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Sylvan C Baca,
Davide Prandi,
Michael S Lawrence,
Juan Miguel Mosquera,
Alessandro Romanel,
Yotam Drier,
Kyung Park,
Naoki Kitabayashi,
Theresa Y Macdonald,
Mahmoud Ghandi, [......],
Michael F Berger,
Stacey B Gabriel,
Todd R Golub,
Matthew Meyerson,
Eric S Lander,
Olivier Elemento,
Gad Getz,
Francesca Demichelis,
Mark A Rubin,
Levi A Garraway
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ABSTRACT: The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
Cell 04/2013; 153(3):666-77. · 32.40 Impact Factor
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European urology 10/2012; 62(4):731-2. · 7.67 Impact Factor
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Ashutosh Tewari,
Wesley Ludwig,
Atsushi Takenaka,
Abhishek Srivastava,
Sameer Chopra,
Anthony Pham,
Prasanna Sooriakumaran,
Matthieu Durand,
Bilal Chughtai,
Siobhan Gruschow,
Alexandra Peyser,
Niyati Harneja,
Robert Leung,
Richard Lee,
Michael Herman,
Brian Robinson,
Maria Shevchuk
European urology 09/2012; · 7.67 Impact Factor
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Abhishek Srivastava,
Sameer Chopra,
Anthony Pham,
Prasanna Sooriakumaran,
Matthieu Durand,
Bilal Chughtai,
Siobhan Gruschow,
Alexandra Peyser,
Niyati Harneja,
Robert Leung,
Richard Lee,
Michael Herman,
Brian Robinson,
Maria Shevchuk, Ashutosh Tewari
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ABSTRACT: BACKGROUND: The impact of nerve sparing (NS) on urinary continence recovery after robot-assisted laparoscopic radical prostatectomy (RALP) has yet to be defined. OBJECTIVE: To evaluate the effect of a risk-stratified grade of NS technique on early return of urinary continence. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from 1546 patients who underwent RALP by a single surgeon at a tertiary care center from December 2008 to October 2011. Patients were categorized preoperatively by a risk-stratified approach into risk grades 1-4, with risk grade 1 patients more likely to receive NS grade 1 or complete hammock preservation. This categorization was also conducted for risk grades 2-4, with grade 4 patients receiving a non-NS procedure. INTERVENTION: Risk-stratified grading of NS RALP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate and multivariate analysis identified predictors of early return of urinary continence, defined as no pad use at ≤12 wk postoperatively. RESULTS AND LIMITATIONS: Early return of continence was achieved by 791 of 1417 men (55.8%); of those, 199 of 277 (71.8%) were in NS grade 1, 440 of 805 (54.7%) were in NS grade 2, 132 of 289 (45.7%) were in NS grade 3, and 20 of 46 (43.5%) were in NS grade 4 (p<0.001). On multivariate analysis, better NS grade was a significant independent predictor of early return of urinary continence when NS grade 1 was the reference variable compared with NS grade 2 (p<0.001; odds ratio [OR]: 0.46), NS grade 3 (p<0.001; OR: 0.35), and NS grade 4 (p=0.001; OR: 0.29). Lower preoperative International Prostate Symptom Score (p=0.001; OR: 0.97) and higher preoperative Sexual Health Inventory for Men score (p=0.002; OR: 1.03) were indicative of early return of urinary continence. Positive surgical margin rates were 7.2% (20 of 277) of grade 1 cases, 7.6% (61 of 805) of grade 2 cases, 7.6% (22 of 289) of grade 3 cases, and 17.4% (8 of 46) of grade 4 cases (p=0.111). Extraprostatic extension occurred in 6.1% (17 of 277) of NS grade 1 cases, 17.5% (141 of 805) of NS grade 2 cases, 42.5% (123 of 289) of NS grade 3 cases, and 63% (29 of 46) of NS grade 4 cases (p<0.001). Some limitations of the study are that the study was not randomized, grading of NS was subjective, and possible selection bias existed. CONCLUSIONS: Our study reports a correlation between risk-stratified grade of NS technique and early return of urinary continence as patients with a lower grade (higher degree) of NS achieved an early return of urinary continence without compromising oncologic safety.
