Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.

A novel grading approach predicts worse outcomes in stage pT1 non-muscle-invasive bladder cancer.

OBJECTIVE: To develop a prognostically relevant scoring system for stage pT1 non-muscle-invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. PATIENTS AND METHODS: The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. RESULTS: The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG-unresponsive tumours (P = 0.006). Study limitations include the retrospective, single-centre design, diverse therapies and small cohort. CONCLUSIONS: We present a morphology-based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy-to-use low-cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results.

Ureteroplasty with buccal mucosa graft without omental wrap: an effective method to treat ureteral strictures.

PURPOSE: Successful treatment options for ureteral strictures are limited. Surgical options such as ileal interposition and kidney autotransplantation are difficult and associated with morbidity and complications. Techniques such as Boari flap and psoas hitch are limited to distal strictures. Only limited case studies on the success of open buccal mucosa graft (BMG) ureteroplasty exist to this date. The purpose of this study was to evaluate the success of open BMG ureteroplasty without omental wrap. METHODS: In this single-center retrospective study between July 2020 and January 2023, we included 14 consecutive patients with ureteric strictures who were treated with open BMG ureteroplasty without omental wrap. The primary outcome was the success of open BMG ureteroplasty. Further endpoints were complications and hospital readmission. Outcome variables were assessed by clinical examination, kidney sonography, and patient anamnesis. RESULTS: Out of 14 patients, 13 were stricture and ectasia-free without a double-J stent at a median follow-up of 15 months (success rate 93%). No complications were observed at the donor site, and the complication rate overall was low with 3 out of 14 patients (21%) having mild-to-medium complications. CONCLUSIONS: Open BMG ureteroplasty without omental wrap is a successful and feasible technique for ureteric stricture repair.

Risk factors for bladder neck contracture after transurethral resection of the prostate.

INTRODUCTION: Transurethral resection of the prostate (TURP) is the most frequently used treatment of benign prostate hyperplasia with a prostate volume of <80 mL. A long-term complication is bladder neck contracture (BNC). The aim of the present study was to identify the risk factors for BNC formation after TURP. METHODS: We conducted a retrospective analysis of all TURP primary procedures which were performed at one academic institution between 2013 and 2018. All patients were analyzed and compared with regard to postoperative formation of a BNC requiring further therapy. Uni- and multivariable logistic regression analyses (MVAs) were performed to identify possible risk factors for BNC development. RESULTS: We included 1368 patients in this analysis. Out of these, 88 patients (6.4%) developed BNC requiring further surgical therapy. The following factors showed a statistically significant association with BNC development: smaller preoperative prostate volume (p = 0.001), lower resected prostate weight (p = 0.004), lower preoperative levels of prostate-specific antigen (PSA, p < 0.001), shorter duration of the surgery (p = 0.027), secondary transurethral intervention (due to urinary retention or gross hematuria) during inpatient stay (p = 0.018), positive (≥100 CFU/mL) preoperative urine culture (p = 0.010), and urethral stricture (US) formation requiring direct visual internal urethrotomy (DVIU) postoperatively after TURP (p < 0.001), in particular membranous (p = 0.046) and bulbar (p < 0.001) strictures. Preoperative antibiotic treatment showed a protective effect (p = 0.042). Histopathological findings of prostate cancer (PCA) in the resected prostate tissue were more frequent among patients who did not develop BNC (p = 0.049). On MVA, smaller preoperative prostate volume (p = 0.046), positive preoperative urine culture (p = 0.021), and US requiring DVIU after TURP (p < 0.001) were identified as independent predictors for BNC development. CONCLUSION: BNC is a relevant long-term complication after TURP. In particular, patients with a smaller prostate should be thoroughly informed about this complication.

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy.

OBJECTIVES: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). MATERIALS AND METHODS: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as 'organ-confined' (≤pT2N0), 'locally advanced' (pT3-4N0) and 'node-positive' (pTanyN1-3). RESULTS: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. CONCLUSIONS: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

Short-Term and Long-Term Morbidity after Radical Cystectomy in Patients with NMIBC and Comparison with MIBC: Identifying Risk Factors for Severe Short-Term Complications.

