[Show abstract][Hide abstract] ABSTRACT: Site-dependent and interindividual histological differences in Denonvilliers' fascia (DF) are not well understood. This study aimed to examine site-dependent and interindividual differences in DF and to determine whether changes in the current approach to radical prostatectomy are warranted in light of these histological findings.
Twenty-five donated male cadavers (age range, 72-95 years) were examined. These cadavers had been donated to Sapporo Medical University for research and education on human anatomy. Their use for research was approved by the university ethics committee. Horizontal sections (15 cadavers) or sagittal sections (10 cadavers) were prepared at intervals of 2-5 mm for hematoxylin and eosin staining. Elastic-Masson staining and immunohistochemical staining were also performed, using mouse monoclonal anti-human alpha-smooth muscle actin to stain connective tissues and mouse monoclonal anti-human S100 protein to stain nerves.
We observed that DF consisted of disorderly, loose connective tissue and structures resembling "leaves", which were interlacing and adjacent to each other, actually representing elastic or smooth muscle fibers. Variations in DF were observed in the following: 1) configuration of multiple leaves, including clear, unclear, or fragmented behind the body and tips of the seminal vesicles, depending on the site; 2) connection with the lateral pelvic fascia at the posterolateral angle of the prostate posterior to the neurovascular bundles, being clear, unclear, or absent; 3) all or most leaves of DF fused with the prostatic capsule near the base of the seminal vesicles, and periprostatic nerves were embedded in the leaves at the fusion site; and 4) some DF leaves fused with the prostatic capsule anteriorly and/or the fascia propria of the rectum posteriorly.
Site-dependent and interindividual variations in DF were observed in donated elderly male cadavers. All or most DF leaves are fused with the prostatic capsule near the base of the seminal vesicles and some DF leaves are fused with the fascia propria of the rectum posterior. Based on our results, surgeons should be aware of variations and search for them to create a suitable dissection plane to avoid iatrogenic positive margins and rectal injury.
[Show abstract][Hide abstract] ABSTRACT: Treatment possibilities for clinically localised prostate cancer include radical prostatectomy (RP), external beam radiotherapy, brachytherapy, focal therapy and active surveillance. Conflicting and methodologically flawed observational data from the last two decades have led to uncertainty as to the best oncological option. However, recently, there has been a series of high-quality studies that point to disease specific and overall survival advantages for those men undergoing RP. This article reviews the latest evidence and argues that at the current time, RP must be considered the gold standard treatment for the majority of men with clinically localised prostate cancer.
Current Urology Reports 05/2015; 16(5):504. DOI:10.1007/s11934-015-0504-z · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Several smaller single-center studies have reported a prognostic role for Ki-67 labeling index in prostate cancer. Our aim was to test whether Ki-67 is an independent prognostic marker of biochemical recurrence (BCR) in a large international cohort of patients treated with radical prostatectomy (RP).
Ki-67 immunohistochemical staining on prostatectomy specimens from 3,123 patients who underwent RP for prostate cancer was retrospectively performed. Univariable and multivariable Cox regression models were used to assess the association of Ki-67 status with BCR.
Ki-67 positive status was observed in 762 (24.4 %) patients and was associated with lymph node involvement (LNI) (p = 0.039). Six hundred and twenty-one (19.9 %) patients experienced BCR. The estimated 3-year biochemical-free survivals were 85 % for patients with negative Ki-67 status and 82.1 % for patients with positive Ki-67 status (log-rank test, p = 0.014). In multivariable analysis that adjusted for the effects of age, preoperative PSA, RP Gleason sum, seminal vesicle invasion, extracapsular extension, positive surgical margins, lymphovascular invasion, and LNI, Ki-67 was significantly associated with BCR (HR = 1.19; p = 0.019). Subgroup analysis revealed that Ki-67 is associated with BCR in patients without LNI (p = 0.004), those with RP Gleason sum 7 (p = 0.015), and those with negative surgical margins (p = 0.047).
We confirmed Ki-67 as an independent predictor of BCR after RP. Ki-67 could be particularly informative in patients with favorable pathologic characteristics to help in the clinical decision-making regarding adjuvant therapy and optimized follow-up scheduling.
