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.

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.

Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and MAPK signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.

Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges. Antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2), trophoblast cell surface antigen 2 (TROP-2), and nectin cell adhesion molecule 4 (NECTIN4) offer promising therapeutic options. This study examined the spatial expression of HER2, TROP-2, and NECTIN4 in MIBC and metastases, their association with molecular subtypes, and clinical outcomes. Formalin-fixed, paraffin-embedded tissue samples from 251 patients with MIBC were analyzed using immunohistochemistry and tissue microarray analysis. Expression patterns between the tumor front and tumor center (TC) were compared, and statistical analyses assessed associations with molecular subtypes and clinical parameters. Additionally, 67 matched lymph node metastases and a secondary cohort comprising 16 distant metastases, including 7 matched primary tumors, were examined to explore the expression patterns in advanced tumor stages. In primary tumors, HER2 was predominantly negative (83%) but showed higher positivity in the TC. TROP-2 exhibited high overall expression (58% score 3+), whereas NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Spatial overexpression of TROP-2 and NECTIN4 at the tumor front relative to the TC was associated with a better disease-free survival. Accurate assessment required 4 biopsies for HER2 and NECTIN4 and 3 for TROP-2. HER2 expression was associated with urothelial-like and genomically unstable molecular subtypes, whereas TROP-2 was widely expressed except in the mesenchymal-like subtype. NECTIN4 showed the absence of staining in basal, Mes-like, and Sc/NEC-like subtypes. Paired lymph node metastases showed higher expression scores for all 3 markers, whereas distant metastases showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed a considerable heterogeneity for HER2 compared with their matched primary tumors. The spatial heterogeneity of HER2, TROP-2, and NECTIN4 expression necessitates multiple biopsies, particularly from the TC, for accurate evaluation. These findings underscore the need for personalized treatment strategies in MIBC, considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the TC. Implementing a multibiopsy approach is critical to enhancing diagnostic accuracy.

Introduction: Enhanced recovery after surgery (ERAS) concepts are implemented in various surgical disciplines. For patients undergoing radical cystectomy, prospective data are still rare. In the year 2014, our group could prove significant benefits of ERAS for these patients in a prospective randomized study compared to a conservative regimen. Objective: To evaluate long-term follow-up results of ERAS concepts in patients undergoing radical cystectomy for bladder cancer. Methods: Of the 101 patients who had initially prospectively been randomized to ERAS or a conservative regimen, 35 patients could be included in the study. Median follow-up time was 83 months. Primary end point assessed quality of life. Secondary end points were cancer-specific survival and overall survival. Results: Five to seven years after the initial inclusion to the study, no significant difference regarding quality of life parameters was detected (p values range between 0.112 and 0.970). Continence status in patients with neobladder showed no significant differences between ERAS and conservative regimens (p = 0.785). Cancer-specific survival in the ERAS group did not differ significantly from that in the conservative group (49 vs. 58%, p = 0.725). Conclusions: While ERAS represents an excellent way to improve postoperative reconvalescence and quality of life in the short-term follow-up, our data do not support the idea that there is also a long-term effect in terms of quality of life issues.