4506 Background: Muscle-invasive bladder cancer (MIBC) is an aggressive disease, with substantial recurrence risk after radical cystectomy and pelvic lymph node dissection (RC + PLND) alone. SHR-A2102 is a nectin-4-targeted antibody-drug conjugate carrying topoisomerase I inhibitor payload. This phase 2/3 study (NCT06879145) evaluates the efficacy and safety of SHR-A2102 in combination with adebrelimab (an anti-PD-L1 antibody) as perioperative treatment for MIBC. Here, we report the preliminary results from the phase 2 study. Methods: In the multicenter phase 2 part, pts aged ≥18 years, ECOG PS 0-1, with pathologically and radiographically confirmed T2-4aN0M0 or T1-4aN1M0 MIBC, and scheduled for RC + PLND were enrolled. Pts received neoadjuvant treatment with 4 cycles of intravenous SHR-A2102 (8 mg/kg, day 1 Q3W) and adebrelimab (1200 mg, day 1 Q3W), followed by surgical resection and 5 additional cycles of adjuvant SHR-A2102 (8 mg/kg, day 1 Q3W) plus 13 additional cycles of adjuvant adebrelimab (1200 mg, day 1 Q3W). The primary endpoints are the recommended phase 3 dose (RP3D) and investigator-assessed pathological complete response (pCR, defined as pT0N0). Results: As of Nov 24, 2025, 37 pts were enrolled; 91.9% were male and the median age was 66 years (IQR 59-74). The ECOG PS was 0 in 24.3% of pts and 1 in 75.7%. Regarding disease stage, 29.7% were classified as T2N0, 51.4% as T3-4aN0, and 18.9% as T1-4aN1. Among 7 pts with target lesions, the neoadjuvant regimen achieved an objective response rate of 71.4% (5/7; 95% CI 29.0–96.3) and a disease control rate of 100.0% (95% CI 59.0–100.0). A total of 27 pts underwent RC + PLND, 13 (48.1%, 95% CI 28.7-68.1) achieved pCR and 16 (59.3%, 95% CI 38.8-77.6) attained pathological downstaging ( < pT2N0). Consistent pCR benefits were observed across all predefined subgroups, with creatinine clearance ＜60 mL/min showing no discernible effect on pCR rates. Of the 10 pts who refused or were ineligible for radical surgery after neoadjuvant therapy, 5 received transurethral resection of bladder tumor and 3 of whom achieved a complete clinical response (cCR, defined as T0N0M0). With the median follow-up of 4.7 months (IQR 2.1-6.6), 3 event-free survival events were reported. Grade 3 or higher adverse events occurred in 40.5% (15/37) of the pts, primarily decreased neutrophil count (16.2%) and decreased lymphocyte count (10.8%). No patient was ineligible for surgery due to adverse events. Conclusions: Perioperative treatment with SHR-A2102 plus adebrelimab showed promising efficacy and was well tolerated in pts with MIBC. This combination holds potential benefit even for pts with renal impairment, suggesting its clinical applicability may extend beyond cisplatin-eligible populations. These results support further investigation for SHR-A2102 plus adebrelimab in this population. Clinical trial information: NCT06879145 .

BACKGROUND:Early detection of urothelial carcinoma (UCa) remains challenging because of the limitations of current diagnostic methods. The objective of this study was to evaluate a novel, urine-based H4C6/TWIST1 methylation assay for its diagnostic accuracy in UCa. METHODS:In a prospective, multicenter study, 743 urine samples (387 patients with UCa and 356 controls) from four hospitals were analyzed. DNA was extracted from 3.5 mL of morning urine, and H4C6/TWIST1 methylation status was assessed by using quantitative polymerase chain reaction analysis. Histopathology served as the reference standard. RESULTS:The assay demonstrated high diagnostic accuracy, with 93.02% sensitivity (95% confidence interval, 90.01%-95.35%) and 92.13% specificity (95% confidence interval, 88.83%-94.71%). The positive and negative predictive values were 92.78% and 92.39%, respectively. Performance was particularly strong for high-grade tumors (97.64%) and muscle-invasive tumors (97.50%). Diagnostic efficacy was consistent across age, sex, and tumor location, covering both lower and upper urinary tract carcinomas. CONCLUSIONS:H4C6/TWIST1 methylation detection is a noninvasive, highly accurate, and consistent tool with significant clinical potential for the initial diagnosis and monitoring of UCa across all grades and stages.

