17p13 (TP53) Deletions Are Associated With an Aggressive Phenotype but Unrelated to Patient Prognosis in Urothelial Bladder Carcinomas.

17p13 deletions including TP53 and other genes represent a common cause for reduced/lost p53 function in tumor cells. In this study, we analyzed the impact of 17p13 (TP53) deletions and p53 expression on tumor aggressiveness and patient prognosis in urothelial carcinoma. The 17p13 copy number status was analyzed by fluorescence in situ hybridization (FISH) on more than 2700 urothelial bladder carcinomas in a tissue microarray format. 17p13 deletion data were compared to p53 expression data measured by immunohistochemistry (IHC) in a previous study. Different types of p53 alterations were compared with tumor phenotype and clinical outcome data. Deletions of 17p13 occurred in 23% of 2185 analyzable carcinomas. The fraction of tumors with 17p13 deletions increased from pTa G2 low (9%) to pTa G3 (24%, p < 0.0001). In muscle-invasive carcinomas, 17p13 deletions were associated with advanced pT stage (p = 0.0246), but unrelated to patient prognosis (p > 0.5). 17p13 deletions were significantly related to p53 immunostaining (p = 0.0375). 17p13 deletions were most common in tumors with complete lack of p53 staining (31%), which supports the concept that many of these tumors have a complete loss of p53 function (p53 null phenotype). 17p13 deletions were also increased in tumors with high p53 staining (25%). In conclusion, 17p13 deletions were most commonly seen in p53 negative cancers, supporting their role as a cause for the p53 null phenotype in urothelial cancer. The association of 17p13 deletions with high grade and advanced pT stage may reflect increasing genomic instability going along with stage and grade progression.

Urinary function in female patients after traditional, organ-sparing and nerve-sparing radical cystectomy for bladder cancer: a systematic review and pooled analysis.

OBJECTIVES: To determine and summarize the available data on urinary, sexual, and health-related quality-of-life (HRQOL) outcomes after traditional radical cystectomy (RC), reproductive organ-preserving RC (ROPRC) and nerve-sparing RC (NSRC) for bladder cancer (BCa) in female patients. METHODS: The PubMed, SCOPUS and Web of Science databases were searched to identify studies reporting functional outcomes in female patients undergoing RC and urinary diversion for the treatment of BCa. The outcomes of interest were voiding function (for orthotopic neobladder [ONB]), sexual function and HRQOL. The following independent variables were derived and included in the meta-analysis: pooled rate of daytime and nighttime continence/incontinence, and intermittent self-catheterization (ISC) rates. Analyses were performed separately for traditional, organ- and/or nerve-sparing surgical approaches. RESULTS: Fifty-three studies comprising 2740 female patients (1201 traditional RC and 1539 organ-/nerve-sparing RC, and 264 nerve-sparing-alone RC) were eligible for qualitative synthesis; 44 studies comprising 2418 female patients were included in the quantitative synthesis. In women with ONB diversion, the pooled rates of daytime continence after traditional RC, ROPRC and NSRC were 75.2%, 79.3% and 71.2%, respectively. The pooled rate of nighttime continence after traditional RC was 59.5%; this rate increased to 70.7% and 71.7% in women who underwent ROPRC and NSRC, respectively. The pooled rate of ISC after traditional RC with ONB diversion in female patients was 27.6% and decreased to 20.6% and 16.8% in patients undergoing ROPRC and NSRC, respectively. The use of different definitions and questionnaires in the assessment of postoperative sexual and HRQOL outcomes did not allow a systematic comparison. CONCLUSIONS: Female organ- and nerve-sparing surgical approaches during RC seem to result in improved voiding function. There is a significant need for well-designed studies exploring sexual and HRQOL outcomes to establish evidence-based management strategies to support a shared decision-making process tailored towards patient expectations and satisfaction. Understanding expected functional, sexual and quality-of-life outcomes is necessary to allow individualized pre- and postoperative counselling and care delivery in female patients planned to undergo RC.

