Robot-assisted partial prostatectomy for anterior prostate cancer: a step-by-step guide.

OBJECTIVE: To describe a step-by-step guide to robot-assisted anterior partial prostatectomy (RA-APP) for isolated magnetic resonance imaging (MRI)-detected anterior prostate cancer (APC). PATIENTS AND METHODS: After Institutional Review Board approval, over an 8-year period (2008-2015), 17 consenting patients were enrolled in a prospective, single-arm, single-centre, Idea, Development, Evaluation, Assessment and Long-term evaluation of innovative surgery (IDEAL) phase 2a study. The inclusion criteria comprised pre-urethral, low-intermediate risk APC diagnosed by MRI and targeted biopsies. Patient position and port placement were identical to the transperitoneal RA radical prostatectomy procedure. Three steps of dissection were identified in the following order: (i) retrograde apical, after dorsal venous plexus division, transition zone (TZ) enucleation, and distal peripheral zone (PZ) sectioning; (ii) antegrade, at the bladder neck (BN) after anterior BN sectioning, TZ enucleation up to the verumontanum; and (iii) lateral dissections, including anterolateral PZ sectioning without incision of the endopelvic fascia. We report the incidence of perioperative complications. The RA completion of prostatectomy in four cases with cancer recurrence was performed at 0.3, 2.5, 2 and 2 years, respectively. RESULTS: The RA-APP comprised en bloc excision of the anterior part of the prostate comprising of the anterior fibromuscular stroma, BN, prostate adenoma (TZ and median lobe) along with the proximal prostate urethra, PZ apical anterior horns, anterior aspect of the distal (sub-montanal) urethra, and anterior BN. The posterolateral parts of the PZ and distal (sub-montanal) urethra and peri-prostatic tissues were preserved intact. The bladder opening was sutured to the anterior sphincteric urethra wall and PZ lateral edges. The technique was feasible in all cases with no conversion to an open procedure. Perioperative complications were only Clavien-Dindo grade II. RA completion of prostatectomy was feasible in the four cases with cancer recurrence. CONCLUSION: PZ prostate-sparing RA-APP for isolated APC is feasible and safe, and represents an option for highly selected men with APCs as an alternative to other focal ablative therapy.

Localized chromophobe carcinomas treated by nephron-sparing surgery have excellent oncologic outcomes.

OBJECTIVE: To evaluate the oncologic outcomes of nephron-sparing surgery (NSS) for localized chromophobe renal cell carcinoma (cRCC). MATERIAL AND METHODS: We performed a multicenter international study involving the French Network for Research on Kidney Cancer (UroCCR) and 5 international teams. Data from 808 patients treated with NSS between 2004 and 2014 for non-clear cell RCCs were analyzed. RESULTS: We included 234 patients with cRCC. There were 123 (52.6%) females. Median age was 61 (23-88) years. Median tumor size was 3 (1-11)cm. A positive surgical margin was identified in 14 specimens (6%). Pathologic stages were T1, T2, and T3a in 202 (86.3%), 9 (3.8%), and 23 (9.8%) cases, respectively. After a mean follow-up of 46.6 ± 36 months, 2 (0.8%) patients experienced a local recurrence. No patient had metastatic progression, and no patient died from cancer. Three-years estimated cancer-free survival and cancer-specific survival were 99.1% and 100%, respectively. CONCLUSION: Oncological results of NSS for localized cRCC are excellent. In this series, only 2 patients had a local recurrence, and no patient had metastatic progression or died from cancer.

Partial Prostatectomy for Anterior Cancer: Short-term Oncologic and Functional Outcomes.

