Pallauf, Maximilian

Objectives To evaluate the benefit of neoadjuvant chemotherapy (NAC) for patients with high‐risk upper tract urothelial carcinoma (UTUC) using a large, well‐curated multi‐institutional database. Patients and Methods This study was a multi‐institutional retrospective analysis conducted by the UTUC Collaborative Network (UCAN), combining data from 2276 patients with UTUC who underwent radical nephroureterectomy at seven high‐volume tertiary care centres in the United States. The UCAN data were analysed to evaluate the impact of response to NAC on survival outcomes in patients with UTUC. Results A total of 378 patients in the UCAN database underwent NAC. On final surgical pathology, 101 patients (26.8%) had ≤ypT1N0 disease and were defined as NAC treatment responders. Patients who responded to NAC had significantly longer overall survival (OS) and progression‐free survival (PFS) compared to non‐responders. At 5 years post‐surgery, 81.5% of responders were alive compared to 59.8% of non‐responders. The median OS and PFS times among non‐responders were 7.0 years (95% confidence interval [CI] 5.6–9.7) and 6.0 years (95% CI 4.6–9.3) respectively, while the median OS and PFS were not reached among responders. Limitations of this study include its retrospective design, heterogeneity in chemotherapy regimens, and the absence of clearly defined patient selection criteria for treatment. Conclusion These data suggest that NAC can play a pivotal role in the treatment of well‐selected UTUC patients who respond positively. Non‐responders had clearly inferior outcomes. More work is needed to find predictors of response which can improve patient selection.

475 Background: Emerging evidence supports use of neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for appropriately selected patients with upper tract urothelial carcinoma (UTUC). However, oncologic outcomes have not been well characterized for patients with residual muscle-invasive disease after NAC. Methods: We used a multi-institutional cohort from 24 centers in the U.S., Europe, and Japan to retrospectively identify patients who underwent RNU for UTUC from 1985-2022 and had high-grade muscle-invasive disease. We stratified the cohort based on receipt of NAC (>ypT2 vs. >pT2). Exclusion criteria included receipt of adjuvant chemotherapy, concurrent cystectomy with RNU, and distant metastatic disease. Baseline characteristics were compared between groups. Kaplan-Meier survival analysis with log-rank test was used to compare differences in recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Multivariable Cox regression and Fine-Gray competing risk regression were used to determine predictors of these outcomes. Results: A total of 1,233 patients were included, 62 of whom received NAC prior to RNU. A platinum-based regimen was used in 90% of NAC recipients, and the median number of cycles administered was 4 (IQR: 3-5). Median follow-up time among all patients was 22 months (IQR: 8-47 mo.). NAC recipients were more likely to have pathologic node positivity (35% vs. 13%) and less likely to have positive tumor margins (8% vs. 28%). On Kaplan-Meier analysis, NAC recipients with residual >ypT2 disease had poorer outcomes than those with >pT2 disease (2-year RFS [NAC vs. no NAC]: 52% vs. 80%, p<0.001; 2-year OS: 60% vs. 78%, p=0.003; 2-year CSS: 61% vs. 86%, p<0.001). Multivariable analyses also showed a statistically significant association between residual muscle-invasive disease after NAC and poorer RFS, OS, and CSS (Table). Conclusions: NAC recipients with >ypT2 disease at RNU after exhibit poorer outcomes than stage-matched chemotherapy naïve counterparts. This may reflect effects of occult micrometastatic disease or chemoresistant primary tumors in non-responders. Our data highlight the need to improve prospective identification of candidates most likely to respond to NAC prior to RNU for UTUC in order to maximize its therapeutic benefit. [Table: see text]

Background: Measuring quality of care indicators is important for clinicians and decision making in health care to improve patient outcomes. Objective: The primary objective was to identify quality of care indicators for patients with upper tract urothelial carcinoma (UTUC) and to validate these in an international cohort treated with radical nephroureterectomy (RNU). The secondary objective was to assess the factors associated with failure to validate the pentafecta. Design: We performed a retrospective multicenter study of patients treated with RNU for EAU high-risk (HR) UTUC. Outcome measurements and statistical analysis: Five quality indicators were consensually approved, including a negative surgical margin, a complete bladder-cuff resection, the absence of hematological complications, the absence of major complications, and the absence of a 12-month postoperative recurrence. After multiple imputations and propensity-score matching, log-rank tests and a Cox regression were used to assess the survival outcomes. Logistic regression analyses assessed predictors for pentafecta failure. Results: Among the 1718 included patients, 844 (49%) achieved the pentafecta. The median follow-up was 31 months. Patients who achieved the pentafecta had superior 5-year overall- (OS) and cancer-specific survival (CSS) compared to those who did not (68.7 vs. 50.1% and 79.8 vs. 62.7%, respectively, all p < 0.001). On multivariable analyses, achieving the pentafecta was associated with improved recurrence-free survival (RFS), CSS, and OS. No preoperative clinical factors predicted a failure to validate the pentafecta. Conclusions: Establishing quality indicators for UTUC may help define prognosis and improve patient care. We propose a pentafecta quality criteria in RNU patients. Approximately half of the patients evaluated herein reached this endpoint, which in turn was independently associated with survival outcomes. Extended validation is needed.

SummaryMitochondrial dysfunction is often observed in aging skeletal muscle and is implicated in age‐related declines in physical function. Early evidence suggests that dietary omega‐3 polyunsaturated fatty acids (n‐3 PUFAs) improve mitochondrial function. Here, we show that 10 weeks of dietary eicosapentaenoic acid (EPA) supplementation partially attenuated the age‐related decline in mitochondrial function in mice, but this effect was not observed with docosahexaenoic acid (DHA). The improvement in mitochondrial function with EPA occurred in the absence of any changes in mitochondrial abundance or biogenesis, which was evaluated from RNA sequencing, large‐scale proteomics, and direct measurements of muscle mitochondrial protein synthesis rates. We find that EPA improves muscle protein quality, specifically by decreasing mitochondrial protein carbamylation, a post‐translational modification that is driven by inflammation. These results demonstrate that EPA attenuated the age‐related loss of mitochondrial function and improved mitochondrial protein quality through a mechanism that is likely linked with anti‐inflammatory properties of n‐3 PUFAs. Furthermore, we demonstrate that EPA and DHA exert some common biological effects (anticoagulation, anti‐inflammatory, reduced FXR/RXR activation), but also exhibit many distinct biological effects, a finding that underscores the importance of evaluating the therapeutic potential of individual n‐3 PUFAs.