Three-dimensional ultrastructural and anatomical analysis of prostatic neuroendocrine cells in mice.

BACKGROUND: A few studies have examined the ultrastructure of prostatic neuroendocrine cells (NECs), and no study has focused on their ultrastructure in three dimensions. In this study, three-dimensional ultrastructural analysis of mouse prostatic NECs was performed to clarify their anatomical characteristics. METHODS: Three 13-week-old male C57BL/6 mice were deeply anesthetized, perfused with physiological saline and 2% paraformaldehyde, and then placed in 2.5% glutaraldehyde in 0.1 M cacodylate (pH 7.3) buffer for electron microscopy. After perfusion, the lower urinary tract, which included the bladder, prostate, coagulation gland, seminal vesicle, upper vas deferens, and urethra, was removed, and the specimen was cut into small cubes and subjected to postfixation and en bloc staining. Three-dimensional ultrastructural analysis was performed on NECs, the surrounding cells, tissues, and nerves using focused ion beam/scanning electron microscope tomography. RESULTS: Twenty-seven serial sections were used in the present study, and 32 mouse prostatic NECs were analyzed. Morphologically, the NECs could be classified into three types: flask, flat, and closed. Closed-shaped NECs were always adjacent to flask-shaped cells. The flask-shaped and flat NECs were in direct contact with the ductal lumen and always had microvilli at their contact points. Many of the NECs had accompanying nerves, some of which terminated on the surface in contact with the NEC. CONCLUSIONS: Three-dimensional ultrastructural analysis of mouse prostatic NECs was performed. These cells can be classified into three types based on shape. Novel findings include the presence of microvilli at their points of contact with the ductal lumen and the presence of accompanying nerves.

Comparing Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen-Positron Emission Tomography for Prediction of Extraprostatic Extension of Prostate Cancer and Surgical Guidance: A Prospective Nonrandomized Clinical Trial.

PURPOSE: Survivors of surgically managed prostate cancer may experience urinary incontinence and erectile dysfunction. Our aim was to determine if 68Ga-prostate-specific membrane antigen-11 positron emission tomography CT (PSMA-PET) in addition to multiparametric (mp) MRI scans improved surgical decision-making for nonnerve-sparing or nerve-sparing approach. MATERIALS AND METHODS: We prospectively enrolled 50 patients at risk for extraprostatic extension (EPE) who were scheduled for prostatectomy. After mpMRI and PSMA-PET images were read for EPE prediction, surgeons prospectively answered questionnaires based on mpMRI and PSMA-PET scans on the decision for nerve-sparing or nonnerve-sparing approach. Final whole-mount pathology was the reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic curves were calculated and McNemar's test was used to compare imaging modalities. RESULTS: The median age and PSA were 61.5 years and 7.0 ng/dL. The sensitivity for EPE along the posterior neurovascular bundle was higher for PSMA-PET than mpMRI (86% vs 57%, P = .03). For MRI, the specificity, positive predictive value, negative predictive value, and area under the curve for the receiver operating characteristic curves were 77%, 40%, 87%, and 0.67, and for PSMA-PET were 73%, 46%, 95%, and 0.80. PSMA-PET and mpMRI reads differed on 27 nerve bundles, with PSMA-PET being correct in 20 cases and MRI being correct in 7 cases. Surgeons predicted correct nerve-sparing approach 74% of the time with PSMA-PET scan in addition to mpMRI compared to 65% with mpMRI alone (P = .01). CONCLUSIONS: PSMA-PET scan was more sensitive than mpMRI for EPE along the neurovascular bundles and improved surgical decisions for nerve-sparing approach. Further study of PSMA-PET for surgical guidance is warranted in the unfavorable intermediate-risk or worse populations. CLINICALTRIALS.GOV IDENTIFIER: NCT04936334.

Can nerve monitoring during radical prostatectomy improve functional outcomes? A randomised trial.

