by surgeons who performed at least 100 procedures were considered.
EF before and after RP was assessed by the International Index of Erectile Function 6 (IIEF-6), with recovery defined as IIEF-6 ≥24.
We analyzed EF recovery rates of patients treated with bilateral nerve-sparing surgery and free from adjuvant/salvage treatment at the time of EF assessment. Local polynomial regression analyses explored changes in the outcomes over time. Linear and logistic regression analyses were used to estimate the influence of year of surgery on baseline variables and EF recovery.
We observed a significant decrease over time of the EF recovery rates at both 12 and 24mo post-RP (all p=0.01). However, patient's age at surgery increased over time (mean increase of 0.5 per year; p<0.01), with a resultant increase in risk of comorbidity (odds ratio OR=1.1, 95% confidence interval CI: 1.02–1.15; p=0.008) and thus decrease in baseline IIEF-6 score (0.35 points per year; p=0.0003). After accounting for baseline and pathological characteristics, urinary function, and type of surgery in a multivariable analysis, year of surgery was not associated with EF recovery (12mo: OR=0.97, 95% CI: 0.91–1.03, p=0.4; 24mo: OR=0.97, 95% CI: 0.91–1.03, p=0.3).
Findings from a high-volume center suggest that, despite the advancements in surgical and postoperative care, EF outcomes after RP have not improved over the last decade. Additional strategies are required to improve EF recovery after RP.
The probability of regaining potency after surgery for prostate cancer did not improve over the last decade; more efforts are needed to improve patient's care after radical prostatectomy.
Despite the widespread use of robotic surgery and advances in surgical technique and patient postoperative management, we did not observe an improvement in the rate of post-radical prostatectomy (RP) erectile function (EF) recovery over the last decade. These findings encourage research for additional strategies to improve EF after RP.
Abstract Context Pelvic lymph node dissection (PLND) in prostate cancer is the most effective method for detecting lymph node metastases. However, a decline in the rate of PLND during radical ...prostatectomy (RP) has been noted. This is likely the result of prostate cancer stage migration in the prostate-specific antigen-screening era, and the introduction of minimally invasive approaches such as robot-assisted radical prostatectomy (RARP). Objective To assess the efficacy, limitations, and complications of PLND during RARP. Evidence acquisition A review of the literature was performed using the Medline, Scopus, and Web of Science databases with no restriction of language from January 1990 to December 2012. The literature search used the following terms: prostate cancer, radical prostatectomy, robot-assisted , and lymph node dissection. Evidence synthesis The median value of nodal yield at PLND during RARP ranged from 3 to 24 nodes. As seen in open and laparoscopic RP series, the lymph node positivity rate increased with the extent of dissection during RARP. Overall, PLND-only related complications are rare. The most frequent complication after PLND is symptomatic pelvic lymphocele, with occurrence ranging from 0% to 8% of cases. The rate of PLND-associated grade 3–4 complications ranged from 0% to 5%. PLND is associated with increased operative time. Available data suggest equivalence of PLND between RARP and other surgical approaches in terms of nodal yield, node positivity, and intraoperative and postoperative complications. Conclusions PLND during RARP can be performed effectively and safely. The overall number of nodes removed, the likelihood of node positivity, and the types and rates of complications of PLND are similar to pure laparoscopic and open retropubic procedures.
Annotation of prostate cancer genomes provides a foundation for discoveries that can impact disease understanding and treatment. Concordant assessment of DNA copy number, mRNA expression, and focused ...exon resequencing in 218 prostate cancer tumors identified the nuclear receptor coactivator
NCOA2 as an oncogene in ∼11% of tumors. Additionally, the androgen-driven
TMPRSS2-ERG fusion was associated with a previously unrecognized, prostate-specific deletion at chromosome 3p14 that implicates
FOXP1,
RYBP, and
SHQ1 as potential cooperative tumor suppressors. DNA copy-number data from primary tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. The genomic and clinical outcome data from these patients are now made available as a public resource.
► Integrated genomic profiling of 218 prostate tumors provides a unique public resource ► Androgen receptor coactivator
NCOA2 is amplified in primary and metastatic disease ►
TMPRSS2-ERG
+
tumors associate with 3p14 loss and candidates
FOXP1,
RYBP, and
SHQ1 ► Degree and pattern of CNAs in primary tumors is associated with risk of relapse
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.
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