A New Proximal Adjustable Sling ATOMS SSP® Implantation Technique with Focus on the Urethral Bulb: Lessons Learned from Revision Surgery.

BACKGROUND: Adjustable sling ATOMS-SSP results in ventral compression of the urethra with favorable results in the treatment of men with mild to moderate stress incontinence. However, with transobturator tunneling and mesh fixation, the surgeon has a range of options, which leads to different results and sometimes unfavorable positioning of the silicone cushion. Using retrograde urethrography (RUG), we identified ATOMS patients with considerable misplacement. We then modified the implantation technique when we performed the revision, and now present here our first experiences with this new surgical technique. METHODS: Patients after ATOMS-SSP implantation at our clinic were systematically subjected to a RUG if incontinence persisted after adjustments. In case of unfavorable positioning, a revision was performed with the aim of achieving an idealized urethroproximal position of the silicone pad. During follow-up, a repeat RUG was performed, and both subjective and objective outcome parameters were recorded. RESULTS: Four men met the above criteria and underwent revision with reimplantation using our new technique. All patients postoperatively experienced significantly improved continence. RUGs demonstrated an ideal ATOMS position immediately below the proximal bulbar urethra. CONCLUSIONS: Our proximal implantation technique, presented here for the first time, allows optimal positioning of the ATOMS SSP, which is reflected in the objective parameters and RUG. Its use in primary implantation should also be considered and an expansion to the indication of severe stress incontinence seems possible, but this should only be done in studies.

Is the Standard Artificial Urinary Sphincter AMS 800 Still a Treatment Option for the Irradiated Male Patient Presenting with a Devastated Bladder Outlet?

BACKGROUND: Circular urethral compression with an artificial sphincter allows control of voiding, even in patients with severe stress urinary incontinence, but it heightens the risk of urethral atrophy and erosion. This study of one of the largest populations of patients treated with radiotherapy investigates the additive effect of the post-radiogenic stricture of the membranous urethra/bladder neck on AMS 800 artificial urinary sphincter outcomes. METHODS: In a retrospective multicenter cohort study, we analyzed patients fitted with an AMS 800, comparing those who had received radiotherapy with patients presenting a devastated bladder outlet (stricture of the membranous urethra/bladder neck). We determined the correlation between these groups of patients using both univariate and stepwise adjusted multivariate regression. The revision-free interval was estimated by a Kaplan-Meier plot and compared by applying the log-rank test. A p value below 0.05 was considered statistically significant. RESULTS: Of the 123 irradiated patients we identified, 62 (50.4%) had undergone at least one prior desobstruction for bladder-neck/urethra stenosis. After a mean follow-up of 21 months, the latter tended to achieve social continence less frequently (25.7% vs. 35%; p = 0.08). Revision was required significantly more often for this group (43.1% vs. 26.3%; p = 0.05) due to urethral erosion in 18 of 25 cases. A stenosis recurred in five cases; desobstruction was performed in two cases, leading to erosion in both. Multivariate analysis revealed a significantly higher risk of revision when recurrent stenosis necessitated at least two prior desobstructions (HR 2.8; p = 0.003). CONCLUSIONS: A devastated bladder outlet is associated with a lower proportion of men with social continence and a significantly higher need for revision compared with irradiated patients without a history of urethral stenosis. Alternative surgical procedures should be discussed beforehand, especially in cases of recurrent urethral stenosis.

Comparison of circulating tumor cells and AR-V7 as clinical biomarker in metastatic castration-resistant prostate cancer patients.

Biomarker in metastatic castration resistant prostate cancer (mCRPC) treatment are rare. We aimed to compare the clinical value of circulating tumor cells (CTCs) and androgen receptor splice variant 7 (AR-V7) as biomarker in mCRPC patients undergoing androgen receptor-targeted agent (ARTA) treatment. Overall cohort (65 patients) was stratified regarding either CTC or AR-V7 status followed by further sub-stratification of the respective other marker. Subsequently, prostate specific antigen (PSA) response, progression free survival (PFS) and overall survival (OS)) of subgroups was compared. CTCs and AR-V7 were detected in 54 (83%) and 33 (61%) patients, respectively. All AR-V7 + were CTC +. We detected PSA response in all subgroups. For PFS and OS, biomarker stratification revealed differences between all subgroups. Interestingly, no significant differences of AR-V7 transcript copy numbers were detected between responding and non-responding patients. Additionally, multivariable analysis revealed no independent prognostic value of AR-V7 positivity. Both biomarkers show clinical value in prognosticating clinical outcome. Nonetheless, AR-V7 stratification underestimates the heterogenous subgroup of CTC - and CTC + patient, the latter requiring more intense clinical surveillance. Additionally, AR-V7 level does not correlate with clinical response. Thus, the value of AR-V7 as a clinical biomarker must be considered skeptically.