OBJECTIVE: To explore how the use of the ProPep® Nerve Monitoring System (ProPep Surgical, Austin, TX, USA) for intraoperative specific sparing of the pudendal nerve fibres influences postoperative functional outcomes after unilateral nerve-sparing (UNS) or non-nerve-sparing (NNS) robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: We randomised 100 men undergoing UNS or NNS RARP to ProPep nerve monitoring during RARP (intervention) or standard of care RARP (control). Functional outcomes were assessed at 3, 6, and 12 months using the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), the International Prostate Symptom Score, the Danish Prostate Symptom Score, the International Index of Erectile Function, the Erection Hardness Scale, and 24-h pad tests. The primary outcome was the difference in ICIQ-SF score between the groups at 12 months. Secondary outcomes included differences in the remaining outcome measures and continence rates at all time points. Continence was defined as the use of no pads and the answer 'Never' to the question: 'How often do you experience urinary incontinence?' or a urine loss of <8 g on the 24-h pad test. RESULTS: A total of 82 patients were included in the per-protocol analysis at 12 months with 41 in each group. At 12 months the mean ICIQ-SF scores were 5.37 (95% confidence interval [CI] 3.71-7.03) and 5.66 (95% CI 4.05-7.27) for the intervention and control groups, respectively (P = 0.8). There were no statistically significant differences in any of the remaining outcomes. However, the continence rate was higher in the intervention group at 6 months (63% vs 44%, P = 0.09). CONCLUSIONS: Intraoperative nerve monitoring did not result in better functional outcomes following UNS or NNS RARP. Larger studies are needed to explore if ProPep can reduce the time to continence after RARP.

Preclinical and clinical evidence for using perinatal tissue allografts in nerve sparing robot assisted radical prostatectomy to hasten recovery of functional outcomes: a literature review.

INTRODUCTION: Localized prostate cancer (PCa) is one of the most common malignancies in the United States. Despite continued refinement of robot assisted radical prostatectomy (RARP) surgical methods, post-surgical erectile dysfunction and urinary incontinence remain significant challenges due to iatrogenic injury of local nervous tissue. Thus, the development of therapeutic strategies, including the use of biologic adjuncts to protect and/or enhance recovery and function of nerves following RARP is of growing interest. Perinatal tissue allografts have been investigated as one such biologic adjunct to nerve sparing RARP. However, knowledge regarding their clinical efficacy in hastening return of potency and continence as well as the potential underpinning biological mechanisms involved remains understudied. Thus, the objective of this literature review was to summarize published basic science and clinical studies supporting and evaluating the use of perinatal allografts for nerve repair and their clinical efficacy as adjuncts to RARP, respectively. METHODS: The literature as of May 2024 was reviewed non-systematically using PubMed, EMBASE, Scopus, and Web of Science databases. The search terms utilized were "robotic prostatectomy", "prostate cancer", "nerve sparing", "perinatal tissue", "allograft", "potency", and "continence" alone or in combination. All articles were reviewed and judged for scientific merit by authors RP and JM, only peer-reviewed studies were considered. RESULTS: Eight studies of perinatal tissue allograph use in RARP were deemed worthy of inclusion in this nonsystematic review. CONCLUSIONS: Incontinence and impotence remain significant comorbidities despite continued advancement in surgical technique. However, basic science research has demonstrated potential neurotrophic, anti-fibrotic, and anti-inflammatory properties of perinatal tissue allografts, and clinical studies have shown that patients who receive an intra-operative prostatic perinatal membrane wrap have faster return to potency and continence.

Early recovery of urinary continence after robot-assisted radical prostatectomy is associated with membranous urethra and neurovascular bundle preservation.

OBJECTIVES: We investigated the correlation between surgical outcomes and postoperative urinary continence recovery in robot-assisted radical prostatectomy (RARP). METHODS: Patients who underwent RARP in our institution (n = 195) were included in this study. Preserved urethral length (PUL) was assessed during the procedure. Other outcomes of the surgical procedure were collected from operative records. Kaplan-Meier analysis with log-rank test was used to compare urinary continence recovery rate with the PUL, sparing of the neurovascular bundle (NVB), and other surgical procedures. Univariate and multivariate analyses were performed using Cox proportional hazards model, and p-values of <0.05 were considered significant. RESULTS: Patients with a PUL ≥26 mm had 10.0%, 24.7%, 36.6%, and 89.0% continence recovery rates at 30, 60, 90, and 365 days after surgery, respectively, while patients with a PUL <26 mm had 0%, 17.8%, 26.1%, and 80.9% recovery rates, respectively. Kaplan-Meier curves showed significantly better postoperative urinary continence recovery at 30 days after RARP in patients with a PUL ≥26 mm than those with a PUL <26 mm (p = 0.0028) and in patients with NVB preservation than those with no NVB preservation (p = 0.014). Urinary continence recovery within 30, 60, and 90 days after surgery was 90.6% for patients with a PUL of ≥26 mm and NVB preservation, while only 82.3% for patients with a PUL of <26 mm or no NVB preservation. CONCLUSION: Our results suggest that a PUL ≥26 mm and NVB preservation after RARP correlate with a significantly higher postoperative rate of recovery of urinary continence.