INTRODUCTION: RC represents a viable treatment option for certain NMIBC patients. However, studies investigating morbidity in the context of RC for NMIBC are scarce. The goal of the current study was to assess and compare morbidity after RC performed in patients with NMIBC and patients with MIBC and to identify risk factors for severe short-term complications. METHODS: Medical records of 521 patients who underwent RC for bladder cancer were retrospectively reviewed. Patients were divided into patients with NMIBC and patients with MIBC. The groups were compared and risk factors for severe complications were identified. RESULTS: RC for NMIBC was performed in 123 patients (23.6%). Histological upstaging was seen in 47 NMIBC patients (38.2%) and in 231 MIBC patients (58%, p < 0.001). OS was 29.8% and CSS was 15.5%. Both endpoints were higher for RC for MIBC (p < 0.001). More complications affecting the urinary diversion were seen with RC for NMIBC (p = 0.033) and more continent urinary diversions (p = 0.040) were performed in those patients. Obesity (p = 0.008), a higher ASA score (p = 0.004), and preoperative medical drug anticoagulation (p = 0.025) were risk factors for severe short-term morbidity after both, RC for NMIBC and for MIBC. CONCLUSION: Patients who underwent RC for NMIBC are exposed to a comparably high perioperative risk than patients with MIBC. RC seems to be a viable treatment option for certain NMIBC patients with a significant histological upstaging in both groups. In patients with obesity, a high ASA score, and with medical drug anticoagulation, the indication for surgery should be confirmed especially strict and possible treatment alternatives should be considered particularly thorough.

Risk factors associated with positive surgical margins' location at radical cystectomy and their impact on bladder cancer survival.

PURPOSE: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). METHODS: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance. RESULTS: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). CONCLUSIONS: PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Impact of previous urethroplasty on the outcome after artificial urinary sphincter implantation: a prospective evaluation.

PURPOSE: To evaluate the impact of previous urethroplasty on complication rates and postoperative continence after primary artificial urinary sphincter (AUS) implantation in male patients with severe stress urinary incontinence. PATIENTS AND METHODS: A prospective evaluation of patients undergoing primary AUS implantation was conducted. Patients with previous radiotherapy, AUS implantation or urethral stent placement were excluded. Main endpoints were postoperative continence and complication rates including necessity of AUS explantation. Kaplan-Meier analysis evaluated explantation-free survival. Logistic regression analyses were performed to identify potential predictors for AUS explantation. RESULTS: 105 patients were included with a mean follow-up of 76.6 months (SD 15.9). 30 of these patients had a history of urethroplasty. Postoperatively, 96.2% of all patients were objectively continent (≤ 1 pad/day). No differences in postoperative continence and early complication rates were observed. Concerning long-term complications, infection, mechanical implant failure, and tissue atrophy were also comparable. Overall sphincter erosion rate was 12.3%, but significantly higher in urethroplasty patients (23.3% vs. 8.0%, p = 0.038) and sphincter explantation rate was threefold higher (p = 0.016) in the urethroplasty group. Furthermore, explantation-free survival was reduced compared to the non-urethroplasty group (p = 0.044). On logistic regression analysis, the previous urethroplasty was the only significant predictor for AUS explantation (p = 0.016). CONCLUSION: AUS implantation in patients with former urethroplasty can provide satisfying results. Compared to patients without the previous urethroplasty, the higher risk of cuff erosion and AUS explantation has to be addressed during preoperative consultation. Patients with the previous urethroplasty with grafting, long strictures and previous visual internal urethrotomy might be at highest risk.

Complication rate after cystectomy following pelvic radiotherapy: an international, multicenter, retrospective series of 682 cases.

