Browse Articles

HMGB1 binds to and disrupts the hairpin structure of RNA15 and inhibits toll-like receptor activation

Treatment patterns and outcomes with second line (2L) therapies in patients (pts) with advanced urothelial carcinoma (aUC) previously treated with first line (1L) enfortumab vedotin (EV) with pembrolizumab (pembro).

676 Background: EV+pembro has significantly transformed 1L treatment of aUC and has become the standard of care. Treatment selection following progression on EV/pembro has emerged as an important clinical question. Currently, no prospective data are available evaluating outcomes of different therapies in this setting. Methods: This study used the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Inclusion criteria: Pts who received 1L EV+pembro and had 2L therapy data available. The analytical cohort included pts diagnosed with aUC between 01/27/2017 and 01/22/2025, and initiated 2L therapy between 10/20/2021 and 06/26/2025. The data cut-off date was 06/30/2025. 2L treatment types were categorized as cisplatin-based therapy, carboplatin-based therapy, EV rechallenge, or other. Real-world overall survival (rwOS) was defined as the time from 2L initiation to death and was censored at the lost to follow-up according to structured activities. Real-world time to next therapy (rwTTNT) was defined as the time from 2L initiation to 3L initiation or death and was similarly censored at the lost to follow-up according to structured activities. Results: Among 15236 pts in the dataset, 757 received 1L EV+pembro and 118 pts who subsequently received 2L therapy were eligible and included in the analysis. Treatment distribution in 2L was: carboplatin-based regimens in 42 pts (35.0%), cisplatin-based therapy in 16 pts (13.3%), other regimens in 46 pts (38.3%), and EV rechallenge in 16 pts (13.3%). Most common regimens in other category included erdafitinib (11 pts, 24%), fam-trastuzumab deruxtecan (11 pts, 24%), sacituzumab govitecan (10 pts, 22%) and gemcitabine (7 pts, 15%). Median rwTTNT was 3 months (95% CI, 2.4 - NR) for cisplatin-based therapy, 4.7 months (95% CI, 2.8 - 7.5) for carboplatin-based therapy, 8.5 months (95% CI, 5.1 - NR) for EV rechallenge, and 3.9 months (95% CI, 3.3 - NR) for other regimens. Median rwOS was 8.3 months (95% CI, 2.4 - NR) for cisplatin-based therapy, 7.1 months (95% CI, 6.2 - NR) for carboplatin-based therapy, 8.5 months (95% CI, 5.3 - NR) for EV rechallenge, and 14.0 months (95% CI, 7.1 - NR) for other regimens. Baseline characteristics will be presented at the meeting. Conclusions: This is the largest real-world study to date evaluating treatment patterns and outcomes with various 2L therapies after progression on 1L EV+pembro in aUC. Platinum based therapies and antibody drug conjugates are the most common 2L therapies. Median rwOS and rwTTNT were modest across all treatment groups. These findings underscore the limited efficacy of current 2L options in the post EV+pembro setting, highlight the urgent need for novel therapies in this setting and provide survival estimates for future trial design and patient counseling.

Real-world comparative outcomes of enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy in metastatic urothelial carcinoma.

778 Background: Enfortumab vedotin (EV) plus pembrolizumab (Pem) has demonstrated superior efficacy in clinical trials for metastatic urothelial carcinoma (mUC). To assess the performance of this regimen in routine practice, we conducted real-world comparative outcomes analysis versus gemcitabine plus platinum (GEM + Plat) using the TriNetX Research Network. Methods: Adults (≥18 years) with stage IV mUC between 2019 and 2025 were included. Cohorts were defined by index therapy with EV + Pem or GEM + Plat. Propensity-score matching (1:1) was used to match on age, sex, race, ethnicity, metastatic location, and comorbidities. Outcomes were analyzed within 720 days post-index using Kaplan–Meier and risk estimates. Results: Matching yielded 325 patients per arm, and the cohorts were well-balanced (mean age 70 years, 75% male). Overall survival favored EV + Pem, with 12-month survival of 72.5% versus 62.8% (p = 0.017) and 24-month survival of 57.1% versus 48.2% (p = 0.010) (Table 1). Time to next treatment was markedly longer with EV + Pem (HR 0.08, 95% CI 0.06–0.10, p < 0.001), with only 64 of 325 EV + Pem patients initiating subsequent therapy within 24 months. The risk of treatment-related adverse-event proxies (neuropathy, dermatitis, or pruritus) was higher with EV + Pem (p < 0.001), while inpatient/ED visits were less frequent at both six months (p = 0.001) and twelve months (p = 0.008). Laboratory comparisons at 0–12 weeks showed no difference in mean eGFR, creatinine, or albumin, while hemoglobin was higher with EV + Pem (p< 0.0001). Conclusions: In this large propensity-matched real-world cohort, first-line EV + Pem was associated with improved overall survival, prolonged treatment durability, and lower health-care utilization compared with GEM + Plat, albeit with higher adverse effects. Real-world outcomes: EV + Pem vs GEM + Plat. Endpoint EV + Pem GEM + Plat HR * /OR @ (95% CI) P 12-month OS (%) 72.5 62.8 0.70 (0.52–0.94) 0.017 24-month OS (%) 57.1 48.2 0.70 (0.53–0.92) 0.010 Adverse Effect proxies (%) 45.1 27.8 2.71 (2.01–3.64) <0.001 Inpatient/ED visits 6 mo (%) 58.2 71.1 0.76 (0.63–0.92) 0.001 Inpatient/ED visits 12 mo (%) 65.8 78.2 0.67 (0.65–0.94) 0.008 Hb < 10 g/dL (%) 46.5 80.0 0.47 (0.38–0.57) <0.001 eGFR (mean) 63.8 65.1 – 0.59 Albumin (g/dL, mean) 3.57 3.53 – 0.41 AST (U/L, mean) 31.2 26.1 – 0.002 ALT (U/L, mean) 27.4 22.7 – 0.03 *Hazard Ratio. @ Odds Ratio.

Characterization of depth and durability of response in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) who received cabozantinib plus nivolumab (C+N): Long-term follow-up and exploratory analysis of CheckMate 9ER.

508 Background: C+N is approved as first-line treatment in aRCC based on the CheckMate 9ER trial, which demonstrated superior progression-free survival (PFS) and overall survival (OS) versus sunitinib in this pt population. In this exploratory, post hoc analysis, we characterized the depth and durability of response with long-term follow-up (based on the final analysis of CheckMate 9ER) in pts receiving C+N. Methods: Pts received C (40 mg) once daily plus N (240 mg) every 2 weeks. Depth of response (DepOR) subgroups were based on best overall response (blinded independent central review [BICR] per RECIST v1.1) and best tumor reduction threshold, as follows: complete response (CR); partial response subdivided by a tumor reduction of ≥80% (PR1), ≥60%–<80% (PR2), or ≥30%–<60% (PR3); stable disease (SD); and progressive disease (PD). PFS (per BICR) and OS were analyzed by DepOR subgroups after a 6-month post-randomization landmark. Results: Of 323 pts randomized to C+N, 293 pts were alive, and 234 pts were alive and progression-free at the 6-month landmark and were categorized by DepOR subgroup. With a median follow-up of 67.6 months (range: 60.2–80.2), pts with a CR exhibited a durable response and prolonged benefit in DOR, PFS, and OS (Table). Pts who experienced a response (CR or any PR) included those with liver metastases (16%– 29%), sarcomatoid features (6%–15%), ≥2 metastatic sites (60%–78%), and poor IMDC risk (7%–17%). Median duration of therapy was 30.4 (CR), 29.9 (PR1), 35.6 (PR2), 23.0 (PR3), 15.3 (SD), and 9.0 (PD) months. Any-grade treatment-related adverse events were generally consistent across DepOR subgroups. Conclusions: This exploratory analysis of CheckMate 9ER revealed durable responses in pts who experienced a CR. Pts who responded to treatment (CR or any PR) included those with poor prognostic characteristics. Clinical trial information: NCT03141177 . Clinical outcomes by DepOR subgroup in pts treated with C+N. DepOR Median DOR a (95% CI), months PFS DepOR pop n=234n (%) 48-month b PFS (95% CI), % Median PFS b (95% CI), months OS DepOR popn=293n (%) 48-month b OS (95% CI), % Median OS b (95% CI), months CR NR(30.5, NE) 45 (19) 54(38, 68) NR(30.4, NE) 45 (15) 84(70, 92) NR(NE, NE) PR1 22.1(15.1, 26.0) 25 (11) 12(3, 28) 18.8(13.3, 32.7) 27 (9) 56(35, 72) 51.6(32.2, NE) PR2 21.7(14.1, 30.4) 36 (15) 24(11, 39) 18.9(13.3, 27.4) 38 (13) 67(50, 80) 63.2(47.0, NE) PR3 10.8(7.0, 17.3) 63 (27) 3(0, 13) 9.4(5.5, 17.0) 70 (24) 42(30, 53) 41.9(33.8, 49.5) SD NA 65 (28) 4(1, 11) 5.9(3.9, 10.0) 98 (33) 29(20, 39) 28.7(17.5, 35.0) PD NA NA NA NA 15 (5) 20(5, 42) 11.0(4.8, 25.1) a Calculated in the OS DepOR response (CR or any PR) pop. b From the 6-month landmark.DOR, duration of response; NA, not applicable; NE, not estimable; NR, not reached; pop, population.

Circulating tumor DNA (ctDNA) dynamics in bone-dominant metastatic castration resistant prostate cancer (mCRPC) treated with radium-223 with or without olaparib: Biomarker analyses from the multicenter, randomized, phase 2, investigator-initiated COMRADE trial.

158 Background: We previously reported that olaparib significantly improves radiographic progression-free survival (rPFS) when added to radium-223 for bone-dominant mCRPC in the COMRADE study (NCT03317392). Here, we investigate ctDNA and PSA dynamics by arm from patients on the COMRADE study. Methods: Cell free DNA from banked plasma was sequenced on FoundationOne Monitor as a research use test. ctDNA was quantified as ctDNA tumor fraction (TF). rPFS and overall survival (OS) were assessed by Kaplan-Meier analysis and univariate Cox proportional hazard models, landmarked from the relevant sample collection date; patients with progression before the landmark were excluded. Molecular response (MR) and PSA response (PSA50) were defined as ≥50% decrease from C1D1. Results: Of 113 patients receiving any study treatment, ctDNA results were successfully generated for 102 patients at cycle 1 day 1 (C1D1), of whom 53 were randomized to radium-223+olaparib (Arm A) and 49 to radium-223 alone (Arm B). Across arms, the median ctDNA TF at C1D1 was 16% [Interquartile Range: 1.3-43%]. Across arms, 99 patients had ctDNA results at C2D1: 5 with progression prior to C2D1, 9 patients with no result at C1D1, and 8 with unquantifiable ctDNA change were excluded. ctDNA TF clearance from C1D1 to C2D1 was achieved in 13/77 patients (17%; Arm A: 17%, Arm B: 17%), and 50-99% reduction in 14/77 patients (18%; Arm A: 22%, Arm B: 15%). 15/77 patients (19%; Arm A: 22%; Arm B: 17%) were negative at both timepoints and not included in assessment of MR. MR was associated with significant, favorable PFS (MR: 4.6 months vs No MR: 2.0 months, p=0.01) and OS (MR: 21.2 months vs No MR: 12.2 months, p=0.005) with similar trends within both treatment arms. A greater improvement in rPFS with the addition of olaparib was observed for patients who achieved MR (MR: HR = 0.35 [95% confidence interval (CI): 0.14-0.91]; No MR: HR = 0.65 [95% CI 0.29-1.43]). Similar to TF, baseline PSA was prognostic: when stratified at the median (51.6 ng/mL), patients with lower PSA demonstrated significantly improved rPFS (11.0 vs 3.8 months for low vs high PSA, p<0.0001) and OS (26.6 vs 13.2 months, p<0.0001). Of the 13 patients that ever-achieved PSA50, including after crossover, 69% achieved MR compared to 37% in 49 patients without PSA50. Conclusions: Early MR (by C2D1) was achieved in 35% of patients and strongly associated with improved rPFS and OS while PSA50 responses by C2D1 were not observed in any patients. The rPFS benefit of adding olaparib to radium-223 appeared more evident in those who achieved a MR. Early on treatment ctDNA dynamics in bone-dominant mCRPC may be a valuable tool for treatment decisions with radium-223 therapy. Clinical trial information: NCT03317392 .

Material Preparation Information File (MPIF): A Community‐Driven Standard for Reporting MOF Syntheses

ABSTRACT The rapid growth of research on metal–organic frameworks (MOFs) and related porous materials has highlighted a critical need for standardized reporting of synthetic procedures and material properties. Synthesis consistency is often compromised by incomplete protocols and inconsistent nomenclature, with even well‐established MOFs exhibiting substantial variability depending on subtle and frequently unreported factors. To address this critical challenge, we introduce the Material Preparation Information File (MPIF), a modular, machine‐ and human‐readable format for documenting synthesis protocols alongside key characterization data. Built on the Self‐defining Text Archive and Retrieval (STAR) file architecture, MPIF consolidates essential information, including reagents, conditions, equipment, and handling procedures—into a structured format that supports both digital processing and practical laboratory use. To streamline MPIF creation and editing, a web‐based interface has been developed (mpif.jackdevans.com). By aligning with existing standards such as CIF and AIF, MPIF enables integration with databases, promotes FAIR data principles, and provides a foundation for data‐driven materials discovery, informatics, and automation. We envision MPIF becoming a community‐wide standard for transparent and consistent reporting of MOF and related material syntheses.

Innovative Biomaterials Synergize Oncolytic Virus for Elevating Tumor Immunotherapy Potency

ABSTRACT Cancer immunotherapy, particularly using oncolytic viruses (OVs), has been recognized as a promising approach for treating malignant tumors because of its dual ability to selectively kill tumor cells and activate antitumor immunity. However, OV monotherapy faces inherent challenges, including suboptimal viral delivery efficiency, an immunosuppressive tumor microenvironment, and premature systemic‐immune clearance. Recent breakthroughs in biomaterials have provided new avenues for optimizing oncolytic virotherapy by overcoming these limitations using innovative system designs. In this review, we systematically examined the synergistic combination of biomaterials with OVs to enhance cancer immunotherapy, emphasizing two major categories: nanomaterial‐based carriers and cell‐derived materials. Intelligent biomaterial delivery systems can spatiotemporally protect viruses from immune clearance and enable targeted accumulation and controlled release. Functionalized biomaterials can serve as immunomodulators or drug carriers that synergize with OVs to remodel the tumor microenvironment. Particular focus was placed on biomimetic virus‐like nanoparticles, and their design principles, mechanisms, and applications were critically discussed in this review. Finally, we summarize the potential challenges and prospects of combining biomaterials with OVs to enhance cancer immunotherapy, paving the way for a clinical translation of this approach.

Domain-selective folding of the tandem β-propeller protein Coronin 7 (Coro7) by the chaperonin CCT/TRiC

ASPIRE GCT: A single-arm, phase II clinical trial of aspirin to prevent venous thromboembolism in patients with advanced germ cell tumors receiving chemotherapy.

TPS624 Background: Advanced testicular/germ cell tumors (GCT) are highly curable with chemotherapy; however, patients with advanced GCT are at high risk for venous thromboembolism (VTE) during treatment. A role for thromboprophylaxis has not been established. Low-dose aspirin (ASA) is an inexpensive, widely available therapy that reduces VTE risk in orthopedic trauma, hip replacement, and multiple myeloma settings. ASPIRE-GCT aims to evaluate the 6-month VTE-free rate in patients with advanced GCT at high VTE risk who receive standard chemotherapy plus low-dose ASA. Methods: This investigator-initiated, single-arm, prospective phase II study evaluates the 6-month VTE-free rate among patients with advanced GCT at high VTE risk receiving cisplatin-based chemotherapy and ASA 81 mg daily for 6 months. Eligible patients are males aged 18–70 years with testicular, mediastinal, or retroperitoneal GCT (seminoma or non-seminoma) who will receive 3–4 cycles of BEP, EP, or VIP. Participants must have one of the following high-risk features: IGCCCG intermediate/poor risk, AJCC 8th edition Stage IIC or III, or a Khorana score of 2 or higher. Key exclusion: prior VTE, prior anticoagulation, or ASA contraindication. The primary endpoint tests the null hypothesis that the 6-month VTE-free rate is ≤65%, based on a historical VTE rate of 35% in this population. A 2-stage design is used with 13 participants enrolled in the first stage. If at least 9 of the 13 do not experience a VTE then up to 18 additional participants will be enrolled for a total of 31 evaluable patients. Based on a 1-sided alpha = 0.10 significance level, this sample size will provide at least 90% power assuming the true 6-month VTE-free rate is 85%. Secondary endpoints include major bleeding and clinically relevant non-major bleeding rates, relapse-free survival, and overall survival. This is the first prospective study evaluating prophylactic aspirin thromboprophylaxis in advanced GCT. Status: This study is actively accruing at the Advocate Health/Wake Forest Baptist Comprehensive Cancer Center Network. Ethics Approval: This study was approved by the Wake Forest University School of Medicine Institutional Review Board; IRB00126906. Clinical trial information: NCT06866964 .

Clinical burden of recurrence among older adults with muscle invasive bladder cancer undergoing tri-modal therapy in the real world: A SEER-Medicare, population-level study.

679 Background: While radical cystectomy (RC) remains standard of care for muscle-invasive bladder cancer (MIBC), trimodal therapy (TMT) has emerged as a bladder-sparing alternative for select patients, particularly older adults. However, US population-level data on TMT patterns and outcomes remain limited. This study evaluates TMT use and outcomes across the treatment continuum in older adults with MIBC. Methods: SEER-Medicare data (01/01/2007-09/30/2020) were used to identify adults ≥65 years with stage T2-T4a N0M0 MIBC. Eligible patients underwent TMT, defined as maximal transurethral resection of the bladder tumor (TURBT; index) followed within 6 months by concurrent chemoradiotherapy (CRT). Neoadjuvant therapy was identified within 6 months pre-TURBT; adjuvant therapy was captured within 120 days post-TMT. Recurrence was defined based on: (1) cancer-directed treatments received ≥120 days post-TMT (or antibody drug conjugates [ADCs] any time post-TMT); (2) diagnosis of distant metastases or secondary bladder malignancy after 60 days post-TMT; or (3) diagnosis of non-bladder secondary malignancy post-TMT. Categorical data were assessed using chi-square tests at a significance level of α = 0.05. Results: Among 1,032 TMT-treated MIBC patients (median age 79), most were male (71.2%), non-Hispanic (96.2%), and White (92.2%), with clinical stage T2 disease (87.0%). Use of neoadjuvant therapy was rare ( < 1%). Median time from TURBT to CRT initiation was 39 days. During CRT, patients received a median of 34 fractions of radiotherapy; common CRT agents were cisplatin (43.9%, n = 453) and carboplatin (39.3%, n = 406). Adjuvant therapy was administered to 18.6% (n = 192) of patients. Treatment patterns associated with TMT were not significantly different between patients with or without recurrence. Over half of patients (53.5%, n = 552) experienced recurrence (median time to recurrence: 2.5 years). Among these, 134 (24.3%) received intravesical therapy as the first post-recurrence treatment, suggesting non-muscle invasive recurrence. Salvage RC was performed in 10.5% (n = 58) of those with recurrence, and 12 patients received neoadjuvant therapy pre-RC. Over half of the recurrence cohort (n = 330) received post-recurrence systemic treatment, commonly non-cisplatin chemotherapy (n = 176) and ADCs (n = 170). Conclusions: Recurrence was common among older adults with MIBC despite timely initiation of TMT. Most recurrences appeared to be invasive, with high rates of systemic therapy use, underscoring the clinical burden after TMT failure. The absence of differences in TMT patterns between recurrence and non-recurrence cohorts suggests that recurrence risk may be driven by tumor biology rather than care delivery. Further therapeutic strategies are needed to reduce recurrence and improve outcomes in this growing population.

Efficacy and safety of the DLL3 T-cell engager gocatamig in participants (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN).

182 Background: Genitourinary neuroendocrine carcinomas (GU NEC), including small cell carcinoma of the bladder (SCCB) and NEPC, are highly aggressive NEN with poor prognosis and limited treatment options. Delta-like ligand 3 (DLL3) expression is frequently upregulated in NEPC and other high-grade NEN and not expressed in normal tissues. Gocatamig (MK-6070; HPN328) is a DLL3-targeting T-cell engager. Gocatamig monotherapy has shown promising clinical activity and manageable safety in the treatment of DLL3-expressing tumors, including small cell lung cancer. Here we report updated results for pts with NEPC and other NEN treated with gocatamig monotherapy in the ongoing phase 1/2 study MK-6070-001 (NCT04471727). Methods: Pts with relapsed/refractory, metastatic NEPC or other high-grade DLL3-expressing NEN received gocatamig IV monotherapy step-up dosing followed by target doses (6, 12, or 24 mg) every 1 or 2 weeks (QW or Q2W). DLL3-positivity (defined by immunohistochemistry staining of >0% tumor cells) was required for other NEN but not NEPC. Efficacy was evaluated by investigator assessed objective response rate (ORR) per RECIST v1.1. Results: As of 28FEB2025, 20 pts with NEPC and 37 with other NEN, including 12 with SCCB, received gocatamig. The median (range) prior lines of therapy were 3 (1-7) for NEPC and 2 (1-6) for other NEN. Most (93%) pts had received prior platinum-based chemotherapy. Median (range) follow-up was 7.3 (0.8-24.4) months (mo) for pts with NEPC and 6.3 (0.7-26.6) mo for pts with other NEN. Treatment is ongoing for 34 (60%) pts. Across all dose groups, the confirmed objective response rate (ORR) was 15% (95% CI 3-38) for pts with NEPC and 46% (95% CI 30-63) for pts with other NEN. The confirmed ORR for pts in the 24 mg Q2W cohort was 29% (95% CI 4-71) for pts with NEPC (n=7) and 50% (95% CI 21-79) for pts with other NEN (n=12). The median duration of response was not reached for NEPC (range 3.7-7.8+ mo) or other NEN (1.8+-11.8+ mo). Any grade/grade 3-4 treatment-related (TR) AEs occurred in 100%/40% of all pts with NEPC and 97%/53% of all pts with other NEN. There were no grade 5 TRAEs. DLL3 was expressed in 15 of 17 (88%) NEPC available for analysis, and response to gocatamig did not correlate with DLL3 expression levels; data for other NEN are pending and will be presented. In addition, updated results will be presented for pts with NEPC and other NEN, including pts with SCCB. Conclusions: Gocatamig continues to show encouraging clinical activity with a manageable safety profile in pts with heavily pretreated NEN, including confirmed, durable responses in NEPC. Clinical trial information: NCT04471727 .

Impact of tumor mutational burden on clinical outcomes in muscle-invasive bladder cancer patients treated with neoadjuvant chemotherapy.

814 Background: High tumor mutational burden (TMB) has been associated with poor response to cisplatin-based chemotherapy in lung cancer, but the impact of TMB in muscle-invasive bladder cancer (MIBC) patients treated with neoadjuvant chemotherapy (NAC) is unknown. In this study, we sought to test the hypothesis that MIBC patients with high TMB would be less likely to achieve a pathologic complete response (pCR) to cisplatin-based NAC. Methods: 93 patients with MIBC who received cisplatin-based NAC followed by radical cystectomy were identified from institutional databases across two campuses. Sample size was prespecified by statistical design. Diagnostic transurethral resection of bladder tumor specimens were available in 91 patients and used for genomic analysis. Genomic analysis was performed using the Tempus xT platform. Clinically significant TMB thresholds are unknown in MIBC, so high TMB was defined as the upper TMB quintile within the cohort. Correlation of TMB values with clinical outcomes were performed using logistic regression, Cox proportional hazards models, and Kaplan-Meier techniques. Results: Among the 91 patients who underwent genomic analysis, median follow time was 63.6 months. Only 4.4% (4/91) received adjuvant immune checkpoint inhibition (ICI). pCR was achieved in 31.9% (29/91). Mean and median TMB (Mut/Mb) for the entire cohort were 10.6 and 8.9, respectively. TMB threshold for the upper quintile was 14.7. Median TMB for patients who achieved ypT0 vs ypT1+ was 11.1 and 8.9. A statistically significant difference in pCR rates between the TMB upper quintile and lower four quintiles was not observed; however, a trend towards higher pCR rate was detected in the upper quintile (OR 0.43, p = 0.165). The median TMB in patients who relapsed (42%) was 7.7 compared to 10.5 for those who did not. A strong trend for lower relapse rate in the upper TMB quintile was observed (OR 0.30, p = 0.065). The median relapse-free survival (RFS) was not reached and 54.2 months in the upper and lower four quintiles, respectively (HR = 0.46, p = 0.080). Conclusions: We designed this study to test the hypothesis that MIBC patients with high TMB would fare worse clinically; however, we found the contrary association. High TMB was unexpectedly associated with improved pCR and relapse rates as well as longer RFS in this cohort collected before widespread use of peri-operative ICI. These findings suggest that high TMB in MIBC patients improves sensitivity to cisplatin-based NAC. Our results require validation in a contemporary cohort and suggest that TMB may be an important potential biomarker in patients with MIBC.

Engineering Chiroptical Interactions through Integrating Plasmonic Arrays with Cholesteric Nanocellulose

ABSTRACT Achieving scalable fabrication with precise control of chiroptical properties in chiral plasmonic materials remains challenging. We present a new family of engineered chiroptical composites comprising linearly assembled gold nanoparticle arrays integrated with cholesteric self‐assembled cellulose nanocrystals (CNCs). Aqueous CNC suspensions are cast onto pre‐assembled achiral plasmonic nanoparticle arrays via evaporation‐induced transfer imprinting lithography, yielding centimeter‐scale hybrid films with custom‐tailored chiroptical responses. During drying, CNCs co‐assemble with the gold nanoparticles at the interface, preserving the array's linear arrangement and keeping it isolated from the overlying cholesteric CNC layers. This configuration combines the linear dichroism of the plasmonic array with the linear birefringence of the CNC matrix, producing strong and tunable plasmonic circular dichroism at the surface lattice resonance, reaching 1217 ± 51 mdeg with a dissymmetry factor of –0.19 ± 0.02. Our approach provides a sustainable platform for engineering multifunctional chiral plasmonic materials with potential applications in optical sensing, photonic devices, and chiral biointerfaces.