426 Background: To assess the utility of 5.0-Tesla non-enhanced magnetic resonance imaging (5T NE MRI) for preoperative evaluation of renal tumor patients, particularly with renal insufficiency, as an alternative to contrast-enhanced computed tomography (CECT). Methods: We enrolled participants in a sequential cohort based on their renal status. Initially, eighteen patients with renal insufficiency (glomerular filtration rate < 90 mL/min/1.73 m²) underwent a 5T NE MRI for preoperative assessment. Afterward, 68 patients with normal renal function underwent both 5T NE MRI and CECT preoperatively. Imaging diagnoses, tumor staging, and renal arterial visualization were evaluated. Results: In patients with renal insufficiency, 5T NE MRI correctly identified 16 of 17 (94.1%) renal cell carcinoma (RCC) cases and accurately staged 92.9% of T 1–2 stage RCC (13/14) and 100% of T 3–4 stage RCC (3/3). Among patients with normal renal function, 5T NE MRI demonstrated higher diagnostic accuracy for RCC than CECT (59/59, 100% versus 53/59, 89.8%, p = 0.031) and correctly diagnosed all lipid-poor angiomyolipoma cases (2/2 versus 0/2 on CT). 5T NE MRI provided superior accuracy for identifying 57/57 T 1–2 stage (100%) versus 50/57 (87.7%) on CECT (p = 0.016) with no overstaging, while CECT overstaged 7 cases. Both 5T NE MRI and CECT achieved 100% visualization of grade 3 renal arteries. Conclusions: 5T NE MRI offers high diagnostic accuracy and staging, additionally providing grade 3 vascular visualization. It yields excellent diagnostic performance for renal tumors comparable to CECT, without the need for nephrotoxic contrast or radiation. It is especially beneficial for patients with renal insufficiency as a promising alternative in preoperative evaluation. CECT, n/N (%) 5T NE MRI, n/N (%) P-value Diagnostic Accuracy RCC 53/59 (89.8) 59/59 (100.0) 0.031 AML 7/9 (77.8) 9/9 (100.0) 0.500 Lipid-poor AML 0/2 2/2 T stage Accuracy T 1-2 Accordance 50 57 0.016 T 3-4 Accordance 2 2 - Vessel Grade b Grade ≤3 68 (100.0) 68 (100.0) - Grade ≥4 61 (88.1) 46 (64.3) <0.001

The transcriptional program that regulates immunosuppression in CCR7 + conventional dendritic cells (cDCs) is currently unknown. Here, we identify ETS homologous factor (EHF) as a transcription factor that regulates cDC maturation and immunosuppression after TLR7/8/9 stimulation. Mice with conditional deletion of EHF in DCs exhibit increased resistance to autoimmune, infection or tumor challenge. EHF-deficient DCs promotes Th1- and Th17-biased CD4 + helper T cell response in vivo and in vitro. EHF-deficient cDC1s and cDC2s exhibit decreased expression of CCR7, CD200 and PD-L1, increased expression of DC-lineage transcriptional factor IRF4, and decreased expression of inhibitory NFκB family member Rel. EHF overexpression in DCs results in the opposite phenotype. CUT&TAG analysis suggests that EHF directly regulate Ccr7 , Cd200 , Cd274 , Irf4 and Rel expression. Additionally, single-cell RNA-sequencing demonstrates that Ehf expression is highly enriched in CCR7 hi DCs in mice and humans. Our study thus reveals a conserved transcriptional program that regulates cDC maturation and immunosuppression.

4599 Background: Radical cystectomy (RC) was the standard of care for high-risk non-muscle-invasive bladder cancer (HR NMIBC) patients with Bacillus Calmette-Guerin (BCG)-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for patients who were ineligible for or declined RC. Our study was established to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for HR NMIBC patients unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled HR NMIBC patients with BCG-unresponsive papillary tumors (high-grade Ta or T1 tumors without carcinoma in situ). The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Within 2 weeks after TURBT, eligible patients received tislelizumab 200 mg in day 1 (D1), every 21 days for eight cycles and a total radiotherapy dose of 60-66 GY in 30-33 fractions over seven weeks. The primary endpoint was disease-free survival (DFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary endpoints were bladder-preservation rate, OS and safety. Our study estimated a DFS rate at 12 months was no less than 50% and the study would enroll 32 patients to meet the primary endpoint. Results: Between September 4, 2020, and December 11, 2024, 32 patients (26 [81.2%] men and 6 [19.8%] women) who had received a median of eleven (IQR 7-22) previous BCG instillations were enrolled. Patients received a median of 8 cycles (IQR 8–8) of tislelizumab and of radiotherapy doses of 62.0 GY (IQR 62.0–64.0) . Median follow-up was 28.8 months (19.7-43.8). The DFS rate at 12 months was 90.6% (95%CI, 79.8%-99.6%), at 24 months was 70.2% (95%CI, 50.1%-83.4%). The bladder-preservation rate at 24 months was 93.2% (95%CI, 75.4%-98.3%). The OS rate at 24 months was 100% (95%CI, 100%-100%). The OS rate at 36 months was 90.5% (95%CI, 67.0%-97.6%). Treatment-related adverse events (TRAEs) occurred in 27 (84.4%) of 32 patients, 7 (21.9%) patients had a grade 3 TRAEs. The most common 3 TRAEs were diarrhea (9.4%), radiocystitis (3.1%), leukopenia (3.1%) and liver function damage (3.1%) without grade 4-5 TRAEs. Conclusions: Our final results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for BCG-unresponsive HR NMIBC patients who were ineligible for or decline RC. Clinical trial information: ChiCTR2000035275.