PURPOSE: Conflicting evidence exists on the complication rates after cystectomy following previous radiation (pRTC) with only a few available series. We aim to assess the complication rate of pRTC for abdominal-pelvic malignancies. METHODS: Patients treated with radical cystectomy following any previous history of RT and with available information on complications for a minimum of 1 year were included. Univariable and multivariable logistic regression models were used to assess the relationship between the variable parameters and the risk of any complication. RESULTS: 682 patients underwent pRTC after a previous RT (80.5% EBRT) for prostate, bladder (BC), gynecological or other cancers in 49.1%, 27.4%, 9.8% and 12.9%, respectively. Overall, 512 (75.1%) had at least one post-surgical complication, classified as Clavien ≥ 3 in 29.6% and Clavien V in 2.9%. At least one surgical complication occurred in 350 (51.3%), including bowel leakage in 6.2% and ureteric stricture in 9.4%. A medical complication was observed in 359 (52.6%) patients, with UTI/pyelonephritis being the most common (19%), followed by renal failure (12%). The majority of patients (86%) received an incontinent urinary diversion. In multivariable analysis adjusted for age, gender and type of RT, patients treated with RT for bladder cancer had a 1.7 times increased relative risk of experiencing any complication after RC compared to those with RT for prostate cancer (p = 0.023). The type of diversion (continent vs non-continent) did not influence the risk of complications. CONCLUSION: pRTC carries a high rate of major complications that dramatically exceeds the rates reported in RT-naïve RCs.

Introduction of a New Score to Assess Surgical Efficiency in Holmium Laser Enucleation of the Prostate.

INTRODUCTION: While holmium laser enucleation of the prostate (HoLEP) is accepted as safe and efficient, a long learning curve is considered the main reason for its slow adoption in clinical practice. So far, no standardized and easy-to-use parameter has been implemented to measure surgical experience or efficiency which could be useful for training and quality control purposes. The aim of the present study was to evaluate the learning curves of 2 HoLEP beginners and to identify applicable efficiency outcome measures as well as potentially complicating factors in performing HoLEP. PATIENTS AND METHODS: A total of 594 patients treated by HoLEP between September 2016 and May 2019 were enrolled. The procedures were initially performed by 1 HoLEP expert (reference surgeon); over time, 2 further surgeons were trained. Baseline characteristics, enucleation weight, morcellation and enucleation time, laser energy usage, and postoperative results were recorded prospectively. The learning curves of the 2 novices were analyzed and compared to the reference surgeon. Logistic regression analyses were performed to identify predictors for postoperative grade ≥2 complications. RESULTS: Median enucleation ratio and complication rates did not significantly alter along the learning curves. Median enucleation speed and laser energy application of the 2 novices significantly improved with growing experience. Combining these variables, we introduced the "HoLEP efficiency score" (HES) which demonstrated the most appropriate value to reflect the surgical experience and efficiency. The median HES for the reference surgeon was 82.8 min kJ/g. For the 2 novices, a drop from 130 and 124.4 min kJ/g by -57 and -30%, respectively, was observed. Among several tested clinical parameters, the presence of prostate cancer (p = 0.047) and the surgical caseload (p < 0.001) influenced the HES. On multivariable logistic regression, American Society of Anesthesiologists score and prostate cancer were independent predictors for grade ≥2 complications (p = 0.002, odds ratio [OR] 2.042 and p = 0.038, OR 1.940). CONCLUSION: We introduce the HES as an objective and measurable tool to quantify surgical efficiency. In clinical practice, the HES may find application in training and quality control purposes as well as in comparing surgical modifications and hardware. Patients with prostate cancer seem to be more challenging cases and have a higher risk for complications, and may preferably be treated by experienced surgeons.

