Friedemann Zengerling

Purpose: Upper tract urothelial carcinoma (UTUC) is a rare malignancy arising from the renal pelvis or ureter and is often diagnosed at an advanced stage. Prognosis depends strongly on tumor stage and grade, but remains poorer than that of bladder urothelial carcinoma. Methods: This review article summarizes current evidence on the management of locally advanced but resectable UTUC, focusing on perioperative systemic therapy, clinical guideline recommendations, and emerging therapeutic strategies. Results: In high risk cases, radical nephroureterectomy (RNU) with bladder cuff excision is the surgical state of the art. To reduce relapse rates, perioperative systemic therapy is gaining increasing importance. Neoadjuvant platinum-based chemotherapy (+/- durvalumab) has shown promising rates of pathological downstaging, however, high level evidence is still lacking. In contrast, evidence for adjuvant therapy is stronger. Adjuvant platinum-based chemotherapy should be offered to patients with pT2-pT4 or pN+ disease within 90 days after RNU. Immune checkpoint inhibitors show activity in perioperative settings, but potential benefits in UTUC subgroups remain unclear. There are ongoing trials combining immunotherapy, chemotherapy, or targeted agents. Molecular profiling and novel strategies, such as mRNA vaccines and antibody-drug conjugates, may enable more personalized approaches and reshape the therapeutic landscape of UTUC. Conclusion: Management of locally advanced but resectable UTUC is evolving rapidly, driven by advances in perioperative systemic therapies and a growing understanding of the disease’s molecular biology. However, prognosis remains poor, underscoring the need to further improve treatment options.

Background: Bladder cancer (BC) can be characterized clinically as either non-muscle-invasive (NMIBC) or muscle-invasive (MIBC). While NMIBC generally has a favorable prognosis, MIBC is characterized by high morbidity and mortality. Understanding the molecular determinants of tumor invasion is critical, yet research is hampered by the limitations of current experimental models. Standard assays such as the Boyden chamber lack physiological complexity, while porcine bladder models suffer from tissue contamination and genetic variability. There is an urgent need for reliable models that mimic the intact tissue architecture. Methods: We established a unique ex vivo tissue invasion model (EXTIM) to evaluate the invasive capacity of BC cells within a largely intact tissue context, using freshly prepared bladders from mice. The invasiveness of human BC cells (RT4, T24, UMUC3) and the immortal urothelial cell strain (Y235T) was comparably evaluated using EXTIM, the Boyden chamber, and porcine models. Gene knockdown or ectopic expression of GJB3 or ORP3 indicated the suitability of EXTIM to investigate the impact of specific factors on tumor cell invasion. To identify novel genetic regulators of cell invasion, we combined EXTIM with a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout screen. Additionally, we utilized the EXTIM to perform a pharmacological screen of a small molecule library comprising 90 substances to identify compounds capable of suppressing BC cell dissemination. Results: Importantly, by combining EXTIM with genomewide CRISPR-Cas9 screening, we identified several candidate genes involved in BC progression. Notably, discoidin domain receptor tyrosine kinase 1 (DDR1) was identified as a functional inhibitor of tumor cell invasion. Furthermore, the small-molecule screen revealed that PD-156707, a selective antagonist of the endothelin receptor A (ETA), significantly suppresses cancer cell invasion within the EXTIM environment. Conclusions: EXTIM serves as a robust and physiologically relevant tool for assessing tumor cell invasion and migration under ex vivo conditions. EXTIM can be used to identify factors involved in the progression of invasive BC by high-throughput genetic screenings in an ex vivo organ culture system, by culturing cells after transmigration through the bladder tissue. Moreover, the impact of specific genetic factors in the process of tumor cell dissemination can be assessed by placing bladders from genetically modified mice into the EXTIM.

Objectives: The aim of this study was to assess the association of diabetes mellitus and its medications with overall response (ORR) and mortality or cancer-specific survival (CSS) in patients with metastatic urothelial cancer receiving enfortumab vedotin monotherapy. Methods: This multicentre retrospective cohort study was designed according to the guidelines for the synthesis of qualitative research (ENTREQ). Eligible patients were adults (≥18) years treated with enfortumab vedotin monotherapy for metastatic urothelial cancer between June 2024 and January 2025. A total of 125 patients were reported across 11 centres. Results: The cohort included 93 males (74.4%) and 32 females (25.6%), with a mean age of 68.3 years (SD 9.3). The primary tumour site was the bladder in 109 (87.2%) cases and the upper tract (UTUC) in 16 (12.8%) cases. Interestingly, medication with metformin was significantly associated with cancer-specific mortality (37.9% versus 77.8%; p = 0.019), while patients with insulin-dependent diabetes mellitus had a significantly better CSS (Log Rank = 0.004). Upon comparing only patients who already had diabetes mellitus and then received anti-diabetic medication, there was a significant association between patients with diabetes mellitus receiving metformin and a worse 3-month ORR (80.0% versus 55.6%; p = 0.039). Regarding the subpopulation of UTUC, cancer-specific mortality was significantly associated with metformin medication (p = 0.033). Conclusions: Despite recent reports that metformin has protective effects in urothelial cancer, our findings suggest that metformin use may be linked to worse responses and survival outcomes in patients treated with enfortumab vedotin monotherapy. Further research, particularly translational research into the underlying diabetic and pharmacologic pathways, is warranted.