European urology 07/2012; · 7.67 Impact Factor
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ABSTRACT: Much of the progress in improving potency outcomes after radical prostatectomy has been achieved due to a better visualization of the neurovascular bundle responsible for erectile function. We review the current literature evaluating the existing imaging modalities to image the neurovascular bundle around the prostate pre, intra, and postoperatively, thereby enabling development of surgical techniques for better preservation of nerve function.
Imaging modalities like multiphoton microscopy, optical coherence tomography, Coherent anti-Raman spectroscopy, exogenous fluoroscopy using prostate-specific membrane antigen, and so on have led to a better appreciation of the neurovascular bundle, thus encouraging novel techniques in nerve preservation during radical prostatectomy.
In an age of heightened patient expectations and increasing life expectancy, better visualization of the neurovascular bundle around the prostate using novel imaging modalities may provide breakthroughs in improving potency outcomes after radical prostatectomy.
Current opinion in urology 03/2012; 22(2):88-96. · 2.50 Impact Factor
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ABSTRACT: Asymptomatic concomitant vesical calculi are an occasional finding on routine radiologic staging and evaluation of patients with early prostate cancer. We report the first case of single-stage robotic cystolithotomy for multiple bladder stones in a 64-year-old man undergoing robotic-assisted radical prostatectomy, and discuss the approaches available for ensuring complete stone clearance in this unique setting. We show that concomitant bladder stone extraction during robotic-assisted radical prostatectomy is feasible and does not add significantly to operative time. This technique avoids the need to undergo additional general anesthetic procedures with potential complications such as bleeding, urethral stricture formation, and bladder perforation, prior to the prostatectomy.
Indian Journal of Urology 01/2012; 28(1):99-101.
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ABSTRACT: Although oncologic results remain the main outcome assessment for radical prostatectomy (RP), there is a need to include both urinary continence and potency recovery in the assessment of success for this procedure. Unfortunately, the widely used trifecta system does not weigh these outcomes differently. Moreover, the trifecta system-and even more so, the recently described pentafecta system-is only applicable in preoperatively continent and potent patients who receive bilateral nerve-sparing RP, and thus it is not an appropriate reporting tool for the majority of patients undergoing RP.
Perform a systematic review to evaluate critically the trifecta and pentafecta models and describe a novel system that can be used to report the most relevant intermediate- and long-term outcomes after RP. This system has increased generalizability by being applicable to all patients undergoing RP.
A literature search was performed in March 2011 using the Medline, Embase, and Web of Science databases. The Medline search included only a free-text protocol using the terms radical prostatectomy, trifecta, and pentafecta across the Title and Abstract fields of the records. Subsequently, the following limits were used: humans, gender (male), and language (English). The searches of the Embase and Web of Science databases used the same free-text protocol and the same keywords, applying no limits.
Eleven original articles reported trifecta outcomes, and only one original article used the pentafecta model. These systems were correctly applied in only 28-62% of treated patients. A mean of 57% (range: 20-83%) of patients achieved continence and potency without prostate-specific antigen failure after RP. All the original articles were surgical series (level 4 evidence). The new proposed system categorizes the three outcomes using the letter S for biochemical disease-free survival, the letter C for urinary continence, and the letter P for potency recovery. This SCP system can be applied to all patients who undergo RP and is thus analogous to the use of the TNM system for classifying disease stage. Moreover, the SCP system allows us to distinguish four different clinical scenarios: (1) oncologic and functional success, (2) oncologic success and functional failure, (3) oncologic failure and functional success, and (4) oncologic and functional failure.
The proposed novel SCP system offers the opportunity to appropriately classify all patients who undergo RP according to the oncologic and functional outcomes of relevance to them on an individual basis. We contend that this system's greater generalizability may make it more useful than the currently used trifecta and pentafecta systems, though its validation remains to be performed.
European urology 12/2011; 61(3):541-8. · 7.67 Impact Factor
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ABSTRACT: • To investigate orgasmic outcomes in patients undergoing robotic-assisted laparoscopic radical prostatectomy (RALP) and the effects of age and nerve sparing on these outcomes.
• Between January 2005 and June 2007, 708 patients underwent RALP at our institution. • We analysed postoperative potency and orgasmic outcomes in the 408 men, of the 708, who were potent, able to achieve orgasm preoperatively and available for follow-up.
