Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population—embryonal carcinoma (EC)—is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra‐embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three‐dimensional (3D) co‐cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho‐ and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin‐resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.

Background: Large language models (LLMs) such as ChatGPT, Google Gemini, and Microsoft Copilot are increasingly used by patients seeking medical information online. While these tools provide accessible and conversational explanations, their accuracy and safety in emotionally sensitive scenarios—such as an incidental cancer diagnosis—remain uncertain. Objective: To evaluate the quality, completeness, readability, and safety of responses generated by three state-of-the-art LLMs to common patient questions following the incidental discovery of a kidney tumor. Methods: A standardized use-case scenario was developed: a patient learns of a suspicious renal mass following a computed tomography (CT) scan for back pain. Ten plain-language prompts reflecting typical patient concerns were submitted to ChatGPT-4o, Microsoft Copilot, and Google Gemini 2.5 Pro without additional context. Responses were independently assessed by five board-certified urologists using a validated six-domain rubric (accuracy, completeness, clarity, currency, risk of harm, hallucinations), scored on a 1–5 Likert scale. Two statistical approaches were applied to calculate descriptive scores and inter-rater reliability (Fleiss’ Kappa). Readability was analyzed using the Flesch Reading Ease (FRE) and Flesch–Kincaid Grade Level (FKGL) metrics. Results: Google Gemini 2.5 Pro achieved the highest mean ratings across most domains, notably in accuracy (4.3), completeness (4.3), and low hallucination rate (4.6). Microsoft Copilot was noted for empathetic language and consistent disclaimers but showed slightly lower clarity and currency scores. ChatGPT-4o demonstrated strengths in conversational flow but displayed more variability in clinical precision. Overall, 14% of responses were flagged as potentially misleading or incomplete. Inter-rater agreement was substantial across all domains (κ = 0.68). Readability varied between models: ChatGPT responses were easiest to understand (FRE = 48.5; FKGL = 11.94), while Gemini’s were the most complex (FRE = 29.9; FKGL = 13.3). Conclusions: LLMs show promise in patient-facing communication but currently fall short of providing consistently accurate, complete, and guideline-conform information in high-stakes contexts such as incidental cancer diagnoses. While their tone and structure may support patient engagement, they should not be used autonomously for counseling. Further fine-tuning, clinical validation, and supervision are essential for safe integration into patient care.

Prostate Imaging Reporting and Data System version 2.1 (PI-RADS) category 3 lesions are a challenge in the clinical workflow. A better detection of the infrequently occurring clinically significant prostate cancer (csPCa) in PI-RADS 3 lesions is an important objective. The purpose of this study was to evaluate if feature maps calculated from T2-weighted (T2w) 3 Tesla (3T) MRI can help detect csPCa in PI-RADS category 3 lesions. In-house biparametric 3T prostate MRI examinations acquired between January 2019 and June 2023 because of elevated prostate-specific antigen (PSA) levels were retrospectively screened. Inclusion criteria were a PI-RADS 3 lesion and available results of an ultrasound-guided targeted and systematic biopsy. Exclusion criteria were a simultaneous PI-RADS category 4 or 5 lesion and hip replacement. Target lesions with the International Society of Urological Pathology (ISUP) grade group 1 were rated clinically insignificant PCa (ciPCa) and ≥2 csPCa. This resulted in 52 patients being included in the final analysis, of whom 11 (21.1%), 8 (15.4%), and 33 (63.5%) patients had csPCa, ciPCa, and no PCa, respectively, with the latter two groups being combined as non-csPCa. Eight of the csPCas were located in the peripheral zone (PZ) and three in the transition zone (TZ). In the non-csPCa group, 29 were located in the PZ and 12 in the TZ. Target lesions were marked with volumes of interest (VOIs) on axial T2w images. Axial T2w images were then converted to 93 feature maps. VOIs were copied into the maps, and feature quantity was retrieved directly. Features were tested for significant differences with the Mann–Whitney U-test. Univariate models for single feature performance and bivariate models implementing PSA density (PSAD) were calculated. Ten map-derived features differed significantly between the csPCa and non-csPCa groups (AUCs: 0.70–0.84). The diagnostic performance for TZ lesions (AUC: 0.83–1.00) was superior to PZ lesions (AUC: 0.74–0.85). In the bivariate models, performance in the PZ improved with AUCs >0.90 throughout. Parametric feature maps alone and as bivariate models with PSAD can (?) noninvasively identify csPCa in PI-RADS 3 lesions and could serve as a quantitative tool reducing ambiguity in PI-RADS 3 lesions.