World Journal of Urology 10/2014; 33(8). DOI:10.1007/s00345-014-1421-3 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
We hypothesized that there is a reverse stage migration, or a shift toward operating on higher-risk prostate cancer, in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). We therefore evaluated the stage of disease at the time of surgery for patients with prostate cancer at a large tertiary academic medical center.
Materials and Methods:
After institutional review board approval, we reviewed all patients that had undergone robotic prostatectomy. These patients were separated into three categories: An early era of 2005-2008, intermediate era of 2009-2010, and a current era of 2011-2012.
A total of 3451 patients underwent robotic prostatectomy from 2005 to 2012. The proportion men with clinical T1 tumors declined from 88.3% in the early era to 72.2% in the current era (P < 0.0001). Men with preoperative biopsy Gleason 6 disease decreased from the early to the current era (P < 0.0001), while men with preoperative biopsy Gleason ≥ 8 showed the opposite trend, increasing from the early to the current era (P = 0.0002). From the early to the current era, the proportion of patients with National Comprehensive Cancer Network (NCCN) low risk prostate cancer decreased, while those with NCCN intermediate and high-risk disease increased. The proportion of pathologic T3 disease increased from 15.5% in the early to 30.6% in the current era (P < 0.0001). On the other hand, the proportion of pathologic T2/+ SMS (surgical margin status) decreased from 6.6% in the early era to 3.1% in the current era (P = 0.0002).
We have demonstrated a reverse stage migration in men undergoing robotic prostatectomy. Despite the increasing proportion of men with extra-capsular disease undergoing RALP, the surgical margin status has remained similar. This could reflect both the changing dynamics of the population opting for surgery as well as the learning curve of the surgeons.
Indian Journal of Urology 10/2014; 30(4):378-82. DOI:10.4103/0970-1591.142054
[Show abstract][Hide abstract] ABSTRACT: With more than 60% of radical prostatectomies being performed robotically, robotic-assisted laparoscopic prostatectomy (RALP) has largely replaced the open and laparoscopic approaches and has become the standard of care surgical treatment option for localized prostate cancer in the United States. Accomplishing negative surgical margins while preserving functional outcomes of sexual function and continence play a significant role in determining the success of surgical intervention, particularly since the advent of nerve-sparing (NS) robotic prostatectomy. Recent evidence suggests that NS surgery improves continence in addition to sexual function. In this review, we describe the neuroanatomical concepts and recent developments in the NS technique of RALP with a view to improving the "trifecta" outcomes.
Indian Journal of Urology 10/2014; 30(4):399-409. DOI:10.4103/0970-1591.142064
[Show abstract][Hide abstract] ABSTRACT: Background
Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment.
To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value.
Design, setting, and participants
We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices.
Outcome measurements and statistical analysis
The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set.
Results and limitations
We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons.
We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care.
Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer.
European Urology 09/2014; 67(3). DOI:10.1016/j.eururo.2014.08.075 · 12.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
To assess the ability of MPM to visualize, differentiate and track periprostatic nerves in an in vivo rat model, mimicking real-time imaging in humans during RP.To investigate the tissue toxicity and the reproducibility of in vivo MPM on prostatic glands in the rat after imaging and final histological correlation study.Patients and methodsIn vivo prostatic rat imaging was carried out using a custom-built bench-top MPM system generating real-time 3D histologic images, after performing survival surgery consisting of mini-laparotomies under xylazine/ketamine anesthesia exteriorizing the right prostatic lobe.The acquisition time and the depth of anesthesia were adjusted for collecting multiple images in order to track the periprostatic nerves in real-time.The rats were then monitored for 15 days before undergoing a new set of imaging under similar settings.After sacrificing the rats, their prostates were submitted for routine histology and correlation studies.ResultsIn vivo MPM images distinguished periprostatic nerves within the capsule and the prostatic glands from fresh unprocessed prostatic tissue without the use of exogenous contrast agents nor biopsy sampleReal time nerve tracking outlining the prostate was feasible and acquisition was not disturbed by motion artifactsNo serious adverse event was reported during rat monitoring; no tissue damage due to laser was seen on the imaged lobe compared to the contralateral lobe (control) allowing comparison of their corresponding histology.Conclusions
For the first time, we have demonstrated that in vivo tracking of periprostatic nerves using MPM is feasible in rat models.Development of a multiphoton endoscope for intraoperative use in humans is currently in progress and must be assessed.