Supratrigonal cystectomy and augmentation cystoplasty with ileum or ileocecum in the treatment of ulcerative interstitial cystitis/bladder pain syndrome: a 14-year follow-up.

INTRODUCTION AND HYPOTHESIS: This study analyzes the long-term results of supratrigonal cystectomy and augmentation cystoplasty in patients with severe ulcerative interstitial cystitis/bladder pain syndrome (IC/BPS) and reduced bladder capacity. METHODS: Outcome data were retrospectively and prospectively collected and analyzed in women who underwent supratrigonal cystectomy and augmentation cystoplasty for ulcerative IC/BPS at Muenster University Hospital between 1991 and 2006. We used cross-tabulation and Pearson's Chi-squared test to examine how outcome is influenced by age, preoperative functional bladder volume, and choice of augmentation material. RESULTS: After a median 171-month follow-up, analysis could be done in 26 of 27 patients. Persistent pain necessitated early revision in 2 patients (7.7%). Mean postoperative O'Leary Sant IC Score was 12.7 in the prospectively questioned patients. Responses to Patient Global Impression of Improvement (PGI-I) were: "very much better" in 15 cases (65.2%) and "much better" in 7 (30.4%). Twelve patients (52.2%) emptied their augmented bladder voluntarily, whereas 7 (32%) needed intermittent self-catheterization (ISC). The rate of patients requiring ISC tended to be lower when detubularized ileocecal bowel was used. All 5 patients (19.2%) with late relapse of ulcerative IC/BPS needed ISC. CONCLUSIONS: Severe ulcerative IC/BPS can be curatively treated in some patients by supratrigonal cystectomy and augmentation, which is associated with a high satisfaction rate and few long-term complications even over a very long follow-up. In our analysis, the need for ISC is a risk factor for late relapse, although ileocecal augmentation could increase the proportion of patients with sufficient voluntary micturition.

Compression or obstruction: Prospective analysis of the function of the Adjustable Transobturator Male System (ATOMS) based on preand postoperative urodynamic data.

INTRODUCTION: This analysis, based on pre- and postoperative urodynamic data, is the first to elucidate the influence of the Adjustable Transobturator Male System (ATOMS, A.M.I. GmbH, Feldkirch, Austria) on the lower urinary tract and disclose possible obstructive properties. METHODS: A prospective study was performed in patients who had stress urinary incontinence and were scheduled for ATOMS implantation after radical prostatectomy. Apart from continence assessment (24-hour pad test, International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form [ICIQ-SF]), urodynamic testing was done with International Continence Society (ICS)-standardized pressure-flow analysis before and after ATOMS implantation/adjustment. The Wilcoxon signed-rank test was used for statistical analysis. RESULTS: The analysis included 12 consecutive patients from two centers (mean age 69 years) with a mean followup of 246 days. Median urine leakage dropped from 240 (72-1250) to 70 (0-700) g/24 hours postoperatively, with a pad reduction of 4 to 0.9 pads/ day. Pressure-flow analysis revealed a significant change only in the bladder outlet obstruction index (BOOI). The bladder contractility index, intravesical pressure conditions, and uroflowmetry were not significantly affected. None of the patients showed de novo obstruction postoperatively in the ICS analysis. CONCLUSIONS: The ATOMS significantly increases the BOOI in conjunction with good continence results. However, no case reached pathological level according to the BOOI and thus there is no potential danger to the lower urinary tract or urethral integrity.

ATOMS (Adjustable Transobturator Male System) Is an Effective and Safe Second-Line Treatment Option for Recurrent Urinary Incontinence after Implantation of an AdVance/AdVance XP Fixed Male Sling? A Multicenter Cohort Analysis.