HoLEP provides a higher prostate cancer detection rate compared to bipolar TURP: a matched-pair analysis.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) has become a popular alternative to TURP for desobstructive prostate surgery. The prevalence of incidental prostate cancer (iPCa) during surgery varies depending on many preoperative factors. To evaluate whether the surgical procedure itself (HoLEP vs. TURP) influences iPCa detection, we performed a case-by-case matched-pair analysis. METHODS: Preoperative patient age, total PSA, and prostate volume were used as matching criteria. Descriptive statistics were used to confirm matching quality. Parameters were analyzed by Fisher's exact test and T test or Mann-Whitney U test for dichotomous and continuous variables, respectively. Uni- and multivariate logistic regression analyses were performed to identify predictors for iPCa detection. RESULTS: 60 out of 136 patients after HoLEP and 60 out of 1220 patients after bipolar TURP (bTURP) could be included. Mean patient age was 71.5 and 70.3 years in the HoLEP and bTURP group, respectively. Median preoperative total PSA was 4.42 ng/ml for HoLEP and 4.33 ng/ml for bTURP patients. Median preoperative prostate volume was 75.0 cc in both groups. Mean percentage of tissue removed by HoLEP and bTURP was 63.5 and 49.5% (p < 0.001), respectively. IPCa was found in 23.3% of HoLEP specimens compared to 8.3% in bTURP (p = 0.043). PSA density was the only independent predictor for iPCa detection. CONCLUSIONS: In this first matched-pair analysis, HoLEP provides a significantly higher iPCa detection rate than bTURP. This might be a result of a more efficient tissue removal during HoLEP. PSA density was the only independent risk factor for iPCa.

Sarcopenia predicts 90-day mortality and postoperative complications after radical cystectomy for bladder cancer.

PURPOSE: A single-center study was conducted to investigate the impact of sarcopenia as a predictor for 90-day mortality (90 dM) and complications within 90 days after radical cystectomy for bladder cancer. METHODS: In total, 327 patients with preoperative available digital computed tomography (CT) scans of the abdomen and pelvis were identified. The lumbar skeletal muscle index was measured using preoperative abdominal CT to assess sarcopenia. Complications were recorded and graded according to Clavien-Dindo (CD). Predictors of 90 dM and complications within 90 days were analyzed by uni- and multivariable logistic regression. RESULTS: Of the 327 patients, 262 (80%) were male and 108 (33%) patients were classified as sarcopenic. Within 90 days, 28 (7.8%) patients died, of whom 15 patients were sarcopenic and 13 were not. In multivariable logistic regression analysis, sarcopenia (OR 2.59; 95% CI 1.13-5.95; p = 0.025), ASA 3-4 (OR 2.53; 95% CI 1.10-5.82; p = 0.029) and cM + (OR 7.43; 95% CI 2.34-23.64; p = 0.001) were independent predictors of 90-day mortality. Sarcopenic patients experienced significantly more complications, i.e., CD 4a-5 (p = 0.003), compared to non-sarcopenic patients. In multivariable logistic regression analysis, sarcopenia was independently associated with CD ≥ 3b complications corrected for age, BMI, ASA-Score and type of urinary diversion. CONCLUSIONS: We reported that sarcopenia proved an independent predictor for 90 dM and complications in patients undergoing RC for bladder cancer.

Holmium Laser Enucleation of the Prostate Provides Similar Incidental Prostate Cancer Detection Rates as Open Prostatectomy: A Matched Pair Analysis.

INTRODUCTION: Whereas the excellent functional outcomes after Holmium laser enucleation of the prostate (HoLEP) and its equivalency to open prostatectomy (OP) have been studied in detail in the past years, the oncological equivalency has yet to be investigated. Therefore, we conducted a matched pair analysis to evaluate and compare incidental prostate cancer detection rates after HoLEP and OP. PATIENTS AND METHODS: Preoperative patient age, total prostate-specific antigen (PSA), and prostate volume were used as primary matching criteria. Descriptive statistics were used to confirm matching quality. Statistical analyses were performed using Fisher´s exact test and T-test or Mann-Whitney U-test for dichotomous and continuous variables, respectively. RESULTS: After the matching procedure, 72 out of 145 patients after HoLEP and 72 out of 477 patients after OP were included. Mean patient age (70 vs. 71 years), median prostate volume (106 vs. 107 mL), and median preoperative total PSA (4.32 vs. 4.36 ng/mL) were almost identical. The amount of removed tissue did not differ between HoLEP and OP. Incidental prostate cancer detection rate was similar with 9.7% after HoLEP and 8.3% after OP (p = 1.000). CONCLUSION: This first matched pair analysis shows that HoLEP does not have a disadvantage regarding cancer detection rate during desobstructive surgery for large prostates.

