543 Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Molecular subtypes of bladder cancer differ markedly with regard to sensitivity to cisplatinum based chemotherapy and harbour FGFR treatment targets to various content. Previously we did show that lumina tumors respond better to NACT, while FGFR1 expression is associated with chemo resistance (Ecke et al. 2022). The objective of this study was to determine wether radioligand therapy may be an appropriate option in chemoresistent tumors to justify subsequent prospective validation within the "Bladder BRIDGister". Methods: Formalin fixed paraffin embedded (FFPE) tissues from transurethral resections (TUR) before chemotherapy and cystectomy samples after NACT of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (CXCR4, FAP) were analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, hierarchical clustering, Kruskal-Wallis, chi square and contingency tests were done by JMP 9.0.0 (SAS software). Results: The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being histopathologically node negative. When comparing pretreatment with post treatment samples the median expression of KRT20 dropped 128fold, while FGFR1, CXCR4 and FAP mRNA expression increased 6,8fold, 1,9 fold and 2,9 fold, respectively. FAP was positively associated with KRT5, FGFR1 and CXCR4 in treatment naïve TUR biopsies (r=0.4051 p=0.0141, r=0.6458 p<0.0001 and r=0.7586 p<0.0001, respectively), but negatively associated with KRT20 (r=-0.3879 p=0.0194). As previously described, FGFR1 was negatively associated with pCR (r=-0.6418 p<0.0001). Similarly, CXCR4 and FAP trended to be negatively associated with pCR (r=-0.3181 p=0.0586; r=-0.3072 p=0.0684). Hierarchical clustering revealed that CXCR4 and FAP are elevated in stromal rich, KRT5 & KRT20 negative tumors not responding to NACT. Elevated FAP above median mRNA expression was significantly associated with resistance to NACT (chi2 4.314 p=0,0378). Combining elevated FAP and CXCR4 mRNA expression did identify 28% of the patients to be at high risk of NACT resistance (90%). Conclusions: Expression of the radioligand targets CXCR4 and FAP are associated with basal/stromal enriched tumors and resistance to NACT. Theranostic targeting of CXCR4 and FAP before NACT might increase response towards NACT in this poor prognosis group.
545 Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Molecular subtypes of bladder cancer differ markedly with regard to sensitivity to cisplatinum based chemotherapy. Previously we did show that luminal tumors respond better to NACT, while FGFR1 expression is associated with chemo resistance (Ecke et al. 2022). The objective of this study was to determine which patients may benefit from Antibody Drug Conjugate (ADC) treatment in addition to NACT to justify subsequent prospective analysis within the "Bladder BRIDGister". Methods: Formalin fixed paraffin embedded (FFPE) tissues from transurethral resections (TUR) before chemotherapy and cystectomy samples after NACT of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (NECTIN4, TROP2) were analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, hierarchical clustering, Kruskal-Wallis, chi square and contingency tests were done by JMP 9.0.0 (SAS software). Results: The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being pathohistologically node negative. When comparing pretreatment with post treatment samples the median expression of KRT20 dropped 128fold, while FGFR1 expression increased 6.8 fold. Interestingly, TROP2 and NECTIN4 mRNA expression also dropped significantly upon NACT by 5.7 fold and 7.1 fold, respectively. TROP2 and NECTIN4 were positively associated with the response marker KRT20 in therapy naïve TUR biopsies (r=0.5562 p=0.0004; r=0.5833 p=0.0002), but negatively associated with the resistance marker FGFR1 (r=-0.2903 p=0,0858; r=-0.3396 p=0,0427). However, TROP2 and NECTIN4 were not associated with pCR in spearman analysis with minor trend for TROP2 (r=0,2139 p=0,2103). Cluster analysis revealed a subgroup of KRT20 positive and FGFR1 negative tumors expression TROP2 and NECTIN4, which achieved 80% pCR. In addition elevated TROP2 and NECTIN4 expression was found in KRT20 positive tumors coexpressing FGFR1 and being resistant to NACT. Conclusions: Expression of the ADC targets TROP2 and NECTIN4 is associated with KRT20 positive, luminal tumors being highly sensitive to neoadjuvant chemotherapy alone. KRT5 positive, basal tumors do exhibit only very low expression of TROP2 and NECTIN4 mRNA. In view of toxicities the addition of TROP2 and NECTIN4 treatment to NACT might be considered only in luminal tumors exhibiting elevated FGFR1 expression as resistance mechanism and therefore do not respond to NACT.