• Of men aged ≤60 years, 88.4% (198/224) were able to achieve orgasm postoperatively in comparison to 82.6% (152/184) of older men (P < 0.001). • Of patients who received bilateral nerve sparing (BNS) during surgery, 273/301 (90.7%) were able to achieve orgasm postoperatively compared with 46/56 (82.1%) patients who received unilateral nerve sparing and 31/51 (60.8%) men who received non-nerve-sparing surgery (P < 0.001). • In men ≤60 years who also underwent BNS, decreased sensation of orgasm was present in 3.2% of men, and postoperative orgasmic rates were significantly better than men ≤60 years who underwent unilateral or no nerve sparing (92.9% vs 83.3% vs 65.4%, respectively; P < 0.001). • Potency rates were also significantly higher in men ≤60 years and in those who underwent BNS.
• Age and nerve sparing influence recovery of orgasm and erectile function after RALP. • Men ≤60 years old and those who undergo BNS are most likely to maintain normal sexual function.
BJU International 08/2011; 109(4):596-602. · 2.84 Impact Factor
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ABSTRACT: To describe two predictive models that predict for prostate cancer on biopsy derived from a large screening population. There are no published predictive models that predict prostate cancer in a screened population.
The patients from the Tyrol screening study of known age, total prostate-specific antigen (PSA) level, digital rectal examination (DRE) findings, prostate volume, and percentage of free PSA, and who underwent an initial prostate biopsy from January 1992 to June 2004 were included (n = 2271). Multivariate logistic regression models were used to develop the biopsy positivity predictive models: nomogram 1, age, DRE, and total PSA; and nomogram 2, age, DRE, total PSA, and percentage of free PSA. The predictive accuracy of the models was assessed in terms of discrimination and calibration. External validation of the nomograms was performed using a urologically referred population of patients who underwent prostate biopsy (n = 599).
Both nomograms were well-calibrated internally and externally and discriminated well between patients with positive and negative biopsy findings for both the European and U.S. cohorts (model 2 better than model 1).
Our nomogram with age, total PSA, and DRE had good predictive ability to differentiate between screened patients with cancer on the initial prostate biopsy and those without. Adding the percentage of free PSA improves this predictive power further. These models might aid in clinical decision making regarding the need for biopsy in both European and U.S. populations.
Urology 08/2011; 78(4):924-9. · 2.43 Impact Factor
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Harveer Dev,
David Rickman,
Prasanna Sooriakumaran,
Abhishek Srivastava,
Sonal Grover,
Robert Leung,
Robert Kim,
Naoki Kitabayashi,
Raquel Esqueva,
Kyung Park,
Jessica Padilla,
Mark Rubin, Ashutosh Tewari
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ABSTRACT: RNA quality is believed to decrease with ischaemia time, and therefore open radical prostatectomy has been advantageous in allowing the retrieval of the prostate immediately after its devascularization. In contrast, robotic-assisted laparoscopic radical prostatectomies (RALP) require the completion of several operative steps before the devascularized prostate can be extirpated, casting doubt on the validity of this technique as a source for obtaining prostatic tissue. We seek to establish the integrity of our biobanking process by measuring the RNA quality of specimens derived from robotic-assisted laparoscopic radical prostatectomy.
We describe our biobanking process and report the RNA quality of prostate specimens using advanced electrophoretic techniques (RNA Integrity Numbers, RIN). Using multivariate regression analysis we consider the impact of various clinicopathological correlates on RNA integrity.
Our biobanking process has been used to acquire 1709 prostates, and allows us to retain approximately 40% of the prostate specimen, without compromising the histopathological evaluation of patients. We collected 186 samples from 142 biobanked prostates, and demonstrated a mean RIN of 7.25 (standard deviation 1.64) in 139 non-stromal samples, 73% of which had a RIN ≥ 7. Multivariate regression analysis revealed cell type--stromal/epithelial and benign/malignant--and prostate volume to be significant predictors of RIN, with unstandardized coefficients of 0.867(p = 0.001), 1.738(p < 0.001) and -0.690(p = 0.009) respectively. A mean warm ischaemia time of 120 min (standard deviation 30 min) was recorded, but multivariate regression analysis did not demonstrate a relationship with RIN within the timeframe of the RALP procedure.
We demonstrate the robustness of our protocol--representing the concerted efforts of dedicated urology and pathology departments--in generating RNA of sufficient concentration and quality, without compromising the histopathological evaluation and diagnosis of patients. The ischaemia time associated with our prostatectomy technique using a robotic platform does not negatively impact on biobanking for RNA studies.