The potential benefits of concomitant statins treatment in patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To investigate the influence of statins on the survival outcomes of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adjuvant intravesical bacille Calmette-Guérin (BCG) immunotherapy. PATIENTS AND METHODS: A retrospective cohort of consecutive patients with NMIBC who received intravesical BCG therapy from 2001 to 2020 and statins prescription were identified. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS) were analysed between the Statins Group vs No-Statins Group using Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 2602 patients with NMIBC who received intravesical BCG were identified. The median follow-up was 11.0 years. On Kaplan-Meier analysis, the Statins Group had significant better OS (P < 0.001), CSS (P < 0.001), and PFS (P < 0.001). Subgroup analysis indicated statins treatment started before BCG treatment had better CSS (P = 0.02) and PFS (P < 0.01). Upon multivariable Cox regression analysis, the 'statins before BCG' group was an independent protective factor for OS (hazard ratio [HR] 0.607, 95% confidence interval [CI] 0.514-0.716), and CSS (HR 0.571, 95% CI 0.376-0.868), but not RFS (HR 0.885, 95% CI 0.736-1.065), and PFS (HR 0.689, 95% CI 0.469-1.013). CONCLUSIONS: Statins treatment appears to offer protective effects on OS and CSS for patients with NMIBC receiving adjuvant intravesical BCG.

Impact of the extent of lymph node dissection on survival outcomes in clinically lymph node-positive bladder cancer.

OBJECTIVE: To determine the oncological impact of extended pelvic lymph node dissection (ePLND) vs standard PLND (sPLND) during radical cystectomy (RC) in clinically lymph node-positive (cN+) bladder cancer (BCa). PATIENTS AND METHODS: In this retrospective, multicentre study we included 969 patients who underwent RC with sPLND (internal/external iliac and obturator lymph nodes) or ePLND (sPLND plus common iliac and presacral nodes) with or without platin-based peri-operative chemotherapy for cTany N1-3 M0 BCa between 1991 and 2022. We assessed the impact of ePLND on recurrence-free survival (RFS) and the distribution of recurrences (locoregional and distant recurrences). The secondary endpoint was overall survival (OS). We performed propensity-score matching using covariates associated with the extent of PLND in univariable logistic regression analysis. The association of the extent of PLND with RFS and OS was investigated using Cox regression models. RESULTS: Of 969 cN+ patients, 510 were 1:1 matched on propensity scores. The median (interquartile range [IQR]) time to recurrence was 8 (4-16) months, and median (IQR) follow-up of alive patients was 30 (13-51) months. Disease recurrence was observed in 104 patients in the ePLND and 107 in the sPLND group. Of these, 136 (27%), 47 (9.2%) and 19 patients (3.7%) experienced distant, locoregional, or both distant and locoregional disease recurrence, respectively. When stratified by the extent of PLND, we did not find a difference in recurrence patterns (P > 0.05). ePLND improved neither RFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.70-1.19; P = 0.5) nor OS (HR 0.78, 95% CI 0.60-1.01; P = 0.06) compared to sPLND. Stratification by induction chemotherapy did not change outcomes. CONCLUSION: Performing an ePLND at the time of RC in cN+ patients improved neither RFS nor OS compared to sPLND, regardless of induction chemotherapy status. Pretreatment risk stratification is paramount to identify ideal candidates for RC with ePLND as part of a multimodal treatment approach.

The optimal number of induction chemotherapy cycles in clinically lymph node-positive bladder cancer.

OBJECTIVE: To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node-positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. PATIENTS AND METHODS: We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose-dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1-3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni- and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer-specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. RESULTS: Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles (P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2-year OS estimates were 63% (95% confidence interval [CI] 0.53-0.74) and 63% (95% CI 0.58-0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni- or multivariable Cox regression analyses. CONCLUSION: Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation.