Influence of Body Mass Index on Clinical Outcome Parameters, Complication Rate and Survival after Radical Cystectomy: Evidence from a Prospective European Multicentre Study.

Background/Aims/Objectives: To evaluate the influence of body mass index (BMI) on complications and oncological outcomes in patients undergoing radical cystectomy (RC). METHODS: Clinical and histopathological parameters of patients have been prospectively collected within the "PROspective MulticEnTer RadIcal Cystectomy Series 2011". BMI was categorized as normal weight (<25 kg/m2), overweight (≥25-29.9 kg/m2) and obesity (≥30 kg/m2). The association between BMI and clinical and histopathological endpoints was examined. Ordinal logistic regression models were applied to assess the influence of BMI on complication rate and survival. RESULTS: Data of 671 patients were eligible for final analysis. Of these patients, 26% (n = 175) showed obesity. No significant association of obesity on tumour stage, grade, lymph node metastasis, blood loss, type of urinary diversion and 90-day mortality rate was found. According to the -American Society of Anesthesiologists score, local lymph node (NT) stage and operative case load patients with higher BMI had significantly higher probabilities of severe complications 30 days after RC (p = 0.037). The overall survival rate of obese patients was superior to normal weight patients (p = 0.019). CONCLUSIONS: There is no evidence of correlation between obesity and worse oncological outcomes after RC. While obesity should not be a parameter to exclude patients from cystectomy, surgical settings need to be aware of higher short-term complication risks and obese patients should be counselled -accordingly.

Infiltrative lamina propria invasion pattern as an independent predictor for cancer-specific and overall survival of instillation treatment-naïve stage T1 high-grade urothelial bladder cancer.

OBJECTIVES: To investigate established prognostic factors and relatively new histopathological tumor characteristics including metric substage and lamina propria invasion patterns in a large series of T1 high-grade non-muscle-invasive bladder cancer. METHODS: Between 1989 and 2012, 322 patients with initial stage T1 high-grade bladder cancer underwent transurethral resection, followed by re-transurethral resection and a conservative approach with follow-up regime alone or instillation treatment. Transurethral resection specimens were reassessed by two experienced urological pathologists for tumor grade according to the World Health Organization 1973 classification, metric T1 substage, lamina propria invasion pattern and associated carcinoma in situ. The median follow-up period was 42 months (interquartile range 25-72 months). In addition to Kaplan-Meier analyses, uni- and multivariable Cox regression analyses were used to compare progression-free survival, cancer-specific survival and overall survival for the studied parameters comparing two subcohorts. RESULTS: While in patients after instillation treatment no examined feature was shown as an independent predictor for prognosis, there were predictive histopathological features in multivariable Cox regression analyses in instillation treatment-naïve patients: associated carcinoma in situ (hazard ratio 2.278, 95% confidence interval 1.119-4.634, P = 0.023) and World Health Organization 1973 grade 3 (hazard ratio 2.950, 95% confidence interval 1.021-8.536, P = 0.046) for worse progression-free survival, infiltrative lamina propria tumor pattern for worse cancer-specific survival (hazard ratio 2.369, 95% confidence interval 1.034-5.429, P = 0.042) and overall survival (hazard ratio 1.049, 95% confidence interval 1.024-1.075, P = 0.001). CONCLUSIONS: The results of the present T1 high-grade bladder cancer series suggest that lamina propria invasion pattern is a promising parameter to predict the prognosis of T1 high-grade bladder cancer in an instillation treatment-naïve subcohort. Prospective multicenter evaluations are warranted. The need for instillation treatment in T1 high-grade bladder cancer is clearly demanded.

Optimizing outcome reporting after radical cystectomy for organ-confined urothelial carcinoma of the bladder using oncological trifecta and pentafecta.