Zusammenfassung: Das Urothelkarzinom des oberen Harntrakts („upper tract urothelial carcinoma“, UTUC) stellt eine seltene Tumorerkrankung dar, die häufig erst in fortgeschrittenen Stadien diagnostiziert wird. Die Diagnostik basiert auf einer CT-Urografie, Spülzytologie aus dem oberen Harntrakt und einer Ureterorenoskopie (URS). Die Risikostratifizierung in eine Low- und High-Risk-UTUC dient als Grundlage für die Therapieentscheidung. Beim High-Risk-UTUC stellt die radikale Nephroureterektomie (RNU) mit Blasenmanschettenresektion den operativen Standard dar, wobei in selektionierten Fällen auch nierenerhaltene Verfahren erwogen werden können. Da die RNU einen signifikanten Rückgang der Nierenfunktion mit sich bringt und erste prospektive Daten eine gute radiologische und pathologische Remissionsrate zeigen, wird die neoadjuvante Chemotherapie beim UTUC zunehmend diskutiert. Der Behandlungsstandard hingegen für Tumoren im pT2–pT4-Stadium oder bei einem positiven Lymphknotenstatus (pN+) ist die adjuvante platinbasierte Kombinationschemotherapie, sofern diese nicht bereits als neoadjuvante Therapie erfolgt ist. Die adjuvante Immuntherapie mit Nivolumab zeigte in der UTUC-Kohorte im Vergleich zum Harnblasenkarzinom keinen signifikanten Therapievorteil und sollte nur Patienten im Tumorstadium ≥pT3 und/oder pN+ (oder ≥ypT2 und/oder ypN+ nach neoadjuvanter Chemotherapie) angeboten werden, die für eine platinbasierte Kombinationschemotherapie ungeeignet sind oder diese ablehnen.

Purpose: To systematically analyze gender-specific differences in recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) as well as adverse events and quality of Life (QoL) as secondary aims in NMIBC patients undergoing cytostatic intravesical chemotherapy. Methods: A systematic review and meta-analysis were conducted on studies published between 1976 and 2024, following PRISMA guidelines. MEDLINE, Embase and Cochrane Library were used as literature sources. No restrictions were made concerning language, study region or publication type. Data from 12 studies encompassing 1,527 patients were analyzed. Outcomes were assessed using random-effects models, with gender as a primary variable of interest. A risk of bias assessment was done using the ROBINS-I tool or RoB2 as appropriate. Results: The pooled analysis demonstrated no statistically significant gender-specific differences in RFS (HR = 1.0625, 95% CI 0.8094–1.0526) or PFS (HR = 1.0861, 95% CI 0.7038–1.6760). Data on CSS and OS were insufficient for meaningful conclusions. Two included studies analyzed in univariate or multivariate regression gender as risk factor for recurrence or progression, but gender was not a significant risk factor. Adverse events and QoL outcomes were notably underreported, with no gender-specific data available. Conclusions: While this study found no significant gender-based differences in NMIBC outcomes following intravesical chemotherapy, the findings are limited by the small number of studies, underrepresentation of women, and inconsistent reporting of critical outcomes. Future research should prioritize gender-focused analyses and explore the molecular and genetic basis of potential differences to inform precision medicine and equitable care.

Accurate prediction of lymph node metastasis (LNM) in patients with testicular cancer is highly relevant for treatment decision-making and prognostic evaluation. Our study aimed to develop and validate clinical radiomics models for individual preoperative prediction of LNM in patients with testicular cancer. We enrolled 91 patients with clinicopathologically confirmed early-stage testicular cancer, with disease confined to the testes. We included five significant clinical risk factors (age, preoperative serum tumour markers AFP and B-HCG, histotype and BMI) to build the clinical model. After segmenting 273 retroperitoneal lymph nodes, we then combined the clinical risk factors and lymph node radiomics features to establish combined predictive models using Random Forest (RF), Light Gradient Boosting Machine (LGBM), Support Vector Machine Classifier (SVC), and K-Nearest Neighbours (KNN). Model performance was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). Finally, the decision curve analysis (DCA) was used to evaluate the clinical usefulness. The Random Forest combined clinical lymph node radiomics model with the highest AUC of 0.95 (±0.03 SD; 95% CI) was considered the candidate model with decision curve analysis, demonstrating its usefulness for preoperative prediction in the clinical setting. Our study has identified reliable and predictive machine learning techniques for predicting lymph node metastasis in early-stage testicular cancer. Identifying the most effective machine learning approaches for predictive analysis based on radiomics integrating clinical risk factors can expand the applicability of radiomics in precision oncology and cancer treatment.