Background/Objectives: Kidney transplantation is associated with an increased risk of renal cell carcinoma (RCC). This study aimed to evaluate the outcomes of de novo RCC in kidney transplant recipients (KTRs). Methods: We retrospectively identified 50 de novo RCC cases among 4012 KTRs transplanted from 2005 to 2024. Data on patient characteristics and outcomes were collected. Propensity score matching (PSM) compared 34 localized RCC cases in KTRs with 34 non-transplant RCC cases. The statistical analyses used Kaplan–Meier estimates, the log-rank test, and the Cox regression. Results: The RCC incidence was 0.64 per 1000 person-years, with a standardized incidence ratio of 4.40 (95% CI: 3.33–5.80). In the KTR cohort, clear cell RCC was present in 42%, and papillary RCC was present in 42%. RCC developed predominantly in native kidneys (92%). UICC stage I was present in 74%. The treatment for the non-metastatic RCC was nephrectomy in the majority of cases (91%). For the metastatic RCC, 71% received a tyrosine kinase inhibitor (TKI). In the KTR cohort, the 3- and 5-year overall survival (OS) rates were 85% and 72%, respectively, with a median OS of 199 months; the synchronous metastasized (M1) patients had a median OS of 14 months. Rejection, age, advanced UICC stage, higher pT stage, clinical positive lymph nodes, M1, and higher grade were significantly associated with poor OS. The 5-year OS (96% vs. 84%, p = 0.72) and MFS (92% vs. 93%, p = 0.61) were comparable in the PSM cohort between the KTRs and the non-KTRs in the localized RCC. Conclusions: KTRs have a higher risk of RCC and present at a localized stage with comparable OS rates to non-transplant RCC patients. Adverse tumor characteristics, including synchronous metastases, significantly affect the prognosis, highlighting the need for surveillance and individualized treatment, particularly for metastatic RCC.

Background: The presence of multiple renal arteries (MRAs) is a common anatomical variant in living kidney donors. While MRAs are not considered a contraindication to donation, it remains uncertain whether leaving the donor with a kidney containing MRAs affects long-term outcomes. This study aimed to evaluate renal and clinical outcomes in donors based on the vascular anatomy of the remnant kidney. Methods: We conducted a retrospective cohort study of living kidney donors who underwent nephrectomy at our institution between 2011 and 2016. Donors were categorized according to the vascular anatomy of the remaining kidney: single renal artery (SRA) vs. multiple renal arteries (MRAs). Data on renal function, hypertension, diabetes mellitus, and cardiovascular events were collected at baseline and follow-up. The primary outcome was long-term renal function, which was measured by the estimated glomerular filtration rate (eGFR). Secondary outcomes included clinical comorbidities and postoperative complications. Results: Among 190 donors, 132 had a remaining kidney with a single artery and 58 had MRAs. Over a median follow-up of 89.5 months (SRA) and 74.5 months (MRA), there were no significant differences in eGFR (SRA: 66 mL/min vs. MRA: 65 mL/min, p = 0.60), serum creatinine (p = 0.86), or the incidence of hypertension (31.8% vs. 34.5%, p = 0.35). Rates of diabetes mellitus and cardiovascular events were similarly low and comparable between groups. Conclusions: Living kidney donors left with a remnant kidney containing multiple renal arteries have similar long-term renal function and clinical outcomes as those with a single renal artery. These findings support the feasibility of MRA retention in donor selection and contribute to evidence-based surgical planning and donor counseling.