Journal of Translational Medicine 07/2011; 9:121. · 3.41 Impact Factor
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ABSTRACT: Low-risk prostate cancer patients clinically eligible for active surveillance can also be managed surgically. We evaluated the pathologic outcomes for this cohort that was treated by radical prostatectomy and devised nomograms to predict patients at risk of upgrading and/or upstaging.
Seven hundred and fifty patients treated by radical prostatectomy from Jan 2005 to the present fulfilled conventional active surveillance criteria and formed the study cohort. Preoperative data on standard clinicopathologic parameters were available. The radical prostatectomy specimens were graded and staged, and any upgrading to Gleason sum >6 or upstaging to ≥pT3 ('worsening prognosis') were noted. Multivariable logistic regression models were used to develop predictive nomograms.
Of the 750 patients, 303 (40.4%) patients were either upgraded or upstaged. Multivariable analysis found that preoperative PSA, number of positive cores, and prostate volume were significantly predictive of worsening prognosis and formed the nomogram criteria.
Of patients deemed eligible for active surveillance based on conventional criteria, 40.4% have worse prognostic factors after radical prostatectomy. Current active surveillance criteria may be too relaxed, and the use of nomograms which we have devised, may aid in counseling primary prostate cancer patients considering active surveillance as their therapy of choice.
International Urology and Nephrology 06/2011; 44(2):459-70. · 1.47 Impact Factor
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ABSTRACT: Robotic assisted radical prostatectomy (RARP) is gaining widespread acceptance for the management of localized prostate cancer. However, data regarding patient expectations and satisfaction outcomes after RARP are scarce.
We developed a structured program for preoperative education and evidence-based counseling using a multi-disciplinary team approach and measured its impact on patient satisfaction in a cohort of 377 consecutive patients who underwent RARP at our institution. Responses regarding overall, sexual, and continence satisfaction were assessed.
Fifty percent of our patient cohort replied to the questionnaire assessments. Ninety-three percent of responding patients expressed overall satisfaction after RARP with only 0.5% expressing regret at having had the operation. Biochemical recurrence and lack of continence correlated significantly with low levels of satisfaction, though sexual function was not significantly different among those satisfied and those not. Most patients (97%) valued oncologic outcome as their top priority, with regaining of urinary control being the commonest second priority (60%).
RARP appears to be associated with a high degree of patient satisfaction in a cohort of patients subjected to a structured preoperative education and counseling program. Oncologic outcomes are most important to these patients and have the largest influence on satisfaction scores.
International Urology and Nephrology 06/2011; 43(2):405-15. · 1.47 Impact Factor
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BJU International 05/2011; 107(9):1344-6. · 2.84 Impact Factor
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Michael F. Berger,
Michael S. Lawrence,
Francesca Demichelis,
Yotam Drier,
Kristian Cibulskis,
Andrey Y. Sivachenko,
Andrea Sboner,
Raquel Esgueva,
Dorothee Pflueger,
Carrie Sougnez, [......],
Lynda Chin,
Stacey B. Gabriel,
Mark B. Gerstein,
Todd R. Golub,
Matthew Meyerson, Ashutosh Tewari,
Eric S. Lander,
Gad Getz,
Mark A. Rubin,
Levi A. Garraway
Nature 02/2011; 470(7333):214-220. · 36.28 Impact Factor
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Michael F Berger,
Michael S Lawrence,
Francesca Demichelis,
Yotam Drier,
Kristian Cibulskis,
Andrey Y Sivachenko,
Andrea Sboner,
Raquel Esgueva,
Dorothee Pflueger,
Carrie Sougnez, [......],
Lynda Chin,
Stacey B Gabriel,
Mark B Gerstein,
Todd R Golub,
Matthew Meyerson, Ashutosh Tewari,
Eric S Lander,
Gad Getz,
Mark A Rubin,
Levi A Garraway
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ABSTRACT: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.
Nature 02/2011; 470(7333):214-20. · 36.28 Impact Factor
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ABSTRACT: There is a paucity of data investigating the relationship between histopathological variables of oncologic importance and prostate volume, and we aimed to investigate this.