Although thermal ablation, surgery, and radiotherapy are established locoregional therapies for adrenal metastases, direct comparisons among these treatments are limited. This study aimed to compare the clinical effectiveness and safety of locoregional treatments for adrenal metastases. This multicenter retrospective cohort study included patients with adrenal metastases treated with locoregional therapies, including thermal ablation, surgery, or radiotherapy. Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics. Local progression-free survival (LPFS), overall survival (OS), complication rates, and cost were evaluated. Nomograms for OS prediction were developed using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression models. A total of 496 patients (median age, 57 years; 384 men) were included: surgery (n = 231), ablation (n = 132), and radiotherapy (n = 133). After IPTW adjustment, surgery and radiotherapy showed significantly improved LPFS compared with ablation (p = 0.021). Subgroup analysis demonstrated no significant differences in LPFS among treatment modalities for tumors smaller than 5 cm (p = 0.23). Regarding OS, surgery had a significantly better survival compared with ablation and radiotherapy (p = 0.004). Thermal ablation exhibited the lowest complication rates and lowest treatment cost (p < 0.001). The OS nomogram showed moderate predictive ability. Locoregional therapy strategies for adrenal metastases should be individualized. For tumors smaller than 5 cm, thermal ablation offers local tumor control comparable to surgery and radiotherapy, while providing superior safety and lower treatment costs. QuestionDirect comparative evidence among thermal ablation, surgery, and radiotherapy for adrenal metastases is limited. How do clinical effectiveness, safety, and cost of these treatment modalities compare? FindingsFor adrenal metastases smaller than 5 cm, thermal ablation provides local control comparable to surgery and radiotherapy, while being associated with significantly fewer complications and lower treatment costs. Clinical relevanceFor patients with adrenal metastases smaller than 5 cm, thermal ablation offers a minimally invasive, safer, and less costly treatment option. It provides local tumor control comparable to surgery or radiotherapy, supporting individualized treatment selection based on tumor size.

Neutrophils are crucial immune components within the tumor microenvironment, significantly impacting tumor progression and anti-tumor immunity. To systematically characterize the heterogeneity of neutrophils in bladder cancer (BLCA), we integrated large-scale single-cell RNA sequencing (scRNA-seq) data of BLCA to define the transcriptomic landscape of neutrophil subtypes. Functional enrichment, pseudotime analysis, cell-cell communication, and deconvolution of bulk RNA sequencing (RNA-seq) samples from BLCA were conducted to comprehensively characterize the biological profiles and functions, as well as the prognostic relevance of neutrophil subtypes. A machine learning-based predictive model was developed based on the balance of prognosis-related neutrophil subtypes. We identified five distinct subtypes of neutrophils in BLCA and focused on two subtypes that were prognostically antagonistic. VEGFA+ neutrophils (Neu_0), characterized by pro-angiogenic, immunosuppressive, and extracellular matrix remodeling signatures, showed a significant correlation with poorer survival. GBP1 + neutrophils (Neu_4), characterized by response to interferon, exhibited increased innate immune activities and the production of cytokines that activate anti-tumor immunity, significantly correlated with improved survival. Pseudotime analysis positioned both Neu_0 and Neu_4 as terminal states. Cell-cell communication further identified Neu_0 as a hub orchestrating multiple pro-tumorigenic interactions. The predictive model based on the balance of Neu_0 and Neu_4 effectively stratified BLCA patients into distinct risk groups with significant differences in clinical outcomes, immune landscapes, and response profiles to antibody-drug conjugate (ADC) treatment. The investigation provided novel insights into the functional profiles of neutrophils in BLCA and offered a novel tool for guiding therapeutic strategies in BLCA.