(1) Background: This study examined outcomes of second-line ATOMS implantation after failure of the fixed male sling (FMS) AdVance/AdVance XP. (2) Methods: A retrospective multicenter cohort analysis was carried out in men implanted with an ATOMS between 2011 and 2020 after failure of an AdVance/AdVance XP. Success was assessed on the basis of objective (dryness, 0-1 pad/24 h or >20 g/24 h pad test) and subjective results (PGI-I). We performed the Wilcoxon rank sum test, Fisher's exact test, logistic regression, and multivariate analysis. (3) Results: The study included 88 patients from 9 centers with a mean age of 71.3 years. No Clavien-Dindo > II complications occurred within the first 3 months after ATOMS implantation. A total of 10 cases (9%) required revision in the ensuing clinical course. After a mean follow-up of 42.5 months, 76.1% achieved social continence, and 56.8% used no pads at all. Mean urine leakage/24 h dropped from 422 g (3.9 pads) to 38 g (0.69 pads) and the mean ICIQ-SF decreased from 16.25 to 5.3 (p < 0.0001). PROMs (patient-reported outcome measures) showed improvement in 98.9% of cases, and 63.6% gave a "very much better" PGI-I rating. Multivariate analysis identified a lower probability of achieving maximum satisfaction for the following factors: the AdVance XP as first-line therapy (OR 0.35), a lower ICIQ-SF question 1 (OR 0.26), status post-irradiation (OR 0.14), and more severe pain prior to ATOMS implantation (OR 0.51). (4) Conclusions: Implantation of an ATOMS is an effective and safe second-line treatment option for recurrent urinary incontinence after implantation of an AdVance/AdVance XP sling. High patient satisfaction was demonstrated in a long-term follow-up.

High/low-volume center experience predicts outcome of AMS 800 in male stress incontinence: Results of a large middle European multicenter case series.

AIM: To analyze the influence of implantation volume of artificial sphincters (AMS 800) on outcome in a large central European multicenter cohort study. METHODS: As part of the DOMINO (Debates on Male Incontinence) project, the surgical procedures and outcomes were retrospectively analyzed in a total of 473 patients who received an artificial sphincter (AMS 800) between 2010 and 2012. Clinics that implanted at least 10 AMS 800 per year were defined as high-volume centers. RESULTS: Sixteen centers had a mean rate of 9.54 AMS 800/y of which five clinics were identified as high-volume centers. They implanted significantly more double cuffs (55% vs 12.1%; P < .001), used the perineal approach significantly more often (78% vs 67.7%; P = .003) and chose larger mean cuff sizes (4.63 cm vs 4.42 cm; P = .002). With a mean follow-up of 18 months, the revision rate was significantly higher at low-volume centers (38.5% vs 26.7%; P = .037), urethral erosion being the main reason for revision. Social continence (0-1 pads/24 h) was achieved significantly more often in high-volume centers (45.5% vs 24.2%; P = .002). CONCLUSIONS: Our study showed significantly better continence results and lower revision rates at high-volume centers, confirming earlier results that are still true in this decade. We, therefore, recommend surgery for male incontinence at qualified centers.

Artificial Urinary Sphincter Cuff Size Predicts Outcome in Male Patients Treated for Stress Incontinence: Results of a Large Central European Multicenter Cohort Study.

PURPOSE: The aim was to study the correlation between cuff size and outcome after implantation of an AMS 800 artificial urinary sphincter. METHODS: A total of 473 male patients with an AMS 800 sphincter implanted between 2012 and 2014 were analyzed in a retrospective multicenter cohort study performed as part of the Central European Debates on Male Incontinence (DOMINO) Project. RESULTS: Single cuffs were implanted in 54.5% and double cuffs in 45.5% of the patients. The cuffs used had a median circumference of 4.5 cm. Within a median follow of 18 months, urethral erosion occurred in 12.8% of the cases and was associated significantly more often with small cuff sizes (P<0.001). Multivariate analysis showed that, apart from cuff size (P=0.03), prior irradiation (P<0.001) and the penoscrotal approach (P=0.036) were associated with an increased erosion rate. Continence rate tended to be highest with median cuff sizes (4-5.5 cm). CONCLUSION: Apart from irradiation and the penoscrotal approach, small cuff size is a risk factor for urethral erosion. Results are best with cuff sizes of 4.5-5.5 cm.

Detecting predictive androgen receptor modifications in circulating prostate cancer cells.

Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two most common AR modifications (AR-V7 splice variant and AR point mutations) in circulating tumor cells (CTCs). We devised a single-tube assay to detect AR-V7 splice variants and AR point mutations in CTCs using immunomagnetic cell isolation, followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 patients with PSA progression awaiting therapy switch. Comparison of response to newly administered therapy and CTC-AR-status allowed effect size estimation. Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Seventeen patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We estimated a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. Based on a conservative calculation, we estimated the effect size for molecularly-informed therapy switches for prospective clinical trial planning to ~27%. In summary, the ability to determine key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.