Preoperative high serum total testosterone levels predict preserved postoperative sexual function in patients after nerve-sparing robot-assisted radical prostatectomy.

OBJECTIVE: To assess the association among preoperative total testosterone levels, postoperative sexual function, and prognosis after robot-assisted radical prostatectomy. METHODS: Patients who underwent robot-assisted radical prostatectomy in our institution were included in the study. Based on preoperative total testosterone levels, they were divided into low (<3.0 ng/mL) and high (≥3.0 ng/mL) total testosterone groups. Sexual function was evaluated using the International Index of Erectile Function scores, Expanded Prostate Cancer Index Composite scores, and the potency rate from preoperatively to 12 months after surgery. Oncological outcomes were evaluated based on biochemical recurrence. RESULTS: Out of 233 patients included, no significant difference in sexual function was found between the high (n = 183) and the low (n = 50) total testosterone groups at any point before or after surgery. However, in nerve-sparing cases, preservation in postoperative sexual function was observed only in the high total testosterone group (International Index of Erectile Function scores and Expanded Prostate Cancer Index Composite sexual function scores, at any point after surgery, p < 0.05; potency rate, at 3, 6, and 12 months after surgery; p < 0.05). Additionally, the high total testosterone group showed better biochemical recurrence-free survival than the low total testosterone group (p = 0.008). CONCLUSIONS: In the high total testosterone group, preservation in sexual function was observed after the nerve-sparing procedure, while the biochemical recurrence rate was low. Therefore, patients with high levels of total testosterone may be advised to consider nerve-sparing interventions.

Impact of mpMRI targeted biopsy on intraoperative nerve-sparing (NeuroSAFE) during robot-assisted laparoscopic radical prostatectomy.

BACKGROUND: The aim of our study was to evaluate the impact of prostate biopsy technique (transrectal ultrasound (US)-prostate biopsy (PBx) versus multiparametric magnetic resonance imaging (mpMRI) targeted prostate biopsy (MRI-PBx) on intraoperative nerve-sparing and the rate of secondary neurovascular-bundle resection (SNR) in patients undergoing robot-assisted laparoscopic radical prostatectomy (RARP). A real-time investigation with a frozen-section examination (NeuroSAFE) microscopically excluded or confirmed prostate cancer invasion of the nerve structures resulting in preservation of the neurovascular bundle or SNR. Additionally, we analyzed risk factors related to SNR, such as longer operation time and postoperative complications. METHODS: The total study cohort was stratified according to non-nerve-sparing versus nerve-sparing RARP. Patients with nerve-sparing approach were then stratified according to biopsy technique (PBx vs. MRI-PBx). Further, we compared PBx versus MRI-PBx according to SNR rate. RESULTS: We included a total of 470 consecutive patients, who underwent RARP for PCa at our institution between January 2016 and December 2019. Patients with a preoperative MRI-PBx had a 2.12-fold higher chance of successful nerve-sparing (without SNR) compared to patients with PBx (p < 0.01). Patients with preoperative MRI-PBx required 73% less intraoperative SNR compared to patients with PBx (p < 0.0001). Prior MRI-PBx is thus a predictor for successful nerve-sparing RARP approach. CONCLUSION: Preoperative MRI-PBx led to better oncological outcomes and less SNR. Young patients with good erectile function could benefit from a preoperative MRI-PBx before nerve-sparing RARP.

