Addition of neoadjuvant chemotherapy to a 'quadrifecta' composite in radical cystectomy.

OBJECTIVES: To evaluate the impact of incorporating neoadjuvant chemotherapy (NAC) into the 'quadrifecta' outcomes composite for reporting outcomes of radical cystectomy (RC) creating a pentafecta score. PATIENTS AND METHODS: This is a retrospective multicentre analysis of patients treated with RC, with or without NAC, for bladder cancer between 2002 and 2023. The primary outcome was the effect of adding NAC to a quadrifecta outcomes composite on cancer-specific (CSS) and overall survival (OS). The quadrifecta outcomes composite included a yield of ≥16 lymph nodes, negative soft tissue surgical margin, absence of major complication within 30 days from surgery, and no delay in RC. RESULTS: A total of 590 patients were included in the analyses. A total of 233 (39.5%) patients achieved all quadrifecta outcomes and 82 (13.9%) patients were additionally treated with NAC, achieving the pentafecta. Achieving the quadrifecta outcomes composite was significantly associated with better CSS (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.32-0.75; P = 0.001) and OS (HR 0.48, 95% CI 0.34-0.69; P < 0.01). The addition of NAC to the quadrifecta composite outcomes significantly improved the discrimination of patients more likely to have better CSS (HR 0.21, 95% CI 0.08-0.57; P = 0.002) and OS (HR 0.26, 95% CI 0.12-0.55; P < 0.01). CONCLUSION: We propose a new pentafecta that may serve as a tool for standardising outcomes reporting and measuring the quality of RC.

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 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.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Diagnostic Accuracy of Clinical Lymph Node Staging for Upper Tract Urothelial Cancer Patients: A Multicenter, Retrospective, Observational Study.

PURPOSE: Treatment options for the management of upper tract urothelial cancer are based on accurate staging. However, the performance of conventional cross-sectional imaging for clinical lymph node staging (N-staging) remains poorly investigated. This study aims to evaluate the diagnostic accuracy of conventional cross-sectional imaging for upper tract urothelial cancer N-staging. MATERIALS AND METHODS: This study was a multicenter, retrospective, observational study. We included 865 nonmetastatic (M0) upper tract urothelial cancer patients treated with curative intended surgery and lymph node dissection who had been staged with conventional cross-sectional imaging before surgery. We compared clinical (c) and pathological (p) N-staging results to evaluate the concordance of node-positive (N+) and node-negative (N0) disease and calculate cN-staging's diagnostic accuracy. RESULTS: Conventional cross-sectional imaging categorized 750 patients cN0 and 115 cN+. Lymph node dissection categorized 641 patients pN0 and 224 pN+. The cN-stage was pathologically downstaged in 6.8% of patients, upstaged in 19%, and found concordant in 74%. The sensitivity and specificity of cN-staging were 25% (95% CI 20; 31) and 91% (95% CI 88; 93). Positive and negative likelihood ratios were 2.7 (95% CI 2.0; 3.8) and 0.83 (95% CI 0.76; 0.89). The area under the receiver operating characteristics curve (0.58, 95% CI 0.55; 0.61) revealed low diagnostic accuracy. CONCLUSIONS: Conventional cross-sectional imaging had low sensitivity in detecting upper tract urothelial cancer pN+ disease. However, cN+ increased the likelihood of pN+ by almost threefold. Thus, conventional cross-sectional imaging is a rule-in but not a rule-out test. Lymph node dissection should remain the standard during extirpative upper tract urothelial cancer surgery to obtain accurate N-staging. cN+ could be a strong argument for early systemic treatment.

Surgical checklist adherence across urology expertise levels impacts transurethral resection of bladder tumour quality indicators.

OBJECTIVES: To address the association of perioperative surgical checklist across variable surgical expertise with transurethral resection of bladder tumour (TURBT) accuracy and oncological outcomes in non-muscle-invasive bladder cancer. PATIENTS AND METHODS: We relied on our prospective collaborative database of patients treated with TURBT between 2012 and 2017. Surgical experience was stratified into three groups: resident vs young vs expert consultants. The association of surgical experience with detrusor muscle (DM) presence and adherence to the standardised peri-procedural nine-items TURBT checklist was evaluated with logistic regression models. A Cox regression model was used to investigate the association of surgical experience with recurrence-free survival (RFS). RESULTS: A total of 503 patients were available for analysis. TURBT was performed by expert consultants in 265 (52.7%) patients, by young consultants in 149 (29.6%) and by residents in 89 (17.7%). Residents were more likely to have DM in the TURBT specimen than expert consultants (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.03-2.99, P = 0.04). Conversely, no differences in DM presence were seen between young vs expert consultants (OR 1.09, 95% CI 0.71-1.70, P = 0.69). The median checklist completion rate was higher for both residents and young consultants when compared to experts' counterparts (56% and 56% vs 44%, P = 0.009). When focusing on patients receiving a second-look TURBT, the persistent disease was associated with resident status (OR 4.24, 95% CI 1.14-17.70, P = 0.037) at initial TURBT. Surgical experience was not associated with 5-years RFS. CONCLUSION: Surgeon's experience in the case of adequate perioperative surgical checklist implementation was inversely associated with the presence of DM in the specimen but directly linked to higher probability of persistent disease at re-TURBT, although no 5-year RFS differences were noted.

Oncological and safety profiles in patients undergoing simultaneous transurethral resection (TUR) of bladder tumour and TUR of the prostate.

OBJECTIVES: To determine the oncological impact and adverse events of performing simultaneous transurethral resection of bladder tumour (TURB) and transurethral resection of the prostate (TURP), as evidence on the outcomes of simultaneous TURB for bladder cancer and TURP for obstructive benign prostatic hyperplasia is limited and contradictory. PATIENTS AND METHODS: Patients from 12 European hospitals treated with either TURB alone or simultaneous TURB and TURP (TURB+TURP) were retrospectively analysed. A propensity score matching (PSM) 1:1 was performed with patients from the TURB+TURP group matched to TURB-alone patients. Associations between surgery approach with recurrence-free (RFS) and progression-free (PFS) survivals were assessed in Cox regression models before and after PSM. We performed a subgroup analysis in patients with risk factors for recurrence (multifocality and/or tumour size >3 cm). RESULTS: A total of 762 men were included, among whom, 76% (581) underwent a TURB alone and 24% (181) a TURB+TURP. There was no difference in terms of tumour characteristics between the groups. We observed comparable length of stay as well as complication rates including major complications (Clavien-Dindo Grade ≥III) for the TURB-alone vs TURB+TURP groups, while the latest led to longer operative time (P < 0.001). During a median follow-up of 44 months, there were more recurrences in the TURB-alone (47%) compared to the TURB+TURP group (28%; P < 0.001). Interestingly, there were more recurrences at the bladder neck/prostatic fossa in the TURB-alone group (55% vs 3%, P < 0.001). TURB+TURP procedures were associated with improved RFS (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.29-0.53; P < 0.001), but not PFS (HR 1.63, 95% CI 0.90-2.98; P = 0.11). Within the PSM cohort of 254 patients, the simultaneous TURB+TURP was still associated with improved RFS (HR 0.33, 95% CI 0.22-0.49; P < 0.001). This was also true in the subgroup of 380 patients with recurrence risk factors (HR 0.41, 95% CI 0.28-0.62; P < 0.001). CONCLUSION: In our contemporary cohort, simultaneous TURB and TURP seems to be an oncologically safe option that may, even, improve RFS by potentially preventing disease recurrence at the bladder neck and in the prostatic fossa.

En bloc resection of bladder tumour: the rebirth of past through reminiscence.

PURPOSE: To learn about the history and development of en bloc resection of bladder tumour (ERBT), and to discuss its future directions in managing bladder cancer. METHODS: In this narrative review, we summarised the history and early development of ERBT, previous attempts in overcoming the tumour size limitation, consolidative effort in standardising the ERBT procedure, emerging evidence in ERBT, evolving concepts in treating large bladder tumours, and the future directions of ERBT. RESULTS: Since the first report on ERBT in 1980, there has been tremendous advancement in terms of its technique, energy modalities and tumour retrieval methods. In 2020, the international consensus statement on ERBT has been developed and it serves as a standard reference for urologists to practise ERBT. Recently, high-quality evidence on ERBT has been emerging. Of note, the EB-StaR study showed that ERBT led to a reduction in 1-year recurrence rate from 38.1 to 28.5%. An individual patient data meta-analysis is currently underway, and it will be instrumental in defining the true value of ERBT in treating non-muscle-invasive bladder cancer. For large bladder tumours, modified approaches of ERBT should be accepted, as the quality of resection is more important than a mere removal of tumour in one piece. The global ERBT registry has been launched to study the value of ERBT in a real-world setting. CONCLUSION: ERBT is a promising surgical technique in treating bladder cancer and it has gained increasing interest globally. It is about time for us to embrace this technique in our clinical practice.

Impact of sex on outcomes after surgery for non-muscle-invasive and muscle-invasive bladder urothelial carcinoma: a systematic review and meta-analysis.

PURPOSE: To assess the prognostic value of sex for non-muscle-invasive/muscle-invasive bladder urothelial carcinoma (NMIBC/MIBC) treated with radical surgery. METHODS: The PubMed, Web of Science, and Scopus databases were searched in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they involved the comparison of the overall, cancer-specific, progression, and recurrence-free survival of patients with NMIBC/MIBC. Formal sex-stratified meta-analyses of these outcomes were performed. RESULTS: Thirty-one studies, which included 32,525 patients with NMIBC, and 63 studies, which included 85,132 patients with MIBC, were eligible for review and meta-analysis. Female sex was associated with worse cancer-specific survival (pooled hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.11-1.31) and overall survival (pooled HR, 1.02; 95% CI, 1.00-1.05) in patients with MIBC. In contrast, however, sex was not associated with cancer-specific survival (pooled HR, 1.01; 95% CI, 0.70-1.46), progression-free survival (pooled HR, 1.04; 95% CI, 0.88-1.24), and recurrence-free survival (pooled HR, 1.06; 95% CI, 0.98-1.16) in patients with NMIBC. CONCLUSIONS: Sex is associated with an increased risk of worse survival outcomes in patients with MIBC but not in those with NMIBC. Given the genetic and social differences between sexes, sex may represent a key factor in the clinical decision-making process.

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.

En-bloc resection of non-muscle invasive bladder cancer: does it really make a difference?

PURPOSE OF REVIEW: Transurethral resection of bladder tumour (TURBT) followed by pathology investigation of the obtained specimens is the initial step in the management of urinary bladder cancer (UBC). By following the basic principles of oncological surgery, en-bloc resection of bladder tumour (ERBT) aims to overcome the limitations associated with conventional transurethral resection, and to improve the quality of pathological specimens for a better decision making. The current bulk of evidence provides controversial results regarding the superiority of one technique over the other. The aim of this article is to summarize the recent data and provide evidence on this unanswered question. RECENT FINDINGS: Despite heterogeneous and controversial data, ERBT seems to have a better safety profile and deliver higher quality pathologic specimens. However, the recent evidence failed to support the hypothesized oncological potential benefits of ERBT in the initial surgical treatment of patients with UBC. SUMMARY: ERBT has gained increasing interest globally in the past decade. It continues to represent a promising strategy with a variety of features intended to solve the inherent limitations of TURBT. However, the current quality of evidence does not allow solid conclusions to be drawn about its presumed superiority compared with the conventional technique.

Age represents the main driver of surgical decision making in patients candidate to radical cystectomy.

BACKGROUND AND OBJECTIVES: Age might influence the choice of surgical approach, type of urinary diversion (UD) and lymph node dissection (LND) in patients candidate to radical cystectomy (RC) for urothelial bladder cancer (UBC). Similarly, age may enhance surgical morbidity and worsen perioperative outcomes. We tested the impact of age (octogenarian vs. younger patients) on surgical decision making and peri- and postoperative outcomes of RC. METHODS: Non-metastatic muscle-invasive UBC patients treated with RC at 18 high-volume European institutions between 2006 and 2021 were identified and stratified according to age (≥80 vs. <80 years). Intraoperative Complications Assessment and Reporting with Universal Standards and European Association of Urology guidelines recommendations were accomplished in collection and reporting of, respectively, intraoperative and postoperative complications. Multivariable logistic regression models (MVA) tested the impact of age on outcomes of interest. Sensitivity analyses after 1:3 propensity score matching were performed. RESULTS: Of 1955 overall patients, 251 (13%) were ≥80-year-old. Minimally invasive RC was performed in 18% and 40% of octogenarian and younger patients, respectively (p < 0.001). UD without bowel manipulation (ureterocutaneostomy, UCS) was performed in 31% and 7% of octogenarian and younger patients (p < 0.001). LND was delivered to 81% and 93% of octogenarian and younger patients (p < 0.001). At MVA, age ≥80 years independently predicted open approach (odds ratio [OR]: 1.55), UCS (OR: 3.70), and omission of LND (OR: 0.41; all p ≤ 0.02). Compared to their younger counterparts, octogenarian patients experienced higher rates of intraoperative (8% vs. 4%, p = 0.04) but not of postoperative complications (64% vs. 61%, p = 0.07). At MVA, age ≥80 years was not an independent predictor of length of stay, intraoperative or postoperative transfusions and complications, and readmissions (all p values >0.1). These results were replicated in sensitivity analyses. CONCLUSIONS: Age ≥80 years does not independently portend worse surgical outcomes for RC. However, octogenarians are unreasonably more likely to receive open approach and UCS diversion, and less likely to undergo LND.

Biological and prognostic implications of biopsy upgrading for high-grade upper tract urothelial carcinoma at nephroureterectomy.

OBJECTIVES: Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. METHODS: Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens. RESULTS: This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low-grade biopsy. CONCLUSIONS: High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU.

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.

En Bloc Resection for Bladder Tumors: An Updated Systematic Review and Meta-Analysis of Its Differential Effect on Safety, Recurrence and Histopathology.

PURPOSE: En bloc resection for bladder tumors has been developed to overcome shortcomings of conventional transurethral resection of bladder tumors with regard to safety, pathological evaluation and oncologic outcomes. However, the potential benefits and utility compared to conventional transurethral resection of bladder tumors have not been conclusively demonstrated. We aimed to update the current evidence with focus on the pathological benefits of en bloc resection for nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: The PubMed®, Web of Science™ and Scopus® databases were searched in August 2021 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they compared safety, and pathological and clinical outcomes in patients who underwent en bloc resection with conventional transurethral resection of bladder tumors. RESULTS: Overall, 29 studies comprising 4,484 patients were eligible for this meta-analysis. Among 13 randomized controlled trials, the pooled 12- and 24-month recurrence risk ratios were not statistically different between the 2 surgical techniques (0.96, 95% CI 0.74-1.23 and 0.83, 95% CI 0.55-1.23, respectively). The pooled risk ratio for bladder perforation was 0.13 (95% CI 0.05-0.34) in favor of en bloc resection. In randomized controlled trials, the differential rates of detrusor muscle presence (pooled RR 1.31, 95% CI 1.19-1.43) and of detectable muscularis mucosae (pooled RR 2.69, 95% CI 1.81-3.97) were more likely in patients receiving en bloc resection. Patients who underwent en bloc resection had a lower rate of residual tumor at repeat transurethral resection than those treated with conventional transurethral resection of bladder tumors in 1 randomized controlled trial and 3 observational studies (pooled RR 0.47, 95% CI 0.31-0.71). CONCLUSIONS: En bloc resection for bladder tumors seems to be safer, and to yield superior histopathological information and performance compared to conventional transurethral resection of bladder tumors. Despite the failure to improve the recurrence rate, the more accurate histopathological analysis is likely to improve clinical decision making and care delivery in nonmuscle-invasive bladder cancer.