BACKGROUND: Focal ablative therapy may be a suboptimal option for anterior prostate cancers (APCs) reaching the prostate apex due to concerns for thermal injury to the external sphincter. OBJECTIVE: To explore the technical feasibility of anterior partial prostatectomy (APP) for isolated APCs detected by magnetic resonance imaging (MRI), and to report short-term oncologic and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: Following institutional review board approval, over an 8-yr period (2008-2015) 17 consenting patients were enrolled in a prospective single-arm single-center Innovation, Development, Exploration, Assessment, Long-term (IDEAL) phase 2a study. Inclusion criteria comprised preurethral, low- to intermediate-risk APC diagnosed by MRI, and targeted biopsies. Robotic template APP was performed; posterolateral aspect of the submontanal urethra, peripheral zone, and periprostatic tissues were preserved intact. Median follow-up was 30 mo (interquartile range [IQR]: 25-70). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We noted the incidence of perioperative complications and examined reports of pathology, prostate-specific antigen (PSA), imaging, biopsies, and questionnaires. RESULTS AND LIMITATIONS: Preoperatively, median PSA was 9.8 ng/ml, Gleason score was 6-7 (3 + 4), and cancer volume was 3.7cm3 (IQR: 1.7-4.6). The technique was feasible in all cases. Perioperative complications included anastomotic leak (12%; G2), urinary tract infection (6%; G2), and transient intestinal ileus in one case (6%; G2). At 3 mo, continence and potency rates were 100% and 83%, respectively. Median nadir PSA was 0.4 ng/ml (IQR: 0.3-0.7). All margins and posterolateral margins rates were 55% and 35%, respectively. APC recurrence-free survival at 2 yr was 0.86 (95% confidence interval [CI], 0.55-0.96). Four patients (24%) who recurred underwent an uncomplicated completion of robot-assisted prostatectomy. Regarding limitations, CIs are quite wide for reported outcomes. CONCLUSIONS: Robotic partial prostatectomy for isolated APC is feasible with good functional results. While promising, much more research is needed to verify our initial outcomes and appropriately position APP in the treatment paradigms for APC. PATIENT SUMMARY: We explored a novel approach for partial prostatic surgical ablation for prostate cancer located in the anterior part of the prostate as an alternative to other focal ablative techniques.

What do we know about treatment sequencing of abiraterone, enzalutamide, and chemotherapy in metastatic castration-resistant prostate cancer?

PURPOSE: To present a systematic review of the different therapeutic sequences in metastatic castration-resistant prostate cancer (mCRPC). METHODS: Evidence acquisition on therapeutic sequences in mCRPC was performed by a MEDLINE search using combination of the following key words: "prostate cancer," "metastatic," "castration resistant," "enzalutamide," "abiraterone," "treatment sequencing," "cabazitaxel," "docetaxel." A total of 17 studies were included for analysis. RESULTS: Different sequences have been reported for the treatment of mCRPC: docetaxel after abiraterone, cabazitaxel after docetaxel and abiraterone, abiraterone after cabazitaxel and docetaxel, abiraterone after docetaxel and enzalutamide, and enzalutamide after docetaxel and abiraterone. There are arguments from the preclinical observations suggesting a cross-resistance between docetaxel and abiraterone, and between abiraterone and enzalutamide in mCRPC. Despite limitations, several retrospective clinical reports support these data. CONCLUSION: No study of high level of evidence is available to support any recommendation on sequential treatment for mCRPC. There are only clues that prospective clinical studies need to confirm.

The subclassification of papillary renal cell carcinoma does not affect oncological outcomes after nephron sparing surgery.

OBJECTIVES: To evaluate the oncological outcomes of papillary renal cell carcinoma (pRCC) following nephron sparing surgery (NSS) and to determine whether the subclassification type of pRCC could be a prognostic factor for recurrence, progression, and specific death. MATERIALS AND METHODS: An international multicentre retrospective study involving 19 institutions and the French network for research on kidney cancer was conducted after IRB approval. We analyzed data of all patients with pRCC who were treated by NSS between 2004 and 2014. RESULTS: We included 486 patients. Tumors were type 1 pRCC in 369 (76 %) cases and type 2 pRCC in 117 (24 %) cases. After a mean follow-up of 35 (1-120) months, 8 (1.6 %) patients experienced a local recurrence, 12 (1.5 %) had a metastatic progression, 24 (4.9 %) died, and 7 (1.4 %) died from cancer. Patients with type I pRCC had more grade II (66.3 vs. 46.1 %; p < 0.001) and less grade III (20 vs. 41 %; p < 0.001) tumors. Three-year estimated cancer-free survival (CFS) rate for type 1 pRCC was 96.5 % and for type 2 pRCC was 95.1 % (p = 0.894), respectively. Three-year estimated cancer-specific survival rate for type 1 pRCC was 98.4 % and for type 2 pRCC was 97.3 % (p = 0.947), respectively. Tumor stage superior to pT1 was the only prognostic factor for CFS (HR 3.5; p = 0.03). CONCLUSION: Histological subtyping of pRCC has no impact on oncologic outcomes after nephron sparing surgery. In this selected population of pRCC tumors, we found that tumor stage is the only prognostic factor for cancer-free survival.