An Algorithm to Personalize Nerve Sparing in Men with Unilateral High-Risk Prostate Cancer.

PURPOSE: Current guidelines do not provide strong recommendations on preservation of the neurovascular bundles during radical prostatectomy in case of high-risk (HR) prostate cancer and/or suspicious extraprostatic extension (EPE). We aimed to evaluate when, in case of unilateral HR disease, contralateral nerve sparing (NS) should be considered or not. MATERIALS AND METHODS: Within a multi-institutional data set we selected patients with unilateral HR prostate cancer, defined as unilateral EPE and/or seminal vesicle invasion (SVI) on multiparametric (mp) magnetic resonance imaging (MRI), or unilateral International Society of Urologic Pathologists (ISUP) 4-5 or prostate specific antigen ≥20 ng/ml. To evaluate when to perform NS based on the risk of contralateral EPE, we relied on chi-square automated interaction detection, a recursive machine-learning partitioning algorithm developed to identify risk groups, which was fit to predict the presence of EPE on final pathology, contralaterally to the prostate lobe with HR disease. RESULTS: A total of 705 patients were identified. Contralateral EPE was documented in 87 patients (12%). Chi-square automated interaction detection identified 3 groups, consisting of 1) absence of SVI on mpMRI and index lesion diameter ≤15 mm, 2) index lesion diameter ≤15 mm and contralateral ISUP 2-3 or index lesion diameter >15 mm and negative contralateral biopsy or ISUP 1, and 3) SVI on mpMRI or index lesion diameter >15 mm and contralateral biopsy ISUP 2-3. We named those groups as low, intermediate and high-risk, respectively, for contralateral EPE. The rate of EPE and positive surgical margins across the groups were 4.8%, 14% and 26%, and 5.6%, 13% and 18%, respectively. CONCLUSIONS: Our study challenges current guidelines by proving that wide bilateral excision in men with unilateral HR disease is not justified. Pending external validation, we propose performing NS and incremental NS in case of contralateral low and intermediate EPE risk, respectively.

Super-veil nerve-sparing extraperitoneal pure single-port robotic-assisted radical prostatectomy on da Vinci Si robotic system.

OBJECTIVES: To investigate the safety profile and short-term outcome of super-veil nerve-sparing extraperitoneal single-port robotic-assisted radical prostatectomy (espRARP) on da Vinci Si platform. METHODS: From December 2018 to March 2021, 106 consecutive patients with treatment-naive prostate cancer were prospectively included. espRARP was performed on da Vinci Si surgical platform. Operative time, estimated blood loss, Clavien-Dindo complication classification, continence, potency recovery, quality-of-life scores, and postoperative prostate-specific antigen (PSA) were documented. RESULTS: Patients aged 52-79 years (mean ± SD, 64.8 ± 6.15 yrs), with a median PSA of 9.2 ng/ml (IQR: 6.70, 16.83) and median prostate volume of 31.9 ml (IQR: 30.01, 38.54). 95.28% (101/106) were clinically localized. All patients underwent espRARP successfully with no open conversions. Operative time was 94.2 ± 30.26 min with an estimated blood loss of 68.5 ml (range, 50-120 ml). No Grade III complications or above were documented. Positive surgical margin was 17.9% (19/106). Median pain score at discharge was 0 (IQR: 0, 1.75) without use of opioid narcotics. Postoperative length of stay was 3 days (IQR: 1, 3), in which 28 patients were discharged within 24 h. Instant, 1-, 3-, and 6 month continence recovery was 18.9, 45.3, 79.2, 93.4, and 96.4%, respectively. Of the 43 patients who received nerve-sparing procedures, 13 (30.23%) resumed potency 6 months postoperatively. 12 month biochemical recurrence-free survival was 92.77% (77/83). CONCLUSIONS: Extraperitoneal single-port robotic-assisted radical prostatectomy is a safe and feasible technique. Combined with super-veil nerve-sparing procedures, it may provide satisfactory outcome in short-term functional recovery.

Toggling Technique Allows Retrograde Early Release to Facilitate Neurovascular Bundle Sparing During Robot-Assisted Radical Prostatectomy: A Propensity Score-Matching Study.