UNLABELLED: Radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) is associated with heterogeneous functional and oncological outcomes. The aim of this study was to generate trifecta and pentafecta criteria to optimize outcome reporting after RC. METHODS: We interviewed 50 experts to consider a virtual group of patients (age ≤ 75 years, ASA score ≤ 3) undergoing RC for a cT2 UCB and a final histology of ≤pT3pN0M0. A ranking was generated for the three and five criteria with the highest sum score. The criteria were applied to the Prospective Multicenter Radical Cystectomy Series 2011. Multivariable binary logistic regression analyses were used to evaluate the impact of clinical and histopathological parameters on meeting the top selected criteria. RESULTS: The criteria with the highest sum score were negative soft tissue surgical margin, lymph node (LN) dissection of at least 16 LNs, no complications according to Clavien-Dindo grade 3-5 within 90 days after RC, treatment-free time between TUR-BT with detection of muscle-invasive UCB and RC <3 months and the absence of local UCB-recurrence in the pelvis ≤12 months. The first three criteria formed trifecta, and all five criteria pentafecta. A total of 334 patients qualified for final analysis, whereas 35.3 and 29 % met trifecta and pentafecta criteria, respectively. Multivariable analyses showed that the relative probability of meeting trifecta and pentafecta decreases with higher age (3.2 %, p = 0.043 and 3.3 %, p = 0.042) per year, respectively. CONCLUSIONS: Trifecta and pentafecta incorporate essential criteria in terms of outcome reporting and might be considered for the improvement of standardized quality assessment after RC for UCB.

Prognostic impact of infiltration of the vagina and/or uterus in women undergoing anterior pelvic exenteration for urothelial carcinoma of the bladder: results of a contemporary multicentre series.

PURPOSE: To evaluate for the first time the prognostic significance of female invasive patterns in stage pT4a urothelial carcinoma of the bladder in a large series of women undergoing anterior pelvic exenteration. PATIENTS AND METHODS: Our series comprised of 92 female patients in total of whom 87 with known invasion patterns were eligible for final analysis. Median follow-up for evaluation of cancer-specific mortality (CSM) was 38 months (interquartile ranges, 21-82 months). The impact on CSM was evaluated using multivariable Cox proportional-hazards regression analysis; predictive accuracy (PA) was assessed by receiver operating characteristic analysis. RESULTS: Vaginal invasion was noted in 33 patients (37.9 %; group VAG), uterine invasion in 20 patients (23 %; group UT), and infiltration of both vagina and uterus in 34 patients (39.1 %; group VAG + UT). Groups VAG and UT significantly differed from group VAG + UT with regard to the presence of positive soft tissue margins (STM) only. Five-year-cancer-specific survival probabilities in the groups VAG, UT, and VAG + UT were 21, 20, and 21 %, respectively (p = 0.955). On multivariable analysis, only STM status (HR = 2.02, p = 0.023) independently influenced CSM. C-indices of multivariable models for CSM with and without integration of invasive patterns were 0.570 and 0.567, respectively (PA gain 0.3 %, p = 0.526). CONCLUSIONS: Infiltration of the vagina, the uterus or both is associated with poor 5-year survival rates. With regard to CSM, no difference was detectable between patients with different invasion patterns, thus justifying further collectively including these invasive patterns as stage pT4a.

Comparative analysis of gender-related differences in symptoms and referral patterns prior to initial diagnosis of urothelial carcinoma of the bladder: a prospective cohort study.

OBJECTIVE: To analyze gender-specific differences regarding clinical symptoms, referral patterns and tumor biology prior to initial diagnosis of urothelial carcinoma of the bladder (UCB). METHODS: A consecutive series of patients with an initial diagnosis of UCB was included. All patients completed a questionnaire on demographics, clinical symptoms and referral patterns. RESULTS: In total, 68 patients (50 men, 18 women) with newly diagnosed UCB at admission for transurethral resection of bladder tumors were recruited. Dysuria was more often observed in women (55.6 vs. 38.0%, p = 0.001). Direct consultation of the urologist was conducted by 84.0% of males and 66.7% of females (p = 0.120). One third of the women saw their general practitioner and/or gynecologist once or twice (p = 0.120) before referral to the urologist. Furthermore, women were significantly more often treated for urinary tract infections than men (61.1 vs. 20.0%, p = 0.005). Cystoscopy at first presentation to the urologist was more often performed in men than women (88.0 vs. 66.7%, p = 0.068), with a more favorable tumor detection rate at first cystoscopy in men (96.0 vs. 50.0%, p < 0.001). CONCLUSIONS: Delayed referral patterns might lead to deferred diagnosis of UCB and consequently to adverse outcome. Thus, primary care physicians might consider referring patients with bladder complaints to specialized care earlier.