161 Background: Although still discussed controversially, cRP represents a therapeutic option for mHSPC patients in the context of a multimodality approach. It was the purpose of our study to retrospectively review the oncological and functional outcome of a single-center cohort of cRP patients. Methods: A total of 134 mHSPC patients underwent cRP with pelvic lymphadenectomy. All patients received neoadjuvant androgen deprivation therapy (ADT, n = 34), ADT + docetaxel (n=15), or ADT plus ABI/ENZA/APA (n=85) for 6 months which was continued postop. Follow-up studies were performed at 3-month intervals, new imaging studies with 68Ga-PSMA PET/CT was done at PSA-levels > 1.0 ng/ml. Perioperative complications were evaluated according to Clavien-Dindo classification. Clinical progression free survival (cPFS) and cancer specific survival (CSS) were calculated via Kaplan-Maier analysis. Multivariate regression analysis was used to assess the impact of biopsy ISUP grade, PSA at diagnosis and preop., PSA decrease, T stage, and metastatic burden on PFS and CSS. Results: 115 and 19 had low and high volume mHSPC, resp. Mean age was 64.2 (42-88) years, mean preop. PSA was 3.2 (0.1-21.6) ng/ml. The median Follow-up ist 53.7 (4 – 168) months. M1a, M1b and M1c were present in 28 (20.9%), 98 (73.1%) and 8 (6.0%) men. Pathohistology demonstrated pT0 in 3 (2.2%), pT2a-c in 21 (15.7%), pT3 and pT4 in 105 (78.3%) and 5 (3.7%). pN0 and pN+ was diagnosed in 38 (28.3%) and 96 (71.7%) pts. There was no significant difference between type of ADT and final pathohistology. Clavien-Dindo Grad 3a-b and 4 complications were observed in 13 (9.7%) and 2 (1.5%) pts. CSS was 88.1% and cPFS was 53%. None of the pts developed locally recurrent disease. Overall survival was reduced in M1 high volume (61.9% vs 92.8%, p=0.002) and pN+ (85.7% vs 96.7%, p=0.001). cT≥3b (HR=2.24, p=0.02) and M1 high volume (HR=2.35, p=0.01) were associated with reduced cPFS; M1 high volume (HR=1.49, p=0.03) and relative PSA decrease £60% (HR=1.37, p=0.03) were associated with reduced CSS. Conclusions: cRP can be performed with minimal morbidity. mHSPC patients with clinically localized high risk PCA, low metastatic burden and good response to nADT benefit most from this approach. The risk for symptomatic local relapse is low. Limitation of the study is its retrospective design.
Introduction: Fournier gangrene is a life-threatening urological disease that requires rapid surgical intervention. Despite major improvements in medical therapy, the mortality of Fournier gangrene has not changed during the past 25 years. To potentially improve the outcome, we analyzed different medical processes for overall mortality in the treatment of Fournier gangrene. Methods: We performed a retrospective single-center study of 21 patients with Fournier gangrene. Patients were grouped according to initial symptoms, first medical advice, blood tests, medical history, and further clinical processes and compared using a t test, χ2 test, or Fisher exact test. A t test for heterogeneous variances was used if a Levene test showed significantly different variances, otherwise a t test for homogeneous variances was used. The log-rank test was applied for survival analysis. Logistic regression was applied to identify potential clinical predictors for mortality. Follow-up was performed until 130 days after the first surgical intervention. Results: There were no significant differences in the mortality rate of patients depending on the day and time of presentation in the hospital. Of the patients first consulting a urologist (either outpatient or hospital), no patient died within the first 120 days. By contrast, approximately 70% of patients who were transferred by a hospital without urologic specialization or a nonurologic outpatient clinic (P = .008) died within the first 130 days after surgery. Multivariate survival analysis showed that the type of first doctor's advice could serve as a significant factor in determining patients' mortality (P = .031), which also correlated with a significantly shorter duration of the first surgical procedure (110 vs 54 minutes, P = .019). Conclusion: Despite the small cohort, we were able to show a significant correlation between the initial doctor's advice, either by a urologist or nonurologist, and the patient's mortality. Considering the life-threatening potential of Fournier gangrene, professionals should develop strategies to educate nonurologists and raise awareness about this disease and its clinical presentation to optimize rapid intervention and reduce mortality.
e16603 Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT, while FGFR1 expression is associated with NACT resistance (Ecke et al. 2022). Interestingly the expression of the radioligand targets CXCR4 and FAP is found in chemoresistant, stroma-associated tumors. The objective of this study was to prospectively validate the predictive value of molecular target typing from TUR biopsy samples and compare PET CT imaging by FDG and FAP radioligand imaging in selected patients after two cycles of NACT to justify subsequent adaptive trial concepts within the "Bladder BRIDGister." Methods: Formalin fixed paraffin embedded tissues (FFPE) from transurethral resections (TUR) before chemotherapy and cystectomy samples after NACT of 36 patients were retrospectively collected and 650 TURB samples were prospectively collected as part of the Bladder BRIDGister. RNA from FFPE tissues were extracted by commercial kits, relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (CXCR4, FAP) were analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). PET CT Imaging by FDG and FAP was performed after two cycles cisplatinum based NACT. Results: The neoadjuvant cohort consisted of 36 patients (median age 69, male 83%, female 17%) with 92% of patients being node negative. Hierarchical clustering revealed CXCR4 and FAP to be elevated in stromal rich, KRT5 & KRT20 negative tumors not responding to NACT. Elevated FAP mRNA expression was sig. associated with resistance to NACT (chi2 4.314 p=0,0378). Combining elevated FAP and CXCR4 mRNA expression did identify 1/3 of the patients to be at high risk of NACT resistance (90%). Exemplarily one pT3 G3 patient was selected for PET CT imaging after two cycles that was predicted to be unresponsive to NACT by molecular subtyping. FDG PET CT revealed a hepatic metastatic lesion. In contrast FAP PET CT indicated multiple hepatic and a pancreatic metastatic lesion indicating tumor progression under NACT. Therapy was switched to MVAC with persistent non response. Then pembrolizumab monotherapy was administered due to PD-L1 positivity of the initial TURB (10% TPS /CPC 15). However there still was fulminant progression of the liver metastasis so that ICI therapy had to be stopped. Conclusions: Expression of the radioligand targets CXCR4 and FAP has been shown to be associated with aggressive stromal associated tumors and being resistant to NACT. This could be validated by selecting patients after two cycles of NACT for PET/CT imaging. Stratified FAP PET/CT turned out to be more sensitive than conventional FDG PET CT and may enable future theranostic treatment combinations in patients unresponsive to standard chemo- or immunotherapies.
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