BACKGROUND: This study aimed to present the surgical facilitation of neurovascular bundle (NVB) sparing using the toggling technique (30° lens down/up switching) and to evaluate erectile dysfunction (ED) recovery after robot-assisted radical prostatectomy (RARP). METHODS: We assessed 144 patients (group with toggling, n = 72; group without toggling, n = 72) who underwent RARP with bilateral NVB sparing using propensity score matching. Inclusion criteria were ≥ 1 year follow-up and preoperative potency as per the Sexual Health Inventory for Men (SHIM) questionnaire (≥ 17 points). Recovery of ED after RARP was defined as return to baseline sexual function or self-assessment regarding successful intercourse. The subjective surgeon's nerve sparing (SNS) score and tunneling success rates were used to evaluate surgical facilitation. The recovery rate of ED between the groups was analyzed using Kaplan-Meier analysis. RESULTS: A better ED recovery trend was confirmed according to the SNS score (R² = 0.142, P = 0.004). In the analysis of NVB sparing ease, the toggling group showed higher SNS scores (on right/left side: P = 0.011 and < 0.001, respectively) and overall tunneling success rates (87% vs. 74%, P = 0.001) than the group without toggling. Overall, ED recovery rates were 82% (59/72) and 75% (54/72) in the groups with and without toggling, respectively, at the 1-year follow-up (P = 0.047), and the toggling group showed a faster ED recovery rate at 3 months (47% vs. 35%, P = 0.013). In a specific analysis of the potent cohort (< 60 years, bilateral full NVB spared, SHIM score ≥ 22), the ED recovery rate reached 87% (14/16) in the toggling group. CONCLUSION: The retrograde early release with the toggling technique improves the facilitation of NVB sparing, leading to improved ED recovery.

Impact of nerve sparing in robot-assisted radical prostatectomy on the risk of positive surgical margin and biochemical recurrence.

OBJECTIVES: Nerve sparing may increase positive surgical margin rate during radical prostatectomy. Our objective was to analyze the positive surgical margin rate and location as well as its impact on biochemical recurrence according to nerve sparing procedure in robot-assisted radical prostatectomy. METHODS: We included 814 patients treated with robot-assisted radical prostatectomy between 2009 and 2021, and evaluated the impact of nerve sparing on positive surgical margin and biochemical recurrence using logistic regression and Cox models. RESULTS: Unilateral nerve sparing and bilateral nerve sparing were performed in 152 (18.6%) cases and 118 (14.5%) cases, respectively. On multivariable analysis, in addition to nerve sparing, bilateral nerve sparing, but not unilateral nerve sparing was associated with an increased risk of positive surgical margin compared with non-nerve sparing. Positive surgical margin at any location increased the risk of biochemical recurrence. During unilateral nerve sparing, positive surgical margin in nerve sparing side, but not in non-nerve sparing side was associated with increased risk of biochemical recurrence on multivariate analysis. CONCLUSIONS: Taken together, surgeons need to notice an increased risk of biochemical recurrence associated with positive surgical margin when performing nerve sparing in robot-assisted radical prostatectomy, and then need to choose the patients suitable for nerve sparing.

Athermal versus ultrasonic nerve-sparing laparoscopic radical prostatectomy: a comparison of functional and oncological outcomes.

PURPOSE: Many urologists emphasize the concept of heat-related damage suggesting the avoidance of any energy to perform nerve-sparing radical prostatectomy. At our institution, both athermal and ultrasonic dissection have been used over the last years to perform a nerve-sparing laparoscopic radical prostatectomy (NSLRP). In this study, we compare functional and oncological outcomes of the two procedures. METHODS: All charts from patients undergoing NSLRP between January 2009 and June 2015 were reviewed. The International Index of Erectile Function (IIEF-5) was recorded preoperatively and 3, 12 and 24 months after surgery; continence was recorded at 3 and 12 months; PSA was recorded at last follow-up. Uni- and multivariate analyses were performed to assess the association of variables with functional and oncological outcomes. RESULTS: Ultrasonic NSLRP was used for 120 patients, while athermal NSLRP on 111. The impact of the cutting technique on erection recovery was different at 3 months, favoring athermal dissection (p = 0.002); however, significance was lost at 12 (p = 0.09) and 24 (p = 0.14) months. Continence recovery was comparable at 3 (p = 0.1) and 12 (p = 0.2) months; the rate of positive surgical margins and PSA recurrence were also similar (p = 0.2 and p = 0.06, respectively). At univariate analysis, age, Gleason sum, nerve-sparing laterality, and extension (intra- vs interfascial) were associated with overall erection recovery; only age and nerve-sparing laterality were independent predictors. Age and preoperative TRUS prostate volume were associated with continence recovery, both at uni- and multivariate analysis. CONCLUSIONS: The use of an ultrasonic device compared to athermal dissection during NSLRP does not affect long-term potency, nor continence and early biochemical recurrence.

Trends in risk-group distribution and Pentafecta outcomes in patients treated with nerve-sparing, robot-assisted radical prostatectomy: a 10-year low-intermediate volume single-center experience.

PURPOSE: To evaluate the trends in risk-group distribution and Pentafecta outcomes in patients treated with nerve-sparing (NS), robot-assisted radical prostatectomy (RARP) in a single low-intermediate volume prostate cancer (PCa) center over a 10-year period. MATERIALS AND METHODS: We queried a prospectively maintained database for patients who underwent NS RARP between 2009 and 2018 in a low-intermediate volume PCa center. Risk-groups were defined according to the D'Amico classification. Pentafecta outcomes referred to the postsurgical presence of potency and continence, and the absence of biochemical recurrence (BCR), positive surgical margins (PSM), and perioperative complications. The Kruskall-Wallis test, the t test and the Mann-Whitney tests were used when appropriate. RESULTS: 603 patients underwent NS RARP and 484 patients were evaluated for Pentafecta outcomes. Median postsurgical follow-up was 28 months. Overall, 137 (22.7%), 376 (62.3%), and 90 (15%) patients were diagnosed in the low-, intermediate-, and high-risk groups, respectively. Patients undergoing NS RARP shifted from 33 to 20% in the low-risk group, from 52 to 62% in the intermediate-risk group, and from 10 to 13% in the high-risk group. Patients reaching Pentafecta increased from 38 to 44%. No postoperative potency was the main reason for non-achieving Pentafecta (71%). BCR strongly limited Pentafecta achievement in the high-risk group (61%), but not in intermediate (24%) and low-risk (30%) groups. CONCLUSIONS: Low-intermediate volume PCa centers show similar trends to high-volume centers regarding risk group distributions over time in PCa patients undergoing NS RARP. We reported an increase in Pentafecta outcomes achievement over time even for experienced surgeons. Pentafecta outcomes achievement is risk-group dependent.

Use of intraoperative fluorescence to enhance robot-assisted radical prostatectomy.

Robot-assisted radical prostatectomy has become the standard of care for the removal of localized prostate cancer. Positive outcomes depend upon the precise removal of the prostate and associated tissue without damage to nearby structures. This process can be aided by fluorescence-guided surgery to enhance the visual contrast between different structures. Here the authors have conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify ten investigations into the use of fluorescence-guided surgery in robot-assisted radical prostatectomy. These studies used fluorescent tracers to identify structures, including the prostate, neurovascular bundle and lymph nodes. These studies demonstrate the safe and effective use of fluorescence-guided surgery in robot-assisted radical prostatectomy and pave the way for further developments in this field.

Cross-organ sensitization between the prostate and bladder in an experimental rat model of lipopolysaccharide (LPS)-induced chronic pelvic pain syndrome.

BACKGROUND: The aim of the current study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function via prostate-to-bladder cross-sensitization in a rat model of lipopolysaccharide (LPS)-induced prostate inflammation. METHODS: Male rats were intraprostatically injected with LPS or saline, serving as control. Micturition parameters were examined in a metabolic cage 10 or 14 days later. Subsequently, to evaluate bladder function, cystometry was performed. Micturition cycles were induced by saline infusion and cholinergic and purinergic contractile responses were measured by intravenous injection with methacholine and ATP, respectively. Thereafter, the prostate and bladder were excised and assessed histopathologically for possible inflammatory changes. RESULTS: Metabolic cage experiments showed increased urinary frequency in rats with LPS-induced CP/CPPS. Cystometry showed a significant increase in the number of non-voiding contractions, longer voiding time and lower compliance in CP/CPPS animals compared to controls. Induction of CP/CPPS led to significantly reduced cholinergic and purinergic bladder contractile responses. Histopathological analysis demonstrated prostatic inflammation in CP/CPPS animals. There were no significant differences between the groups regarding the extent or the grade of bladder inflammation. Prostate weight was not significantly different between the groups. CONCLUSIONS: The present study shows that prostate-to-bladder cross-sensitization can be triggered by an infectious focus in the prostate, giving rise to bladder overactivity and alterations in both afferent and efferent signalling. Future studies are required to fully understand the underlying mechanisms.

Risk assessment of neuromuscular stimulation by energy-based transurethral resection devices: an ex vivo test standard.

BACKGROUND: During transurethral resection of bladder tumours (TURB), radio-frequency (RF) currents can lead to adverse neuromuscular stimulation (NMS). Here we present a novel ex vivo method to determine the risk of RF generators and their bipolar TURB modes to cause NMS. We aimed to develop an experimental platform for safety evaluation of new RF generators and their modes with a newly established test standard, suitable for replacement or reduction of animal testing. METHODS: We tested four contemporary RF generators with their bipolar modes for TURB in saline. A two-stage ex vivo approach was pursued: First, we recorded voltages at possible positions of the obturator nerve behind a porcine bladder wall in a TURB model using 18 RF applications per generator. Second, these voltage records were used as stimuli to evoke nerve compound action potentials (CAPs) in isolated porcine axillary nerves. The NMS potential was defined as the ratio between the observed area under the CAPs and the theoretical CAP area at maximum response and a firing rate of 250 Hz, which would reliably induce tetanic muscle responses in most human subjects. The measurement protocol was tailored to optimise reproducibility of the obtained NMS potentials and longevity of the nerve specimens. RESULTS: As prerequisite for the clinical translation of our results, the robustness of our test method and reproducibility of the NMS potential are demonstrated with an excellent correlation (r = 0.93) between two sets of identical stimuli (n = 72 each) obtained from 16 nerve segments with similar diameters (4.2 ± 0.37 mm) in the nerve model. The RF generators differed significantly (p < 0.0001) regarding NMS potential (medians: 0-3%). CONCLUSIONS: Our test method is suitable for quantifying the NMS potential of different electrosurgical systems ex vivo with high selectivity at a reasonable degree of standardization and with justifiable effort. Our results suggest that the clinical incidence of NMS is considerably influenced by the type of RF generator. Future generations of RF generators take advantage from the proposed test standard through higher safety and less animal testing. Health professionals and treated patients will benefit most from improved RF surgery using generators with a low NMS risk.

Apical peri-prostatic nerve block versus intra-rectal xylocaine gel for trans- rectal ultrasound guided prostate biopsy among Nigerian patients: A prospective randomized study.

AIMS: This study compared the analgesic effect of apical peri-prostatic block with that of intra-rectal xylocaine gel for trans-rectal ultrasound guided prostate biopsy (TRUS-PBx) in Nigeria. METHODS: This is a prospective randomized comparative study carried out over one year in University of Benin Teaching Hospital, Edo State, Nigeria. The participants were randomized into two groups; Group A had 10 mls of intra-rectal xylocaine gel instillation while Group B had apical infiltration of 10 mls of 1% xylocaine all before TRUS-PBx. RESULT: There was a statistically significant difference in the mean pain score during and one hour after TRUS-PBx between Group A and Group B of the study population respectively (p < 0.0001). Those that had intra-rectal xylocaine gel (Group A) had more pain during and after biopsy. There was no difference in the mean pain score during probe insertion between the two groups (p = 0.952). CONCLUSION: This study demonstrated the superiority of apical peri-prostatic nerve block over intra rectal xylocaine gel instillation during TRUS-PBx with respect to its anesthetic efficacy. Therefore, centers providing TRUS-PBx in Nigeria should consider apical peri-prostatic nerve block as their mode of anesthesia for the procedure due to its efficacy and high safety profile.

Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8+ tumor-associated lymphocytes and poor prognosis in prostate cancer.

To investigate immune profile consisting of stromal PD-L1 expression, inhibitory or non-T-cell inflamed tumor microenvironment that may predict response to anti-PD-L1/PD-1 immunotherapy in prostate cancer, we validated the specificity of a PD-L1 monoclonal antibody (E1L3N) and identified PD-L1 specific expression in prostatic stromal nerve cells. PD-L1 expression was analyzed in 73 primary prostate cancers and 7 castration-resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor-associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD-L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD-L1 was frequently observed in the nerve branches in the tumor-associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3-, CD3- and CD8-positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD-L1+ tumor-associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD-L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan-Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD-L1+ TANs was independently prognostic of BCR. In conclusion, PD-L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro-immunological interaction may be a contribution to immune-suppressive microenvironment. Combinatorial treatment regimen designs to neural PD-L1 and TALs should be warranted in future clinical application of anti-PD-L1/PD-1 immunotherapy in prostate cancer.

Vasa nervorum angiogenesis in prostate cancer with perineural invasion.

BACKGROUND: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination in malignancies associated with highly enervated organs. However, the effect of cancer cells on vasa nervorum remains unknown. We studied this effect in locally advanced prostate cancer, a high-risk feature associated with approximately 20% of prostate cancer specific mortality. METHODS: We used immunohistochemistry for CD34, fibroblast growth factor-2 (FGF-2), FSHR, podoplanin, vascular endothelial growth factor (VEGF), and VEGFR-2 as well as histochemical methods to examine the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients. RESULTS: The percentage of the nerve area occupied by CD34-positive vasa nervorum endothelial cells in nerves with PNI was much higher than in nerves without PNI (7.3 ± 1.2 vs 1.9 ± 0.4; P < 0.001 and 5.8 ± 0.6 vs 1.23 ± 0.8; P < 0.001 in pT3a and pT3b prostate cancer specimens, respectively). In 19/85 of the patients the CD34-positive vasa nervorum microvessels have a thick basement membrane, similar to the vessels in diabetic microangiopathy. This subendothelial layer contains collagen fibers. Vasa nervorum endothelia and Schwann cells express FGF-2 (nuclear localization) and FSHR (plasma membrane and cytoplasmic staining). Prostate cancer cells invading nerves express VEGF, a critical cytokine in tumor angiogenesis. The vasa nervorum of prostatic nerves with PNI did not express detectable levels of VEGFR-2. No podoplanin-positive lymphatic vessels were seen in nerves. CONCLUSION: In locally advanced prostate cancer, PNI of cancer cells is associated with formation of new endoneurial capillaries and changes of vasa nervorum morphology.

A temporal and spatial map of axons in developing mouse prostate.

Prostate autonomic and sensory axons control glandular growth, fluid secretion, and smooth muscle contraction and are remodeled during cancer and inflammation. Morphogenetic signaling pathways reawakened during disease progression may drive this axon remodeling. These pathways are linked to proliferative activities in prostate cancer and benign prostate hyperplasia. However, little is known about which developmental signaling pathways guide axon investment into prostate. The first step in defining these pathways is pinpointing when axon subtypes first appear in prostate. We accomplished this by immunohistochemically mapping three axon subtypes (noradrenergic, cholinergic, and peptidergic) during fetal, neonatal, and adult stages of mouse prostate development. We devised a method for peri-prostatic axon density quantification and tested whether innervation is uniform across the proximo-distal axis of dorsal and ventral adult mouse prostate. Many axons directly interact with or innervate neuroendocrine cells in other organs, so we examined whether sensory or autonomic axons innervate neuroendocrine cells in prostate. We first detected noradrenergic, cholinergic, and peptidergic axons in prostate at embryonic day (E) 14.5. Noradrenergic and cholinergic axon densities are uniform across the proximal-distal axis of adult mouse prostate while peptidergic axons are denser in the periurethral and proximal regions. Peptidergic and cholinergic axons are closely associated with prostate neuroendocrine cells whereas noradrenergic axons are not. These results provide a foundation for understanding mouse prostatic axon development and organization and, provide strategies for quantifying axons during progression of prostate disease.