Concomitant seminal vesicle invasion in pT4a urothelial carcinoma of the bladder with contiguous prostatic infiltration is an adverse prognosticator for cancer-specific survival after radical cystectomy.

PURPOSE: To evaluate the prognostic value of concomitant seminal vesicle invasion (cSVI) in patients with urothelial carcinoma of the bladder (UCB) and contiguous prostatic stromal infiltration in a large cystectomy series. METHODS: A total of 385 patients with UCB and contiguous prostatic infiltration comprised our study. Patients were divided in two groups according to cSVI. Median follow-up was 36 months (interquartile range 11-74); the primary end point was cancer-specific mortality. The prognostic impact of cSVI was evaluated using multivariable Cox regression analysis. The predictive accuracy was assessed by a receiver operating characteristic analysis. RESULTS: A total of 229 patients (59.5 %) without cSVI comprised group A, and 156 patients (40.5 %) with cSVI comprised group B. Positive lymph nodes (63 vs. 44 %, p < 0.001) and positive surgical margins (34 % vs. 14 %, p < 0.001) were more common in patients with cSVI. The 5- and 10-year cancer-specific survival rates were 41 % and 32 % (group A) and 21 and 17 % (group B) (p < 0.001). In multivariable analysis, pathological nodal stage (hazard ratio [HR] 2.19, p < 0.001), soft tissue surgical margin (HR 1.57, p = 0.010), clinical tumor stage (HR 1.46, p = 0.010), adjuvant chemotherapy (HR 0.40, p < 0.001), and cSVI (HR 1.69, p < 0.001) independently impacted cancer-specific mortality. The c-indices of the multivariable models with and without inclusion of cSVI were 0.658 (95 % confidence interval 0.60-0.71) and 0.635 (95 % confidence interval 0.58-0.69), respectively, resulting in a predictive accuracy gain of 2.3 % (p = 0.002). CONCLUSIONS: In patients with UCB and prostatic stromal invasion, cSVI adversely affected cancer-specific survival compared to patients without cSVI. The inclusion of cSVI significantly improved the predictive accuracy of our multivariable model regarding survival.

Prostate cancer at the peripheral end of prostate biopsy specimen predicts increased risk of positive resection margin after radical prostatectomy: results of a prospective multi-institutional study.

PURPOSE: To test a novel technique of processing prostate biopsy specimen by marking the peripheral end (PE) as a predictive tool for positive resection margin after radical prostatectomy (RP) or for locally advanced carcinoma of the prostate (PC). METHODS: Prospective, multi-institutional study of a consecutive cohort of men who underwent prostate biopsy with marking the peripheral biopsy end and subsequent RP at the same institution. RESULTS: The study cohort comprised 445 men with a mean age of 63 years (40-77 years). Overall, PE-positive cores were found in 174 men (39.1 %) and R1 status was diagnosed in 132 men after RP (29.7 %). In the multivariate analysis, the presence of at least one PE-positive core was correlated with an increased risk of R1 status (OR 2.29, 95 % CI 1.31-4.00, p = 0.003) and was the strongest predictor followed by Gleason score, PSA and percentage of positive cores. Including all predictive parameters, a nomogram with a concordance index of 72.1 % was calculated. In the pT3/pT4 subgroup, PE positivity was the only predictive factor for R1 status (OR 3.03, 95 % CI 1.36-6.75, p = 0.006). In pT2 stage, no single factor was predictive for R1 status. PE-positive biopsies were not predictive for pT3/pT4 stages. CONCLUSIONS: PC at the peripheral end of prostate biopsy specimen predicts an increased risk of R1 status in subsequent RP. This simple and cheap technique may contribute to an increased accuracy of risk stratification for curative treatment for PC.