Thromboprophylaxis during neoadjuvant chemotherapy for bladder cancer reduces thromboembolism and bleeding.

OBJECTIVES: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy. MATERIALS AND METHODS: We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding. RESULTS: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation. CONCLUSIONS: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy.

PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors.

BACKGROUND: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.

Sunitinib for Metastatic Renal Cell Carcinoma: Real-World Data from the STAR-TOR Registry and Detailed Literature Review.

INTRODUCTION: We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting. METHODS: We analyzed data of adult a/mRCC patients treated with sunitinib. Data were derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups. RESULTS: A total of 116 study sites recruited 702 patients treated with sunitinib (73.1% male; median age 68.0 years; median Karnofsky index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug-related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients). CONCLUSIONS: This study adds further real-world evidence of the persisting relevance of sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile. The STAR-TOR registry is also registered in the database of US library of medicine (NCT00700258).

Oncological validation and discriminative ability of pentafecta criteria after open radical cystectomy.

OBJECTIVES: To validate the pentafecta criteria (PC) proposed by the PROMETRICS group for outcome reporting after radical cystectomy in an open radical cystectomy (ORC) cohort with long-term follow-up and to assess the discriminative ability of PC attainment for oncological endpoints. PATIENTS AND METHODS: Between January 2009 and December 2017, 420 patients underwent ORC with pelvic lymph node dissection and urinary diversion for non-metastatic bladder cancer. The PC were defined as reported by the PROMETRICS group. The primary endpoint was PC attainment, and oncological outcomes comprised further endpoints. We used uni- and multivariable logistic regression analysis to assess predictors of PC attainment. The discriminative ability of PC for overall mortality (OM), cancer-specific mortality (CSM) and other-cause mortality (OCM) was compared using Kaplan-Meier curves and cumulative incidence functions. After stratification by the number of PC attained, the association between PC attainment and the survival endpoints was tested on multivariable Cox regression and competing-risks models. RESULTS: A total of 108 patients (26%) fulfilled all PC, while 195 (46%), 77 (18%), 35 (8.3%) and five (1.2%) attained 4/5, 3/5, 2/5 and ≤1/5 PC, respectively. Increasing age-adjusted Charlson comorbidity index (odds ratio [OR] 0.80, P = 0.015) and incontinent diversion (OR 0.38, P = 0.005) were independent predictors of PC non-attainment. The median follow-up was 73 months. PC attainment (≥4/5 vs 3/5 vs ≤2/5 PC attained) was used to stratify patients into groups at significantly different risk of death (P < 0.001). A decreasing number of PC attained (<4/5) was associated with unfavourable survival estimates for both OM and CSM (all P ≤ 0.005) but not for OCM (all P ≥ 0.2). CONCLUSIONS: The PC proposed by the PROMETRICS group represent accurate quality indicators for oncological outcome reporting after ORC for non-metastatic bladder cancer and have a distinct discriminative ability to predict long-term OM and CSM.

Impact of smoking on urologic cancers: a snapshot of current evidence.

PURPOSE: The purpose of this paper is to present evidence regarding the associations between smoking and the following urologic cancers: prostate, bladder, renal, and upper tract urothelial cancer (UTUC). METHODS: This is a narrative review. PubMed was queried for evidence-based analyses and trials regarding the associations between smoking and prostate, bladder, renal, and UTUC tumors from inception to September 1, 2022. Emphasis was placed on articles referenced in national guidelines and protocols. RESULTS: Prostate-multiple studies associate smoking with higher Gleason score, higher tumor stage, and extracapsular invasion. Though smoking has not yet been linked to tumorigenesis, there is evidence that it plays a role in biochemical recurrence and cancer-specific mortality. Bladder-smoking is strongly associated with bladder cancer, likely due to DNA damage from the release of carcinogenic compounds. Additionally, smoking has been linked to increased cancer-specific mortality and higher risk of tumor recurrence. Renal-smoking tobacco has been associated with tumorigenesis, higher tumor grade and stage, poorer mortality rates, and a greater risk of tumor recurrence. UTUC-tumorigenesis has been associated with smoking tobacco. Additionally, more advanced disease, higher stage, lymph node metastases, poorer survival outcomes, and tumor recurrence have been linked to smoking. CONCLUSION: Smoking has been shown to significantly affect most urologic cancers and has been associated with more aggressive disease, poorer outcomes, and tumor recurrence. The role of smoking cessation is still unclear, but appears to provide some protective effect. Urologists have an opportunity to engage in primary prevention by encouraging cessation practices.