Comparative Analysis of AR Variant AR-V567es mRNA Detection Systems Reveals Eminent Variability and Questions the Role as a Clinical Biomarker in Prostate Cancer.

PURPOSE: Androgen receptor splice variants are known to facilitate resistance of prostate cancer cells toward antihormonal therapies. However, detection of the most prominent variant, AR-V7, on its own, is not sufficiently accurate for prediction of response. Thus, simultaneous detection of other variants might improve prediction. AR-V567es has been shown to be expressed in late stages of prostate cancer. Yet, there have been discrepant results regarding incidence of AR-V567es. We therefore aimed to perform a comprehensive comparison of different detection approaches for AR-V567es mRNA. EXPERIMENTAL DESIGN: We compared a custom-made, probe-based PCR assay with 6 published AR-V567es detection PCR assays in distinct samples, that is, cancer cell lines, LuCaP xenografts, primary and metastatic tumor samples, and circulating tumor cells (CTC). RESULTS: Using distinct approaches, we concordantly detected expression of AR-V567es in only three of 45 samples (LuCaP xenografts 86.2 and 136s2 as well as one CTC sample). We observed varying results in all other samples. Specificity analysis displayed nonspecific binding of 5 previously published PCR assays to AR full-length mRNA in the absence of AR-V567es. CONCLUSIONS: Validation of biomarker detection approaches is one of the most critical steps before transfer into clinical application. By performing comparative analysis of different detection approaches, we revealed eminent variability among previously described systems. Furthermore, we demonstrate an overestimation of AR-V567es in prostate cancer, presumably due to nonspecific detection of AR-FL mRNA. Therefore, any correlation between AR-V567es expression and clinical responses is highly doubtful and does not reflect the biological nature of the disease.

High proliferation rate and TNM stage but not histomorphological subtype are independent prognostic markers for overall survival in papillary renal cell carcinoma.

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ2-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.

Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness.

Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p<0.001) whereas statin intake showed an odds ratio of 0.49 (p=0.005) indicating a negative association with high-risk PC. Despite a limited number of patients using statins (~9.5%), adjusted and weighed multivariate logistic regression models revealed that preoperative hypercholesterolemia is associated with a diagnosis of high-risk PC which is negatively influenced by statin intake.

Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer.

The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC). Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration-resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection. As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited. PATIENT SUMMARY: A subgroup of patients can benefit from abiraterone and/or enzalutamide despite detection of AR-V7 splice variants in their circulating tumour cells.

Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma?

Clinical trials targeting programmed death 1 (PD-1) and its ligand PD-L1 (PD-L1) for metastatic renal cell cancer (RCC) are ongoing. The aim of this study is to validate their roles as prognostic markers in non-clear cell (non-cc) RCC. Sixty-four non-cc RCC tissue specimens were collected from patients undergoing renal tumor surgery. Expressions of biomarkers were assessed using immunohistochemistry and compared with clinical characteristics. Survival analyses were performed with a median follow-up of 77.5 (range: 0-176) months. No significant correlations were found for PD-1(+) tumor-infiltrating mononuclear cells (TIMC) or PD-L1(+) expression and clinical attributes in patients with non-cc RCC. Kaplan-Meier analysis revealed no differences in 5- and 10-year cancer-specific survival (CSS) for PD-1(-) TIMC compared to PD-1(+) TIMC (71.4 and 63 % versus 72.2 and 61.9 %; p = 0.88). Intratumoral expression of PD-L1 did not appear to influence the 5- and 10-year CSS significantly, even though a trend was identified (68 and 53.6 % versus 80.1 and 75.7 %; p = 0.08). In multivariate analysis, neither PD-1(+) TIMC nor intratumoral PD-L1(+) expression proved to be independent predictors of CSS (p = 0.99 and p = 0.68, respectively). Our study demonstrates that PD-1(+) TIMC and intratumoral PD-L1(+) expression did not significantly impact tumor aggressiveness or clinical outcome in non-ccRCC specimens. Due to rare incidence of non-cc RCC in particular according to PD-L1 expression, further analyzes are warranted.

Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer.

UNLABELLED: We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy. METHODS: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for (68)Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with (68)Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared. RESULTS: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with (68)Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on (68)Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 ± 7.8 vs. 2.7 ± 0.9, P< 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%. CONCLUSION: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by (68)Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy.