The effect of hospital caseload on perioperative mortality, morbidity and costs in bladder cancer patients undergoing radical cystectomy: results of the German nationwide inpatient data.

OBJECTIVES: To determine a data-based optimal annual radical cystectomy (RC) hospital volume threshold and evaluate its clinical significance regarding perioperative mortality, complications, length of hospital stay, and hospital revenues. MATERIAL AND METHODS: We used the German Nationwide inpatient Data, provided by the Research Data Center of the Federal Bureau of Statistics (2005-2020). 95,841 patients undergoing RC were included. Based on ROC analyses, the optimal RC threshold to reduce mortality, ileus, sepsis, transfusion, hospital stay, and costs is 54, 50, 44, 44, 71 and 76 cases/year, respectively. Therefore, we defined an optimal annual hospital threshold of 50 RCs/year, and we also used the threshold of 20 RCs/year proposed by the EAU guidelines to perform multiple patient-level analyses. RESULTS: 28,291 (29.5%) patients were operated in low- (< 20 RC/year), 49,616 (51.8%) in intermediate- (20-49 RC/year), and 17,934 (18.7%) in high-volume (≥ 50 RC/year) centers. After adjusting for major risk factors, high-volume centers were associated with lower inpatient mortality (OR 0.72, 95% CI 0.64-0.8, p < 0.001), shorter length of hospital stay (2.7 days, 95% CI 2.4-2.9, p < 0.001) and lower costs (457 Euros, 95% CI 207-707, p < 0.001) compared to low-volume centers. Patients operated in low-volume centers developed more perioperative complications such as transfusion, sepsis, and ileus. CONCLUSIONS: Centralization of RC not only improves inpatient morbidity and mortality but also reduces hospital stay and costs. We propose a threshold of 50 RCs/year for optimal outcomes.

Oncological impact of perioperative blood transfusion in bladder cancer patients undergoing radical cystectomy: Do we need to consider storage time of blood units, donor age, or gender matching?

BACKGROUND: The oncological impact of perioperative blood transfusions (PBTs) of patients undergoing radical cystectomy (RC) because of bladder cancer (BCa) has been a controversial topic discussed in recent years. The main cause for the contradictory findings of existing studies might be the missing consideration of the storage time of red blood cell units (BUs), donor age, and gender matching. STUDY DESIGN AND METHODS: We retrospectively analyzed BCa patients who underwent RC in our department between 2004 and 2021. We excluded patients receiving BUs before RC, >10 BUs, or RC in a palliative setting. We assessed the effect of blood donor characteristics and storage time on overall survival (OS) and cancer-specific survival (CSS) through univariate and multivariable Cox regression analysis. We also performed a propensity score matching with patients who received BUs and patients who did not on a 1:1 ratio. RESULTS: We screened 1692 patients and included 676 patients for the propensity score matching. In the multivariable analysis, PBT was independently associated with worse OS and CSS (p < .001). Postoperative transfusions were associated with better OS (p = .004) and CSS (p = .008) compared to intraoperative or mixed transfusions. However, there was no influence of blood donor age, storage time, or gender matching on prognosis. DISCUSSION: In our study of BCa patients undergoing RC, we demonstrate that PBT, especially if administered intraoperatively, is an independent risk factor for a worse prognosis. However, storage time, donor age, or gender matching did not negatively affect oncological outcomes. Therefore, the specific selection of blood products does not promise any benefits.

Perioperative Outcomes of Same-Session Bilateral vs Unilateral Ureteroscopy for Stone Removal: Results from the GRAND Study.

Background: Same-session bilateral ureteroscopy may reduce the number of surgeries for stone removal but can lead to higher overall complication rates. We aimed to compare same-session bilateral ureteroscopy with unilateral ureteroscopy in terms of perioperative outcomes. Methods: We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2005-2021). We assessed, through multiple patient-level analyses, severe perioperative complications, mortality, length of hospital stay, hospital revenues, intensive care unit admission, and the evolution of ureteroscopy during the last years in Germany. Results: We included 833,609 patients undergoing either same-session bilateral (n = 6914, 0.8%) or unilateral (n = 826,695, 99.2%) ureteroscopy for stone management. Patients undergoing bilateral ureteroscopy presented worse baseline characteristics. After adjusting for these characteristics, same-session bilateral ureteroscopy, compared to unilateral ureteroscopy, was significantly associated with higher odds of postoperative sepsis (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 2-2.8, p < 0.001), myocardial infarction (OR: 2, 95% CI: 1.03-3.5, p = 0.024), acute kidney disease (OR: 2.8, 95% CI: 2.5-3.2, p < 0.001), transfusion (OR: 4.2, 95% CI: 3.6-4.8, p < 0.001), urinary tract infection (OR: 1.6, 95% CI: 1.5-1.7, p < 0.001), intensive care unit admission (OR: 1.9, 95% CI: 1.6-2.3, p < 0.001), and mortality (OR: 3.1, 95% CI: 2.1-4.5, p < 0.001). Similarly, the length of hospital stay was longer, and the in-hospital costs were higher (p < 0.001) after same-session bilateral ureteroscopy. Interestingly, the annual cases of ureteroscopy have undergone about a threefold increase in the last 17 years. Conclusions: The present real-world data demonstrate that same-session bilateral ureteroscopy leads to higher rates of perioperative myocardial infarction, acute kidney disease, transfusion, urinary tract infections, sepsis, and intensive care unit admission, as well as to increased length of hospital stay, costs, and inpatient mortality compared to unilateral ureteroscopy.

Absence of detrusor muscle in TUR-BT specimen - can we predict who is at highest risk?

INTRODUCTION: As a high-quality TUR-BT is important to ensure adequate treatment for bladder cancer patients, the aim of the current study is to investigate the impact of patient-related, surgical and tumor-specific parameters on detrusor muscle (DM) absence (primary objective) and to assess the impact of DM on the prognosis after a TUR-BT (secondary objective). PATIENTS AND METHODS: Transurethral resection of bladder tumors (TUR-BTs) between 2009 and 2021 were retrospectively screened (n = 3237). We included 2058 cases (1472 patients) for the primary and 472 patients for secondary objective. Clinicopathological variables including tumor size, localization, multifocality, configuration, operation time and skill-level of the urologist were assessed. We analyzed predictors for missing DM and prognostic factors for recurrence-free survival (RFS) for the complete cohort and subgroups. RESULTS: DM was present in 67.6% (n = 1371/2058). Surgery duration (continuous, minutes) was an independent predictor for absence of DM in the complete cohort (OR:0.98, r:0.012, 95%CI:0.98-0.99, p = 0.001). Other significant risk factors for missing DM were papillary tumors (OR:1.99, r:0.251, 95%CI:1.22-3.27, p = 0.006) in the complete cohort and bladder-roof and posterior-bladder-wall localization for re-resections. Absence of DM in high-grade BC correlated with reduced RFS (HR:1.96, 95%CI:1.0-3.79, p = 0.045). CONCLUSION: Sufficient time for a TUR-BT is mandatory to assure DM in the TUR-BT specimen. Also, cases with more difficult locations of bladder tumors should be performed with utmost surgical diligence and endourological training should incorporate how to perform such operations. Of note, DM correlates with improved oncological prognosis in high-grade BC.

Enucleation of the prostate as retreatment for recurrent or residual benign prostatic obstruction: a systematic review and a meta-analysis.

BACKGROUND: Anatomical endoscopic enucleation of the prostate (AEEP) is recommended for first line surgical treatment of benign prostatic obstruction (BPO) caused by moderate and large prostatic adenoma. However, its role in the retreatment setting after failed previous surgical treatment for BPO remains uncaptured. In this scope, we performed a systematic review and meta-analysis aiming to assess the safety and efficacy of AEEP in the retreatment setting. METHODS: We searched PubMed, Cochrane Library and Embase databases from inception to March 2022 for prospective or retrospective studies involving patients undergoing prostatic enucleation for recurrent or residual BPO after previous standard or minimally invasive surgical treatments for BPO. Based on data availability, we performed a meta-analysis comparing AEEP in patients with recurrent or residual BPO versus AEEP for primary BPO. PROSPERO: CRD42022308941). RESULTS: We included 15 studies in the systematic review and 10 in the meta-analysis (6553 patients, 841 with recurrent or residual BPO and 5712 with primary BPO). All included studies involved patients undergoing HoLEP or ThuLEP. In terms of Qmax, post-void residual, International Prostate Symptom Score, removed adenoma, operative time, duration of catheterization and hospital stay, as well as complications, HoLEP for recurrent or residual BPO was equally effective compared to HoLEP for primary BPO up to 1 year postoperatively. Importantly, the beneficial effect of HoLEP on the retreatment setting was observed after previous standard or minimally invasive surgical treatments for BPO. The overall strength of evidence for all outcomes was deemed very low. CONCLUSIONS: HoLEP may be safely and effectively used in experienced hands for the surgical treatment of recurrent or residual BPO in patients with large or moderate prostates following previous open, endoscopic or minimally invasive surgical treatment for BPO.

Complications After Radical Cystectomy: A Systematic Review and Meta-analysis of Randomized Controlled Trials with a Meta-regression Analysis.

CONTEXT: Radical cystectomy is considered a procedure of high complexity with a relative high complication rate. OBJECTIVE: To systematically summarize the literature regarding the complications of radical cystectomy and the factors that contribute to them. EVIDENCE ACQUISITION: We searched MEDLINE/PubMed, ClinicalTrials.gov, and Cochrane Library, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for randomized controlled trials (RCTs) on complications related to radical cystectomy. EVIDENCE SYNTHESIS: A total of 3766 studies were screened, and 44 studies were included in this systematic review and meta-analysis. Complications following radical cystectomy are quite common. The most common complications were gastrointestinal complications (20%), infectious complications (17%), and ileus (14%). The majority of complications occurring were Clavien I-II (45%). Specific measurable patient factors are related to certain complications and can be used to stratify risk and assist in preoperative counseling, while proper design of high-quality RCTs may better reflect real-life complication rates. CONCLUSIONS: In our study, RCTs with a low risk of bias had higher complication rates than studies with a high risk of bias, underlining the need for further improvement on complication reporting in order to refine surgical outcomes. PATIENT SUMMARY: Radical cystectomy is usually followed by high complication rates, which affect patients and are, in turn, strongly associated with patients' preoperative health status.

Intratumoral Heterogeneity of Molecular Subtypes in Muscle-invasive Bladder Cancer-An Extensive Multiregional Immunohistochemical Analysis.

BACKGROUND: Molecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant settings. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients. OBJECTIVE: To comprehensively assess the ITH of molecular subtypes in a cohort of muscle-invasive BC. DESIGN, SETTING, AND PARTICIPANTS: A total of 251 patients undergoing radical cystectomy were screened. Three cores of the tumor center (TC) and three cores of the invasive tumor front (TF) of each patient were assembled in a tissue microarray. Molecular subtypes were determined employing 12 pre-evaluated immunohistochemical markers (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3, TUBB2B, EPCAM, CDH1, and vimentin). A total of 18 072 spots were evaluated, of which 15 002 spots were assessed based on intensity, distribution, or combination. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Allocation to one of five different molecular subtypes-urothelial like, genomically unstable, small-cell/neuroendocrine like, basal/squamous cell carcinoma like, and mesenchymal like-was conducted for each patient for the complete tumor, individual cores, TF, and TC separately. The primary objective was to assess the ITH between the TF and TC (n = 208 patients). The secondary objective was the evaluation of multiregion ITH (n = 191 patients). An analysis of the composition of ITH cases, association with clinicopathological parameters, and prognosis was conducted. RESULTS AND LIMITATIONS: ITH between the TF and TC was seen in 12.5% (n = 26/208), and ITH defined by at least two different subtypes of any location was seen in 24.6% (n = 47/191). ITH was more frequent in locally confined (pT2) versus advanced (pT ≥3) BC stages (38.7% vs 21.9%, p = 0.046), and pT4 BC presented with significantly more basal subtypes than pT2 BC (26.2% vs 11.5%, p = 0.049). In our cohort, there was no association of subtype ITH with prognosis or accumulation of specific molecular subtypes in ITH cases. The key limitations were missing transcriptomic and mutational genetic validation as well as investigation of ITH beyond subtypes. CONCLUSIONS: Several molecular subtypes can be found in nearly every fourth case of muscle-invasive BC, when using immunohistochemistry. ITH must be given due consideration for subtype-guided strategies in BC. Genomic validation of these results is needed. PATIENT SUMMARY: Different molecular subtypes can be found in many cases of muscle-invasive bladder cancer. This might have implications for individualized, subtype-based therapeutic approaches.

Assessment of single-probe dual-energy lithotripters in percutaneous nephrolithotomy: a systematic review and meta-analysis of preclinical and clinical studies.

PURPOSE: To evaluate the safety and efficacy of single-probe dual-energy (SPDE) lithotripters in patients undergoing percutaneous nephrolithotripsy (PCNL) through a systematic review and meta-analysis. METHODS: We searched PubMed, Cochrane Library, Scopus and Embase databases until July 2022 for any preclinical or clinical studies, exploring the safety and efficacy of different SPDE lithotripters in patients undergoing PCNL. We performed a meta-analysis to compare stone-free rate, bleeding, or other complications and mean operative time between SPDE lithotripters and other lithotripters (PROSPERO: CRD42021285631). RESULTS: We included 16 studies (six preclinical, seven observational and three randomized with 625 participants) in the systematic review and four in the meta-analysis. Preclinical studies suggest that SPDE lithotripters are safe and effective for the management of renal stones. Among clinical studies, four studies assessed Trilogy with no comparative arm, two compared Trilogy or ShockPulse with a dual-probe dual-energy lithotripter, two compared Trilogy with a laser, one compared ShockPulse with a pneumatic lithotripter, and one directly compared Trilogy with ShockPulse. Comparing SPDE lithotripters to other lithotripters, no significant differences were demonstrated in stone free rate (OR 1.13, 95% CI 0.53-2.38, I2 = 0%), postoperative blood transfusion (OR 1.33, 95% CI 0.34-5.19, I2 = 0%), embolization (OR 0.45, 95% CI 0.02-12.06), operative time (WMD: 2.82 min, 95% CI -7.31-12.95, I2 = 78%) and postoperative complications based on the Clavien-Dindo classification. CONCLUSIONS: SPDE lithotripters represent a promising treatment modality for patients requiring PCNL. Despite the initial encouraging findings of preclinical and isolated clinical studies, it seems that Trilogy or ShockPulse provide similar efficiency compared to older generation devices.

Radiomics Signature Using Manual Versus Automated Segmentation for Lymph Node Staging of Bladder Cancer.

BACKGROUND: Bladder cancer (BC) treatment algorithms depend on accurate tumor staging. To date, computed tomography (CT) is recommended for assessment of lymph node (LN) metastatic spread in muscle-invasive and high-risk BC. However, the diagnostic efficacy of radiologist-evaluated CT imaging studies is limited. OBJECTIVE: To evaluate the performance of quantitative radiomics signatures for detection of LN metastases in BC. DESIGN, SETTING, AND PARTICIPANTS: Of 1354 patients with BC who underwent radical cystectomy (RC) with lymphadenectomy who were screened, 391 with pathological nodal staging (pN0: n = 297; pN+: n = 94) were included and randomized into training (n = 274) and test (n = 117) cohorts. Pelvic LNs were segmented manually and automatically. A total of 1004 radiomics features were extracted from each LN and a machine learning model was trained to assess pN status using histopathology labels as the ground truth. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Radiologist assessment was compared to radiomics-based analysis using manual and automated LN segmentations for detection of LN metastases in BC. Statistical analysis was performed using the receiver operating characteristics curve method and evaluated in terms of sensitivity, specificity, and area under the curve (AUC). RESULTS AND LIMITATIONS: In total, 1845 LNs were manually segmented. Automated segmentation correctly located 361/557 LNs in the test cohort. Manual and automatic masks achieved an AUC of 0.80 (95% confidence interval [CI] 0.69-0.91; p = 0.64) and 0.70 (95% CI: 0.58-0.82; p = 0.17), respectively, in the test cohort compared to radiologist assessment, with an AUC of 0.78 (95% CI 0.67-0.89). A combined model of a manually segmented radiomics signature and radiologist assessment reached an AUC of 0.81 (95% CI 0.71-0.92; p = 0.63). CONCLUSIONS: A radiomics signature allowed discrimination of nodal status with high diagnostic accuracy. The model based on manual LN segmentation outperformed the fully automated approach. PATIENT SUMMARY: For patients with bladder cancer, evaluation of computed tomography (CT) scans before surgery using a computer-based method for image analysis, called radiomics, may help in standardizing and improving the accuracy of assessment of lymph nodes. This could be a valuable tool for optimizing treatment options.

Surgical Trends and Complications in Partial and Radical Nephrectomy: Results from the GRAND Study.

BACKGROUND: We aimed to evaluate the current trends in renal cancer surgery, as well as to compare the perioperative outcomes of partial versus radical nephrectomy. METHODS: We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2005-2021). We report the largest study in the field, with 317,843 patients and multiple patient-level analyses. RESULTS: Overall, 123,924 (39%) patients underwent partial and 193,919 (61%) underwent radical nephrectomy in Germany from 2005 to 2021. Of them, 57,308 (18%) were operated on in low-, 142,702 (45%) in intermediate-, and 117,833 (37%) in high-volume centers. A total of 249,333 (78%) patients underwent open, 44,994 (14%) laparoscopic, and 23,516 (8%) robotic nephrectomy. The number of patients undergoing renal surgery remained relatively stable from 2005 to 2021. Over the study period, the utilization of partial nephrectomy increased threefold, while radical nephrectomy decreased by about 40%. After adjusting for major risk factors in the multivariate regression analysis, radical nephrectomy was associated with 3.2-fold higher odds (95% CI: 3.2 to 3.9, p < 0.001) of 30-day mortality, longer hospitalization by 1.9 days (95% CI: 1.9 to 2, p < 0.001), and higher inpatient costs by EUR 1778 (95% CI: 1694 to 1862, p < 0.001) compared to partial nephrectomy. Furthermore, radical nephrectomy had a higher risk of in-hospital transfusion (p < 0.001), sepsis (p < 0.001), acute respiratory failure (p < 0.001), acute kidney disease (p < 0.001), acute thromboembolism (p < 0.001), surgical wound infection (p < 0.001), ileus (p < 0.001), intensive care unit admission (p < 0.001), and pancreatitis (p < 0.001). CONCLUSIONS: More patients are offered partial nephrectomy in Germany. Patients undergoing radical nephrectomy present with a higher rate of concomitant risk factors and have increased perioperative morbidity and mortality, prolonged hospitalization, and increased in-hospital costs.

Expression of Nectin-4 in Variant Histologies of Bladder Cancer and Its Prognostic Value-Need for Biomarker Testing in High-Risk Patients?

Variant histologies of bladder cancer (BC) often present with advanced tumor stage and the status of perioperative therapy is unclear. Thereby, squamous cell carcinoma (SCC), adenocarcinoma (ADENO), and sarcomatoid urothelial carcinoma (SARCO) are the most frequent variants. Nectin-4 has emerged as a highly interesting target in BC and might guide therapeutic application of antibody−drug conjugates (ADC). We therefore aimed to investigate expression patterns and prognostic value of Nectin-4 in variant histologies of BC. A single-center retrospective analysis was conducted of patients who underwent radical cystectomy (RC) for BC and revealed variant histologies of BC in the final specimens. Immunohistochemical staining for Nectin-4 was performed on tissue microarrays with 59 SCC, 22 ADENO, and 24 SARCO, and Nectin-4 expression was scored using the histochemical scoring system (H-score). Overall survival (OS) and progression-free survival (PFS) was calculated by Kaplan−Meier method. Median expression of Nectin-4 was 150 (range 0−250) in SCC, 140.5 (range 30−275) in ADENO, and 10 (0−185) in SARCO, with significantly lower levels for SARCO compared to SCC or ADENO (p < 0.001). For SCC, ADENO or SARCO no differences regarding OS or PFS were observed based on Nectin-4 expression levels (p > 0.05). Multivariate analysis revealed nodal stage as an independent prognostic factor for OS and PFS and metastases for PFS but not Nectin-4 expression. In conclusion, Nectin-4 was not prognostic in histological subtypes of BC in our study cohort. However, the high expression of Nectin-4 in SCC and ADENO might guide future treatment with novel Nectin-4-directed ADCs and provide this high-risk patient collective with a new promising therapeutic option. Testing Nectin-4 expression as a biomarker should be considered in trials with SARCO, where low Nectin-4 expression has been observed.

Radiomics for the Prediction of Overall Survival in Patients with Bladder Cancer Prior to Radical Cystectomy.

(1) Background: To evaluate radiomics features as well as a combined model with clinical parameters for predicting overall survival in patients with bladder cancer (BCa). (2) Methods: This retrospective study included 301 BCa patients who received radical cystectomy (RC) and pelvic lymphadenectomy. Radiomics features were extracted from the regions of the primary tumor and pelvic lymph nodes as well as the peritumoral regions in preoperative CT scans. Cross-validation was performed in the training cohort, and a Cox regression model with an elastic net penalty was trained using radiomics features and clinical parameters. The models were evaluated with the time-dependent area under the ROC curve (AUC), Brier score and calibration curves. (3) Results: The median follow-up time was 56 months (95% CI: 48−74 months). In the follow-up period from 1 to 7 years after RC, radiomics models achieved comparable predictive performance to validated clinical parameters with an integrated AUC of 0.771 (95% CI: 0.657−0.869) compared to an integrated AUC of 0.761 (95% CI: 0.617−0.874) for the prediction of overall survival (p = 0.98). A combined clinical and radiomics model stratified patients into high-risk and low-risk groups with significantly different overall survival (p < 0.001). (4) Conclusions: Radiomics features based on preoperative CT scans have prognostic value in predicting overall survival before RC. Therefore, radiomics may guide early clinical decision-making.

The Burden of Fear of Cancer Recurrence in Genitourinary Cancers: A Prospective Study (NCT04535921).

INTRODUCTION: Fear of cancer recurrence (FCR) is a challenging and often unaddressed concern, and predictive factors for high FCR remain unclear. Therefore, the aim of the current study was to assess predictive factors for high FCR in patients undergoing surgery for genitourinary cancer. MATERIALS AND METHODS: Overall, 525 patients were prospectively included. FCR was measured using the validated FCR7 questionnaire prior to surgery and after receipt of the histological result. Family support, religiousness, quality-of-life impairment due to FCR, and distress were determined. Patient and tumor-related factors were compared with FCR levels using Mann-Whitney U test or Wilcoxon test. Multivariate analysis was performed by linear/binary regression. RESULTS: FCR after receipt of the final histology was significantly lower (median 13, range 6-34) than before surgery (median 15, range 6-36, p < 0.001). In univariate analysis, significant impact on preoperative FCR was observed for gender (p = 0.017), age (p = 0.002), working status (p = 0.038), and education (p = 0.002). High impairment of QoL was associated with higher FCR levels (p < 0.001). Comparing tumor-related factors with FCR, we observed significantly higher FCR scores in patients with nonorgan-confined disease (p = 0.011). CONCLUSION: This study is the first to describe FCR in patients with genitourinary cancers. Surgical treatment improves FCR. Sociodemographic factors like age, female gender, employment, and education were observed to influence FCR levels. Strong correlations between FCR, QoL, and psychological distress indicate the importance of further clinical screening for FCR. Tumor-related factors however seem to play a less prominent role.

Identification of the Tumor Infiltrating Lymphocytes (TILs) Landscape in Pure Squamous Cell Carcinoma of the Bladder.

Background: Tumor infiltrating lymphocytes (TILs) are known as important prognostic biomarkers and build the fundament for immunotherapy. However, the presence of TILs and its impact on outcome in pure squamous cell carcinoma (SCC) of the bladder remains uncertain. Methods: Out of 1600 patients undergoing radical cystectomy, 61 patients revealed pure bladder SCC in the final histopathological specimen. Retrospectively, immunohistochemical staining was performed on a subset of TILs (CD3+, CD4+, CD8+, CD20+). Endpoints were overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). The Kaplan−Meier method was used to evaluate survival outcomes. Results: Strong infiltration of CD3+ was found in 27 (44%); of CD4+ in 28 (46%); of CD8+ in 26 (43%); and of CD20+ in 27 tumors (44%). Improved OS was observed for strong CD3+ (p < 0.001); CD4+ (p = 0.045); CD8+ (p = 0.001); and CD20+ infiltration (p < 0.001). Increased rates of PFS were observed for CD3+ (p = 0.025) and CD20+ TILs (p = 0.002). In multivariate analyses, strong CD3+ (HR: 0.163, CI: 0.044−0.614) and strong CD8+ TILs (HR: 0.265, CI: 0.081−0.864) were revealed as predictors for OS and the strong infiltration of CD20+ cells (HR: 0.095, CI: 0.019−0.464) for PFS. Conclusions: These first results of TILs in bladder SCC revealed predictive values of CD3+, CD8+ and CD20+.

Outcomes and Prognostic Factors of Patients with Urothelial Carcinoma Undergoing Radical Cystectomy and pT0 in the Final Histology Without Neoadjuvant Chemotherapy.

Purpose: Absence of tumor in the final histopathology after radical cystectomy (RC) is a rare but potentially favorable outcome. Therefore, we aimed to analyze outcomes and prognostic factors of patients with urothelial carcinoma (UC) undergoing RC and T0 in the final histology without neoadjuvant chemotherapy at a high-volume academic center. Patients and Methods: We retrospectively analyzed patients undergoing RC for pure UC between 2004 and 2020. Cancer-specific survival (CSS) and overall survival (OS) were calculated using Kaplan-Meier analysis and group comparison by Log rank test. Potential prognostic factors were analyzed using univariate Cox regression models. Results: A total of 1051 patients with UC underwent RC. 72 patients (6.7%) showed pT0 in the final histology. Across all T-stages, 5-year CSS was significantly different with 88% for pT0, 80% for pTa/pTis, 78% for pT1, 76% for pT2, 51% for pT3 and 27% for pT4 in our cohort (p=0.001). Neither instillation therapy (HR 0.31, 95% CI 0.07-1.43), number of TURB prior RC (HR 1.47, 95% CI 0.25-6.18), use of photodynamic diagnostics (PDD) (HR 0.64, 95% CI 0.14-3.02), performing a second resection (HR 0.87, 95% CI 0.27-2.86), muscle-invasive disease prior RC at any TURB (HR 0.7, 95% CI 0.2-2.39) or muscle-invasive disease in the TURB prior RC (HR 1.0, 0.31-3.29) were associated with CSS in univariate analysis. Conclusion: pT0 reveals a survival benefit in patients undergoing RC for UC and therefore presents a distinctive tumor entity. As clinical and cystoscopic characteristics do not improve patient stratification, further research is warranted to define risk groups in this specific tumor entity.

Selecting the Best Candidates for Cisplatin-based Adjuvant Chemotherapy After Radical Cystectomy Among Patients with pN+ Bladder Cancer.

A trend towards greater benefit from adjuvant chemotherapy (ACT) in pN+ bladder cancer (BCa) has been observed in multiple randomized controlled trials. However, it is still unclear which patients might benefit the most from this approach. We retrospectively analyzed a multicenter cohort of 1381 patients with pTany pN1-3 cM0 R0 urothelial BCa treated with radical cystectomy (RC) with or without cisplatin-based ACT. The main endpoint was overall survival (OS) after RC. We performed 1:1 propensity score matching to adjust for baseline characteristics and conducted a classification and regression tree (CART) analysis to assess postoperative risk groups and Cox regression analyses to predict OS. Overall, 391 patients (28%) received cisplatin-based ACT. After matching, two cohorts of 281 patients with pN+ BCa were obtained. CART analysis stratified patients into three risk groups: favorable prognosis (≤pT2 and positive lymph node [PLN] count ≤2; odds ratio [OR] 0.43), intermediate prognosis (≥pT3 and PLN count ≤2; OR 0.92), and poor prognosis (pTany and PLN count ≥3; OR 1.36). Only patients with poor prognosis benefitted from ACT in terms of OS (HR 0.51; p < 0.001). We created the first algorithm that stratifies patients with pN+ BCa into prognostic classes and identified patients with pTany BCa with PLN ≥3 as the most suitable candidates for cisplatin-based ACT. PATIENT SUMMARY: We found that overall survival among patients with bladder cancer and evidence of lymph node involvement depends on cancer stage and the number of positive lymph nodes. Patients with more than three nodes affected by metastases seem to experience the greatest overall survival benefit from cisplatin-based chemotherapy after bladder removal. Our study suggests that patients with the highest risk should be prioritized for cisplatin-based chemotherapy after bladder removal.

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases.

Background: The APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family-mediated mutagenesis is widespread in human cancers. However, our knowledge of the biological feature and clinical relevance of APOBECs and APOBEC mutagenesis in cancers remains limited. Methods: In this study, with a series of bioinformatic and statistical approaches, we performed a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES) and targeted next-generation sequencing (NGS), transcriptome (bulk RNA-seq and single-cell RNA-seq), immune signatures and immune checkpoint blockade (ICB) potential, patient survival and drug sensitivity, to reveal the distribution characteristics and clinical significance of APOBECs and APOBEC mutagenesis in pan-cancer especially bladder cancer (BLCA). Results: APOBEC mutagenesis dominates in the mutational patterns of BLCA. A higher enrichment score of APOBEC mutagenesis correlates with favorable prognosis, immune activation and potential ICB response in BLCA patients. APOBEC3A and 3B play a significant role in the malignant progression and cell differentiation within the tumor microenvironment. Furthermore, using machine learning approaches, a prognostic APOBEC mutagenesis-related model was established and validated in different BLCA cohorts. Conclusions: Our study illustrates the characterization of APOBECs and APOBEC mutagenesis in multiple cancer types and highlights its potential value as a promising biomarker for prognosis and immunotherapy in BLCA.