Identifying the Optimal Number of Neoadjuvant Chemotherapy Cycles in Patients with Muscle Invasive Bladder Cancer.

PURPOSE: We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer. MATERIALS AND METHODS: In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated. RESULTS: pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57, p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p=0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p=0.08). CONCLUSIONS: Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.

Prognostic Role of Preoperative Vascular Cell Adhesion Molecule-1 Plasma Levels in Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy.

BACKGROUND: Angiogenesis-related marker vascular cell adhesion molecule-1 (VCAM-1) has been shown to be elevated in urothelial carcinoma of the bladder (UCB), but its predictive/prognostic role has not been determined. Thus, this study aimed to investigate the predictive/prognostic role of VCAM-1 for patients who have UCB treated with radical cystectomy (RC). METHODS: The study enrolled 1036 patients with clinically non-metastatic advanced UCB who underwent RC, and plasma VCAM-1 was evaluated preoperatively. The correlation of plasma VCAM-1 with pathologic and survival outcomes was assessed using binominal logistic regression and multivariable Cox regression analyses. Discrimination was assessed using the area under the curve and concordance indices. The clinical net benefit was evaluated using decision curve analysis (DCA). RESULTS: Preoperative VCAM-1 was significantly elevated in patients with adverse pathologic features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node-metastasis (LNM), ≥pT3 disease, and non-organ-confined disease (NOCD (p < 0.001 for each). Preoperative plasma VCAM-1 was independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in pre- and postoperative multivariable models. Adding VCAM-1 to these predictive models improved their discriminatory ability to predict all outcomes by a significant margin. In the DCA, VCAM-1 addition to the reference models for prediction of LNM, NOCD, RFS, and CSS resulted in relevant improvement. CONCLUSIONS: Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from intensified/multimodal therapy. In addition, VCAM-1 improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making.

Comparative effectiveness of moderate hypofractionation with volumetric modulated arc therapy versus conventional 3D-radiotherapy after radical prostatectomy.

PURPOSE: Hypofractionated radiotherapy for prostate cancer is well established for definitive treatment, but not well defined in the postoperative setting. The purpose of this analysis was to assess oncologic outcomes and toxicity in a large cohort of patients treated with conventionally fractionated three-dimensional (3D) conformal radiotherapy (CF) and hypofractionated volumetric modulated arc therapy (HF) after radical prostatectomy. METHODS: Between 1994 and 2019, a total of 855 patients with prostate carcinoma were treated by postoperative radiotherapy using CF (total dose 65-72 Gy, single fraction 1.8-2 Gy) in 572 patients and HF (total dose 62.5-63.75 Gy, single fraction 2.5-2.55 Gy) in 283 patients. The association of treatment modality with biochemical control, overall survival (OS), and gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using logistic and Cox regression analysis. RESULTS: There was no difference between the two modalities regarding biochemical control rates (77% versus 81%, respectively, for HF and CF at 24 months and 58% and 64% at 60 months; p = 0.20). OS estimates after 5 years: 95% versus 93% (p = 0.72). Patients undergoing HF had less frequent grade 2 or higher acute GI or GU side effects (p = 0.03 and p = 0.005, respectively). There were no differences in late GI side effects between modalities (hazard ratio 0.99). Median follow-up was 23 months for HF and 72 months for CF (p < 0.001). CONCLUSION: For radiation therapy of resected prostate cancer, our analysis of this largest single-centre cohort (n = 283) treated with hypofractionation with advanced treatment techniques compared with conventional fractionation did not yield different outcomes in terms of biochemical control and toxicities. Prospective investigating of HF is merited.

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.