Clinical value of cholinesterase in patients treated with radical nephroureterectomy for upper urinary tract carcinoma.

PURPOSE: To evaluate the prognostic value and the clinical impact of preoperative serum cholinesterase (ChoE) levels on decision-making in patients treated with radical nephroureterectomy (RNU) for clinically non-metastatic upper tract urothelial cancer (UTUC). METHODS: A retrospective review of an established multi-institutional UTUC database was performed. We evaluated preoperative ChoE as a continuous and dichotomized variable using a visual assessment of the functional form of the association of ChoE with cancer-specific survival (CSS). We used univariable and multivariable Cox regression models to establish its association with recurrence-free survival (RFS), CSS, and overall survival (OS). Discrimination was evaluated using Harrell's concordance index. Decision curve analysis (DCA) was used to assess the impact on clinical decision-making of preoperative ChoE. RESULTS: A total of 748 patients were available for analysis. Within a median follow-up of 34 months (IQR 15-64), 191 patients experienced disease recurrence, and 257 died, with 165 dying of UTUC. The optimal ChoE cutoff identified was 5.8 U/l. ChoE as continuous variable was significantly associated with RFS (p < 0.001), OS (p < 0.001), and CSS (p < 0.001) on univariable and multivariable analyses. The concordance index improved by 8%, 4.4%, and 7% for RFS, OS, and CSS, respectively. On DCA, including ChoE did not improve the net benefit of standard prognostic models. CONCLUSION: Despite its independent association with RFS, OS, and CSS, preoperative serum ChoE has no impact on clinical decision-making. In future studies, ChoE should be investigated as part of the tumor microenvironment and assessed as part of predictive and prognostic models, specifically in the setting of immune checkpoint-inhibitor therapy.

Cytokeratin 20 expression is linked to stage progression and to poor prognosis in advanced (pT4) urothelial carcinoma of the bladder.

Cytokeratin 20 (CK20) expression is limited to umbrella cells in the normal urothelium. Since CK20 is often upregulated in neoplastic urothelial cells including dysplasia and carcinoma in situ, immunohistochemical CK20 analysis is often used for the assessment of bladder biopsies. CK20 expression is a feature of luminal bladder cancer subtype, but its prognostic relevance is disputed. In this study, we investigated CK20 on >2700 urothelial bladder carcinomas in a tissue microarray format by immunohistochemistry. Cytoplasmic and membranous CK20 staining was seen in 1319 (51.8%) cancers. The fraction of CK20 positive and especially strongly positive cases increased from pTaG2 low grade (44.5% strongly positive) and pTaG2 high grade (57.7%) to pTaG3 high grade (62.3%; p = 0.0006) but was lower in muscle-invasive (pT2-4) carcinomas (51.1% in all pTa vs. 29.6% in pT2-4; p < 0.0001). Within pT2-4 carcinomas, CK20 positivity was linked to nodal metastasis and lymphatic vessel invasion (p < 0.0001 each) and to venous invasion (p = 0.0177). CK20 staining was unrelated to overall patient survival if all 605 pT2-4 carcinomas were jointly analyzed but subgroup analyses revealed a significant association of CK20 positivity with favorable prognosis in 129 pT4 carcinomas (p = 0.0005). CK20 positivity was strongly linked to the expression of GATA3 (p < 0.0001), another feature of luminal bladder cancer. The combined analysis of both parameters showed best prognosis for luminal A (CK20+/GATA3+, CK20+/GATA3-) and worst outcome for luminal B (CK20-/GATA3+) and basal/squamous (CK20-/GATA3-) in pT4 urothelial carcinomas (p = 0.0005). In summary, the results of our study demonstrate a complex role of CK20 expression in urothelial neoplasms including neoexpression in pTa tumors, a subsequent loss of CK20 expression in a subset of tumors progressing to muscle-invasion, and a stage dependent prognostic role in muscle-invasive cancers.

Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors.

BACKGROUND: Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may help to distinguish p53 inactivation in IHC negative cases. MATERIAL AND METHODS: We investigated p53 and p16 immunostaining on 2710 urothelial bladder carcinomas in a tissue microarray format to understand their impact in relation to clinicopathological parameters of disease progression and patient outcome. RESULTS: p16 immunostaining was absent in normal urothelium but occurred in 63.5% (30.4% strong) of cancers. p16 strongly positive cases increased from pTaG2 low-grade (9.6%) to pTaG3 high-grade tumors (46.5%, p < .0001) but decreased from pTaG3 to pT4 (33.3%; p = .0030). Among pT2-4 carcinomas, p16 positivity was linked to high-grade (p = .0005) but unrelated to overall survival. p53 staining was negative in 8.4%, very weak in 15.4%, weak in 55.3%, strong in 4.7%, and very strong in 16.2% cancers. p53 negative (potentially p53 null phenotype), strong, and very strong p53 positivity increased from pTaG2 low-grade to pTaG3 high-grade tumors (p < .0001) and from pTaG3 to pT2-4 cancers (p = .0007). p53 staining was largely unrelated to histopathological parameters or patient prognosis among pT2-4 carcinomas, except of p53 strong/very strong immunostaining. p16 expression predominated in tumors with very strong, strong, and negative p53 staining and the combination of p53 negative/p16 strongly positive cancers was linked to features of tumor aggressiveness. CONCLUSION: Aberrant p53 and p16 immunostaining increases during grade and stage progression although p53 negative and p16 positive immunostaining lack prognostic significance in pT2-4 carcinomas. Potential diagnostic features are that high level p16 expression is limited to neoplastic urothelium and p53 null phenotype to aggressive cancers (grade 3 and invasive).

Anesthetic Technique (Spinal vs. General Anesthesia) in Holmium Laser Enucleation of the Prostate: Retrospective Analysis of Procedural and Functional Outcomes among 1,159 Patients.

OBJECTIVE: The aim of the study was to compare procedural efficacy, early and late functional outcomes in holmium laser enucleation of the prostate (HoLEP) under spinal anesthesia (SA) versus general anesthesia (GA). METHODS: We retrospectively reviewed patients undergoing HoLEP at our institution between 2012 and 2017. Standard pre-, peri-, and postoperative characteristics were compared according to anesthetic technique. Multivariable logistic regression analyses (MVAs) were employed to study the impact of SA on procedural efficacy and postoperative complications. RESULTS: Our study cohort consisted of 1,159 patients, of whom 374 (32%) underwent HoLEP under SA. While a medical history of any anticoagulation/antiplatelet therapy except low-dose acetylsalicylic acid was significantly more common among patients undergoing GA (16% vs. 10%, p = 0.001), no other significant differences in preoperative characteristics were noted including age, body mass index, American Society of Anesthesiologists Classification (ASA), prostate size, or International Prostate Symptom Score (IPSS), and quality of life scores. Patients under SA exhibited shorter times of enucleation 42 min (interquartile range [IQR]:27-59 vs. 45 min [IQR: 31-68], p = 0.002), and combined time of enucleation/morcellation/coagulation (57 min [IQR: 38-85] vs. 64 min [IQR: 43-93], p = 0.002), as well as fewer complications (Clavien-Dindo ≥3) (12 [3.2%] vs. 55 [7%], p = 0.013). These associations were confirmed in MVA. Patients did not differ significantly with regard to early micturition including post-void residual volume and maximum flow-rate improvement. At a median follow-up of 33 months (IQR: 32-44), patients with SA had a lower IPSS score (median 3 [IQR: 1-6] vs. 4 [IQR: 2-7], p = 0.039). However, no significant differences were observed with respect to any urinary incontinence, urge symptoms, and postoperative pain. CONCLUSION: In this large retrospective series, HoLEP under SA was a safe and efficacious procedure with comparable early and long-term functional outcomes.