BJU International 08/2014; DOI:10.1111/bju.12903 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To compare the frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutation in prostate cancer in African American and Caucasian men. Experimental design: Dominant tumor nodules from radical prostatectomy specimens of 105 African American men (AAM) were compared to 113 dominant nodules from Caucasian men (CaM). Clinical and pathologic characteristics of the two groups were similar. SPINK1 overexpression was evaluated by immunohistochemistry, ERG rearrangement and PTEN deletion by FISH, and SPOP mutation by Sanger sequencing. Results: ERG rearrangement was identified in 48/113 tumors (42.5%) in CaM and 29/105 tumors (27.6%) in AAM (p=0.024). PTEN deletion was seen in 19/96 tumors (19.8%) in CaM and 7/101 tumors (6.9%) in AAM (p=0.011). SPINK1 overexpression was present in 9/110 tumors (8.2%) in CaM and 25/105 tumors (23.4%) in AAM (p=0.002). SPOP mutation was identified in 8/78 (10.3%) tumors in CaM and 4/88 (4.5%) tumors in AAM (p=0.230). When adjusted for age, BMI, Gleason score, and pathologic stage, ERG rearrangement and SPINK1 overexpression remain significantly different (p=0.018 and p=0.008, respectively), and differences in PTEN deletion and SPOP mutation approach significance (p=0.061 and p=0.087, respectively). Conclusions: Significant molecular differences exist between prostate cancers in AAM and CaM. SPINK1 overexpression, an alteration associated with more aggressive prostate cancers, was more frequent in AAM, while ERG rearrangement and PTEN deletion were less frequent in this cohort. Further investigation is warranted to determine if these molecular differences explain some of the disparity in incidence and mortality between these two ethnic groups.
Clinical Cancer Research 07/2014; 20(18). DOI:10.1158/1078-0432.CCR-13-2265 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We characterize the diagnostic performance of a multiphoton GRIN endoscope using human prostate samples obtained from radical prostatectomy surgery. Ex vivo images of benign and tumor areas and images of peri-prostatic tissue are shown.
[Show abstract][Hide abstract] ABSTRACT: To analyze the learning curve for cancer control from an initial 250 cases (Group I) and subsequent 250 cases (Group II) of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by a single surgeon. Five hundred consecutive patients with clinically localized prostate cancer received RALP and were evaluated. Surgical parameters and perioperative complications were compared between the groups. Positive surgical margin (PSM) and biochemical recurrence (BCR) were assessed as cancer control outcomes. Patients in Group II had significantly more advanced prostate cancer than those in Group I (22.2% vs 14.2%, respectively, with Gleason score 8-10, 0P= 0.033; 12.8% vs 5.6%, respectively, with clinical stage T3, P= 0.017). The incidence of PSM in pT3 was decreased significantly from 49% in Group I to 32.6% in Group II. A meaningful trend was noted for a decreasing PSM rate with each consecutive group of 50 cases, including pT3 and high-risk patients. Neurovascular bundle (NVB) preservation was significantly influenced by the PSM in high-risk patients (84.1% in the preservation group vs 43.9% in the nonpreservation group). The 3-year, 5-year, and 7-year BCR-free survival rates were 79.2%, 75.3%, and 70.2%, respectively. In conclusion, the incidence of PSM in pT3 was decreased significantly after 250 cases. There was a trend in the surgical learning curve for decreasing PSM with each group of 50 cases. NVB preservation during RALP for the high-risk group is not suggested due to increasing PSM.
Asian Journal of Andrology 05/2014; 16(5). DOI:10.4103/1008-682X.128515 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown.
To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material.
720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features.
Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P < .01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P < .01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes.
SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.
Neoplasia (New York, N.Y.) 04/2014; 16(1):14-20. DOI:10.1016/j.juro.2014.02.1223 · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, while mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination (HR) through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small molecule inhibitors of PARP1. These effects reflected a post-transcriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCA-ness" in sporadic cancers.
Cancer Research 01/2014; 74(6). DOI:10.1158/0008-5472.CAN-13-3159 · 9.28 Impact Factor