Management of Node Only Recurrence after Primary Local Treatment for Prostate Cancer: A Systematic Review of the Literature.

PURPOSE: We analyzed all available studies assessing the management of node only recurrence after primary local treatment of prostate cancer. MATERIALS AND METHODS: We systematically reviewed the literature in January 2015 using the PubMed, Web of Sciences and Embase databases according to PRISMA guidelines. Studies exclusively reporting visceral or bone metastatic disease were excluded from analysis. Eight radiotherapy and 12 salvage lymph node dissection series were included in our qualitative study. RESULTS: All 248 radiotherapy and 480 salvage lymph node dissection studies were single arm case series including a total of 728 patients. Choline positron emission tomography/computerized tomography was the reference imaging technique for nodal recurrence detection. Globally 50% of patients remained disease-free after short-term followup. Nevertheless, approximately two-thirds of patients received adjuvant hormone therapy, leading an overestimation of prostate specific antigen-free survival rates obtained after salvage treatment. Combining radiotherapy with salvage lymph node dissection may improve oncologic control in the treated region without improving the outfield relapse risk or the prostate specific antigen response. Great heterogeneity among series in adjuvant treatments, endpoints, progression definitions and study populations made it difficult to assess the precise impact of salvage treatment on the prostate specific antigen response and compare outcomes between radiotherapy and salvage lymph node dissection series. Toxicity after radiotherapy or salvage lymph node dissection was acceptable without frequent high grade complications. The benefit of early hormone therapy as the only salvage treatment remains unknown. CONCLUSIONS: Although a high level of evidence is currently missing to draw any strong conclusion, published clinical series show that in select patients salvage treatment directed to nodal recurrence could lead to good oncologic outcomes. Although the optimal timing of androgen deprivation therapy in this setting is still unknown, such an approach could delay time to systemic treatment with an acceptable safety profile. Future prospective trials are awaited to better clarify this potential impact on well-defined endpoints.

Robot-assisted laparoscopic approach for artificial urinary sphincter implantation in 11 women with urinary stress incontinence: surgical technique and initial experience.

BACKGROUND: Artificial urinary sphincter (AUS) implantation is recommended for women suffering urinary stress incontinence. Robot-assisted laparoscopy allows improved dexterity and visibility compared to traditional laparoscopy, potentially providing significant advantages for deep pelvic surgery. OBJECTIVE: To report our surgical technique and initial experience in transperitoneal robot-assisted laparoscopic AUS implantation in women with urinary stress incontinence. DESIGN, SETTING, AND PARTICIPANTS: Eleven eligible patients with AUS implantation or revision using robot-assisted laparoscopy for urinary stress incontinence were included between January 2012 and February 2014 at Department of Urology, Lille University Hospital. SURGICAL TECHNIQUE: Procedures were performed with the assistance of a four-arm da Vinci robot. The urethrovaginal space was dissected after transperitoneal access to the Retzius space. An 11-mm port placed in the right iliac fossa allowed introduction of the AUS device. The cuff and balloon tubes were externalised via a 5-mm suprapubic incision. The peritoneum was finally sutured. MEASUREMENTS: Clinical data were prospectively collected before, during, and after the procedure. Results were classified as complete continence (no leakage and no pad usage), social continence (leakage and/or pad usage with no impact on social life), or failure (leakage and/or pad usage impacting social life). RESULTS AND LIMITATIONS: After mean follow-up of 17.6 mo (interquartile range 10.8-26 mo), eight patients (72.7%) had a successful AUS implantation, of whom seven (87.5%) reported complete continence and one had social continence. Two vaginal injuries and two bladder injuries occurred intraoperatively. Two patients experienced early minor postoperative complications and two had a major postoperative complication. CONCLUSIONS: Robot-assisted laparoscopic AUS implantation is a feasible procedure. Further studies will better assess the place of robot-assisted laparoscopy in AUS implantation. PATIENT SUMMARY: We investigated the treatment of 11 patients with stress urinary incontinence using robot-assisted implantation of an artificial urinary sphincter (AUS). The results show that the procedure is feasible procedure, and future studies will to help assess the place of robot-assisted laparoscopy in AUS implantation.

Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models.

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies.

A novel robotic system for single-port urologic surgery: first clinical investigation.

BACKGROUND: The idea of performing a laparoscopic procedure through a single abdominal incision was conceived with the aim of expediting postoperative recovery. OBJECTIVE: To determine the clinical feasibility and safety of single-port urologic procedures by using a novel robotic surgical system. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective institutional review board-approved, Innovation, Development, Exploration, Assessment, Long-term Study (IDEAL) phase 1 study. After enrollment, patients underwent a major urologic robotic single-port procedure over a 3-wk period in July 2010. The patients were followed for 3 yr postoperatively. INTERVENTION: Different types of urologic surgeries were performed using the da Vinci SP Surgical System. This system is intended to provide the same core clinical capabilities as the existing multiport da Vinci system, except that three articulating endoscopic instruments and an articulating endoscopic camera are inserted into the patient through a single robotic port. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcomes were the technical feasibility of the procedures (as measured by the rate of conversions) and the safety of the procedures (as measured by the incidence of perioperative complications). Secondary end points consisted of evaluating other key surgical perioperative outcomes as well as midterm functional and oncologic outcomes. RESULTS AND LIMITATIONS: A total of 19 patients were enrolled in the study. Eleven of them underwent radical prostatectomy; eight subjects underwent nephrectomy procedures (partial nephrectomy, four; radical nephrectomy, two; and simple nephrectomy, two). There were no conversions to alternative surgical approaches. Overall, two major (Clavien grade 3b) postoperative complications were observed in the radical prostatectomy group and none in the nephrectomy group. At 1-yr follow-up, one radical prostatectomy patient experienced biochemical recurrence, which was successfully treated with salvage radiation therapy. The median warm ischemia time for three of the partial nephrectomies was 38 min. At 3-yr follow-up all patients presented a preserved renal function; none had tumor recurrence. Study limitations include the small sample and the lack of a control group. CONCLUSIONS: We describe the first clinical application of a novel robotic platform specifically designed for single-port urologic surgery. Major urologic procedures were successfully completed without conversions. Further assessment is warranted to corroborate these promising findings. PATIENT SUMMARY: A novel purpose-built robotic system enables surgeons to perform safely and effectively a variety of major urologic procedures through a single small abdominal incision. TRIAL REGISTRATION: The study was registered on www.ClinicalTrials.gov (NCT02136121).

Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1.

AIMS: Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression. METHODS AND RESULTS: The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal, with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10-72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases. CONCLUSION: CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour.

Oncologic outcomes and survival in pT0 tumors after radical cystectomy in patients without neoadjuvant chemotherapy: results from a large multicentre collaborative study.

PURPOSE: To assess the postsurgical survival of patients with urothelial carcinoma of the bladder with pT0 tumor at pathologic examination of cystectomy specimens. METHODS: A multi-institutional, retrospective database was analyzed with data from 4758 radical cystectomy (RC) patients who underwent RC without neoadjuvant chemotherapy and who were diagnosed with pT0 on the basis of the pathologic specimen. Survival curves were estimated. A multivariate Cox model was used to evaluate the association between prognosis factors and disease recurrence or survival. RESULTS: Overall, 258 patients (5.4%) were included in the study. The median age was 64 years. At last resection, 171 tumors were invasive (at least pT2), and 87 were not. Median follow-up was 51 months. At multivariate analysis, initial location of the tumor and absence of lymphadenectomy were associated with tumor recurrence (P = 0.03 and P = 0.005, respectively) and specific mortality (P = 0.005 and 0.001, respectively). The main limitation of the study is its retrospective design, which is due to the rarity of this situation. Cancer-specific and recurrence-free survival rates were 89 and 85%, respectively, at 5 years and 82 and 80%, respectively, at 10 years. CONCLUSIONS: Despite acceptable oncological outcomes, patients with a pT0 tumor at the time of RC are still at risk of recurrence and progression and should not be considered to be entirely cured. In this population, stringent follow-up according to current recommendations should be effective.

Targeting monoamine oxidase A in advanced prostate cancer.

PURPOSE: Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. METHODS: Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction. RESULTS: Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. CONCLUSION: Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa.

Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells.

BACKGROUND: Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA). METHODS: We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction. RESULTS: The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 - 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated >or= 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2. CONCLUSION: Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.