2,207 consecutive patients who underwent robotic-assisted radical prostatectomy were studied. Preoperative demographic and both pre- and postoperative histopathological parameters were compared among the small (<40 cm(3)), intermediate (40-70 cm(3)), and large (>70 cm(3)) prostate groups.
Patients with smaller prostates were younger, had slightly lower BMIs, and lower prostate-specific antigen (PSA) levels than those with larger prostates (p < 0.001). They also had worse histopathological criteria (Gleason, core positivity, and maximum percent cancer) on preoperative biopsy and had worse radical specimen Gleason sums (p < 0.001), percent cancer (p < 0.001), and pathological stage (p = 0.016). 11.5% of the men in the small prostate group suffered a positive surgical margin (PSM) compared to 8.3 and 5.6% in the intermediate and large prostate groups, respectively (p = 0.008). Basilar, posterolateral, and multifocal PSMs were commoner in the small prostate group.
Younger men have smaller prostates and worse preoperative histopathological parameters despite lower PSA values. Men with small prostates undergoing robotic-assisted radical prostatectomy have worse final Gleason sums, tumour volume, extraprostatic extension, and PSM rates than those with larger prostates.
Urologia Internationalis 01/2011; 86(2):152-5. · 0.99 Impact Factor
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ABSTRACT: Since the introduction of laparoscopic surgery, the promise of lower postoperative morbidity and improved cosmesis has been achieved. LaparoEndoscopic Single Site (LESS) surgery potentially takes this further. Following the first human urological LESS report in 2007, numerous case series have emerged, as well as comparative studies comparing LESS with standard laparoscopy. Technological developments in instrumentation, access and optics devices are overcoming some of the challenges that are raised when operating through a single site. Further advances in the technique have included the incorporation of robotics (R-LESS), which exploit the ergonomic benefits of ex vivo robotic platforms in an attempt to further improve the implementation of LESS procedures. In the future, urologists may be able to benefit from in vivo micro-robots that will allow the manipulation of tissue from internal repositionable platforms. The use of magnetic anchoring and guidance systems (MAGS) might allow the external manoeuvring of intra-corporeal instruments to reduce clashing and facilitate triangulation. However, the final promise in minimally invasive surgery is natural orifice transluminal endoscopic surgery (NOTES), with its scarless technique. It remains to be seen whether NOTES, LESS, or any of these future developments will prove their clinical utility over standard laparoscopic methods.
BJU International 10/2010; 107(10):1555-9. · 2.84 Impact Factor
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ABSTRACT: Creation of an optimally apposed, tension-free, well-supported vesicourethral anastomosis remains the cornerstone for anastomotic healing after radical prostatectomy. We report the effect of three techniques of bladder neck reconstruction during robot-assisted radical prostatectomy on anastomotic leak, stricture formation, and continence recovery.
Between January 2005 to September 2009, 1900 consecutive patients underwent robotic-assisted laparoscopic prostatectomy (RALP) by a single surgeon. Of these, the first 214 underwent vesicourethral conventional anastomosis (CA); the next 303 men underwent anterior reconstruction (AR) only; and last 1383 men underwent total anatomic restoration (TR). Data elements included patient age, body mass index, preoperative biopsy Gleason score and prostate-specific antigen level, prostate volume, total operative time, console time, time for performing vesicourethral anastomosis, estimated blood loss, tumor stage, and margin status on final pathologic findings. Primary end points were rates of clinically significant anastomotic leaks, bladder neck contractures, and time to return of continence. Chi-square and Fisher exact tests were used for analysis of categoric variables. The Cox proportional hazard model was used for both univariate and multivariate analysis.
Clinically significant anastomotic leakage and bladder neck strictures were significantly fewer in the reconstructed groups (2.3% vs 1.0% vs 0.3% and 3.7% vs 1.3% vs 0.5% in the CA, AR, and TR groups, P < 0.01). Continence rates at 1, 6, 12, 26, and 52 weeks after RALP were also significantly better at all time points with AR and TR compared with CA alone (P < 0.001).
TR of the continence mechanism optimizes vesicourethral anastomosis healing and hastens early continence return after RALP.
Journal of endourology / Endourological Society 10/2010; 24(12):1975-83. · 1.75 Impact Factor
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European urology 09/2010; 58(3):465-6. · 7.67 Impact Factor
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European urology 09/2010; 59(2):222-3. · 7.67 Impact Factor