Abstract Background: CVL006 is a novel bispecific antibody designed for synergic antitumor activity by simultaneously blocking two mechanistically distinct pathways VEGF/VEGFR signaling and the PD-L1/PD-1 axis. In this Open-label, Multicenter Phase I Clinical Study of CVL006, Safety, pharmacokinetics (PK) and preliminary efficacy will be assessed in adult subjects with advanced solid tumors, and, thus, the recommended phase II dose (RP2D) will be established (NCT06621615). Method: All subjects in this study received CVL006 every 2 weeks (Q2W). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). Results: As of the data cutoff date of Nov 14, 2025, 29 subjects with various advanced solid tumors received CVL006 at 0.03-20 mg/kg, 12 subjects in phase Ia, 7 subjects in phase Ib and 10 subjects in phase Ic. Phase Ia and phase Ib were completed and Phase Ic is ongoing. Phase Ia results show that CVL006 is well-tolerate, MTD has not reached, and RP2D is 20 mg/kg. All these AEs were recovered after symptomatic treatment. In the 20 mg/kg dose group, CVL006 showed linear pharmacokinetics and a low incidence of ADA positivity.18 subjects had at least one efficacy assessment. In the 10 mg/kg dose group (N=3), 2 stable disease (SD) cases with lesion shrinkage first appeared. At dose of 20 mg/kg, 9 subjects with different tumour types, were evaluated for efficacy and 6 of 9 subjects had a response : 4 SD and 2 partial response (PR). Conclusion: CVL006 monotherapy appeared to be well tolerated and had encouraging preliminary efficacy in patients with advanced solid tumors, warranting further investigation. Citation Format: Jin Li, Ning Li, Shuhang Wang, Ye Guo, Kai Yao, Yanjie Zhu, Feng Ye, Hao Zeng, Steve Shen, Jin Zhang. An open-label, multicenter Phase I clinical study of CVL006, a novel PD-L1/VEGF bispecific antibody, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2666.

BACKGROUND:The lymph node ratio (LNR) is gaining recognition as a prognostic biomarker for various malignant neoplasms. However, its prognostic role in postoperative chemotherapy for high-risk muscle-invasive bladder cancer (MIBC) remains unclear. METHODS:This study included 2,320 patients with lymph node-positive T2-4N1-3M0 MIBC receiving postoperative chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database, and a validation cohort of 273 patients from Sun Yat-sen University Cancer Center (SYSUCC). Optimal LNR thresholds were identified by using X-tile software. The relationship between LNR and overall survival (OS) was evaluated via Kaplan-Meier analysis, Cox regression, subgroup analyses, and restricted cubic splines. Nomograms and 101 machine learning (ML) algorithms were developed, incorporating LNR and clinical covariates for enhanced prognosis. RESULTS:The Kaplan-Meier and restricted cubic splines analyses revealed that LNR was an independent risk factor of OS in post-radical cystectomy and chemotherapy patients with lymph node-positive MIBC. Furthermore, the logistic regression model demonstrated that a lower LNR was significantly associated with a reduced incidence of second primary malignancies. After adjustment for potential confounders-including age, sex, histology, radiotherapy, and TNM staging-patients with elevated LNR values exhibited markedly inferior OS compared with those with lower LNR values, a finding consistent across both the SEER database and SYSUCC cohort. Additionally, the nomogram and machine learning algorithms, integrating LNR with clinical parameters, exhibited robust discriminative performance, with calibration curves confirming excellent concordance between predicted and observed outcomes. CONCLUSIONS:LNR is an independent prognostic factor for OS in post-radical cystectomy and chemotherapy patients with lymph node-positive MIBC.

Background:Laparoscopic adrenalectomy is the primary treatment for most adrenal tumors. However, gasless single-port retroperitoneal laparoscopic adrenalectomy (GL-SPRLA) is rarely documented, and its safety and effectiveness need further investigation. To address this, we introduced an improved GL-SPRLA technique using a novel peritoneal spreader (PerS) that eliminates the need for CO2 insufflation while maintaining the benefits of minimally invasive surgery. Methods:This single-center retrospective study compared GL-SPRLA (n=58) with conventional single-port retroperitoneal laparoscopic adrenalectomy (SPRLA) (n=106) for adrenal tumors (<4 cm) at Sun Yat-sen University Cancer Center [2021-2023]. All procedures were performed by the same surgeon via retroperitoneal approach. We systematically compared demographic characteristics, intraoperative parameters, postoperative outcomes, and follow-up results. Statistical analysis was performed with Student's t-test, χ2 test and multivariable regression adjusting for potential confounders. Results:All 58 GL-SPRLA procedures were successfully completed using a novel gasless device that replaces carbon dioxide. Compared to SPRLA, GL-SPRLA showed comparable operative time, complication rates, and postoperative hospital stay (P>0.05), but showed smaller perioperative changes in pCO2 and pH in a physiologic subcohort, along with a 12.7% cost reduction (P<0.001), and zero conversions to multi-port versus 14.2% in SPRLA (P=0.001). There were no Clavien-Dindo grade 3-4 complications in either group, and neither tumor recurrence nor metastasis occurred at 12 months. Conclusions:GL-SPRLA may be a feasible minimally invasive option for selected patients with small adrenal tumors, with potential advantages in avoiding CO2 insufflation and reducing hospitalization costs, and requires confirmation in prospective multicenter studies.