Impact of preoperative plasma levels of interleukin 6 and interleukin 6 soluble receptor on disease outcomes after radical cystectomy for bladder cancer.

BACKGROUND: Preoperative plasma levels of Interleukin 6 (IL6) and its soluble receptor (IL6sR) have previously been associated with oncologic outcomes in urothelial carcinoma of the bladder (UCB); however, external validation in patients treated with radical cystectomy (RC) for UCB is missing. PATIENTS/METHODS: We prospectively collected preoperative plasma from 1,036 consecutive patients at two institutes. These plasma specimens were assessed for levels of IL6 and IL6sR. Logistic and Cox regression analyses were used to assess the correlation of plasma levels with pathologic and survival outcomes. The additional clinical net benefits of preoperative IL6 and IL6sR were evaluated using decision curve analysis (DCA). RESULTS: Median IL6 and IL6sR plasma levels were significantly higher in patients with adverse pathologic features. Elevated biomarker levels were independently associated with an increased risk for lymph node metastasis and ≥ pT3 disease. Both biomarkers were independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The addition to, respectively, fitted pre- and postoperative prognostic models improved the predictive accuracy for lymph node metastasis, ≥ pT3 disease, RFS and CSS on DCA. INTERPRETATION: We confirmed that elevated preoperative plasma levels of IL6 and IL6sR levels are associated with worse oncological disease survival in patients treated with RC for UCB in a large multicenter study. Both biomarkers hold potential in identifying patients with adverse pathological features that may benefit from intensified/multimodal therapy and warrant inclusion into predictive/prognostic models. They demonstrated the ability to improve the discriminatory power of such models and thus guide clinical decision making.

Preoperative plasma level of endoglin as a predictor for disease outcomes after radical cystectomy for nonmetastatic urothelial carcinoma of the bladder.

Elevated preoperative plasma level of endoglin has been associated with worse oncologic outcomes in various malignancies. The present large-scale study aimed to determine the predictive and prognostic values of preoperative endoglin with regard to clinicopathologic and survival outcomes in patients treated with radical cystectomy (RC) for nonmetastatic urothelial carcinoma of the bladder (UCB). We prospectively collected preoperative blood samples from 1036 consecutive patients treated with RC for UCB. Logistic and Cox regression analyses were undertaken to assess the correlation of endoglin levels with pathologic and survival outcomes, respectively. The AUC and C-index were used to assess the discrimination. Patients with adverse pathologic features had significantly higher median preoperative endoglin plasma levels than their counterparts. Higher preoperative endoglin level was independently associated with an increased risk for lymph node metastasis, ≥pT3 disease, and nonorgan confined disease (NOCD; all p < 0.001). Plasma endoglin level was also independently associated with cancer-specific and overall survival in both pre- and postoperative models (all p < 0.05), as well as with recurrence-free survival (RFS) in the preoperative model (p < 0.001). The addition of endoglin to the preoperative standard model improved its discrimination for prediction of lymph node metastasis, ≥pT3 disease, NOCD, and RFS (differential increases in C-indices: 10%, 5%, 5.8%, and 4%, respectively). Preoperative plasma endoglin is associated with features of biologically and clinically aggressive UCB as well as survival outcomes. Therefore, it seems to hold the potential of identifying UCB patients who may benefit from intensified therapy in addition to RC such as extended lymphadenectomy or/and preoperative systemic therapy.

A panel of systemic inflammatory response biomarkers for outcome prediction in patients treated with radical cystectomy for urothelial carcinoma.

OBJECTIVES: To determine the predictive and prognostic value of a panel of systemic inflammatory response (SIR) biomarkers relative to established clinicopathological variables in order to improve patient selection and facilitate more efficient delivery of peri-operative systemic therapy. MATERIALS AND METHODS: The preoperative serum levels of a panel of SIR biomarkers, including albumin-globulin ratio, neutrophil-lymphocyte ratio, De Ritis ratio, monocyte-lymphocyte ratio and modified Glasgow prognostic score were assessed in 4199 patients treated with radical cystectomy for clinically non-metastatic urothelial carcinoma of the bladder. Patients were randomly divided into a training and a testing cohort. A machine-learning-based variable selection approach (least absolute shrinkage and selection operator regression) was used for the fitting of several multivariable predictive and prognostic models. The outcomes of interest included prediction of upstaging to carcinoma invading bladder muscle (MIBC), lymph node involvement, pT3/4 disease, cancer-specific survival (CSS) and recurrence-free survival (RFS). The discriminatory ability of each model was either quantified by area under the receiver-operating curves or by the C-index. After validation and calibration of each model, a nomogram was created and decision-curve analysis was used to evaluate the clinical net benefit. RESULTS: For all outcome variables, at least one SIR biomarker was selected by the machine-learning process to be of high discriminative power during the fitting of the models. In the testing cohort, model performance evaluation for preoperative prediction of lymph node metastasis, ≥pT3 disease and upstaging to MIBC showed a 200-fold bootstrap-corrected area under the curve of 67.3%, 73% and 65.8%, respectively. For postoperative prognosis of CSS and RFS, a 200-fold bootstrap corrected C-index of 73.3% and 72.2%, respectively, was found. However, even the most predictive combinations of SIR biomarkers only marginally increased the discriminative ability of the respective model in comparison to established clinicopathological variables. CONCLUSION: While our machine-learning approach for fitting of the models with the highest discriminative ability incorporated several previously validated SIR biomarkers, these failed to improve the discriminative ability of the models to a clinically meaningful degree. While the prognostic and predictive value of such cheap and readily available biomarkers warrants further evaluation in the age of immunotherapy, additional novel biomarkers are still needed to improve risk stratification.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

PURPOSE: To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa). METHODS: We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy. RESULTS: Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively). CONCLUSION: BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

Active surveillance for non-muscle-invasive bladder cancer: fallacy or opportunity?

PURPOSE OF REVIEW: This review aims to analyze the current place of active surveillance (AS) in non-muscle-invasive bladder cancer (NMIBC). RECENT FINDINGS: A growing body of evidence suggests that AS protocols for pTa low-grade (TaLG) NMIBC are safe and feasible. However, current guidelines have not implemented AS due to a lack of high-quality data. Available studies included pTa tumors, with only one study excluding pT1-NMIBC. Inclusion/exclusion criteria were heterogeneously defined based on tumor volume, number of tumors, carcinoma in situ (CIS), or high-grade (HG) NMIBC. Tumor volume <10 mm and <5 lesions were used as cut-offs. Positive urinary cytology (UC) or cancer-related symptoms precluded inclusion. Surveillance within the first year consisted of quarterly cystoscopy. AS stopped upon the presence of cancer-related symptoms, change in tumor morphology, positive UC, or patient's request. With a median time on AS of 16 months, two-thirds of the patients failed AS. Progression to muscle-invasive bladder cancer (MIBC) was rare and occurred only in patients with pT1-NIMBC at inclusion. SUMMARY: AS in NMIBC is an attractive concept in the era of personalized medicine, but strong evidence is still awaited. A more precise definition of patient inclusion, follow-up, and failure criteria is required to improve its implementation in daily clinical practice.