Scalable 2D Spectral‐Spatial Associated Vision Sensor for Multidimensional Feature Fusion

ABSTRACT The perception of multidimensional information (e.g., spatial, temporal, and spectral domains) plays a vital role in fields like remote sensing that require high optical resolution and precision. The current approach typically relies on hyperspectral imaging, a band‐by‐band image acquisition mode with subsequent feature learning and fusion through post‐processing algorithms. Such an asynchronous workflow introduces substantial data redundancy, transmission latency, and high energy consumption, limiting its practical deployment. Here, we propose a novel spectral‐spatial associated vision sensor that enables the synchronous acquisition and feature fusion of spectral and spatial information at the hardware level. Specifically, scalable highly oriented 2D Bi 2 Te 3 thin films with broadband response are employed for the fabrication of highly uniform device arrays, thus achieving simultaneous capture of spectral‐spatial information. The arrays perform enhanced synaptic behavior under multi‐wavelength stimuli, with a maximum enhanced ratio of more than 20, facilitating feature discriminability and recognition efficiency. By leveraging such a synergistic enhancement characteristic, an increased recognition accuracy of 91.12% is achieved for topography recognition on the Indian Pines dataset. These findings demonstrate that the proposed vision sensor streamlines hardware‐level data acquisition while improving processing efficiency, thereby establishing a new paradigm for multidimensional information fusion, particularly in scenarios with massive data streams.

In vitro reconstitution in membrane environment reveals critical lipid dependence of substrate S-acylation by protein palmitoyltransferase enzymes

Radiographic recurrence patterns for prostate cancer with pathologic lymph node involvement following PSMA-PET and radical prostatectomy.

24 Background: Anatomic recurrence patterns for surgically resectable high-risk disease with regional node involvement on PSMA-PET are poorly defined. Improved understanding of recurrence patterns can allow for optimization of adjuvant treatment and surveillance strategies. We characterized radiographic recurrence patterns of patients with high-risk prostate cancer who underwent PSMA-PET imaging followed by radical prostatectomy (RP) with pelvic lymph node dissection (PLND) and had pathologic nodal disease (pN1) at surgery. Methods: We identified patients with pN1 disease who underwent RP/PLND for high-risk prostate cancer at our center from 2021 to 2024. Each patient had pre-operative PSMA-PET imaging; those with distant metastases were excluded. Time to radiographic recurrence and location of the most distant radiographic recurrence were recorded. Radiographic recurrence location was categorized as periprostatic, pelvic nodal, or distant (including non-regional lymph nodes, bone or visceral recurrences). We evaluated for association between nodal involvement on pre-operative PSMA-PET (cN1) and presence of 1.) any radiographic recurrence and 2.) distant radiographic recurrence using multivariable and univariable Cox proportional hazards models, respectively. Results: There were 79 patients with surgically resectable disease in the final cohort. Of these, 24 were cN1 on pre-operative PSMA-PET (sensitivity 30%; 95% CI: 21 - 42%). Median follow up was 7 months (IQR 4-13 mo.) among those who remained free of radiographic recurrence. There were 33 patients who developed radiographic recurrence, including 16 with distant recurrence. The Table depicts the anatomic distribution of the most distant radiographic recurrence site. The 1-year adjusted probability of any radiographic recurrence was 28% (95% CI: 9 - 43%) in cN0 disease and 77% (95% CI: 37 - 87%) in cN1 disease. There was a significant association between cN1 status on pre-operative PSMA-PET and any radiographic recurrence (HR 4.23; 95% CI: 1.86 - 9.58; p<0.001) as well as distant radiographic recurrence (HR 5.81; 95% CI: 1.79 - 18.8; p=0.002). Conclusions: Clinical node involvement on pre-operative PSMA-PET is significantly associated with radiographic recurrence for patients with pN1 status following RP/PLND. The high risk of recurrence in these patients supports offering upfront treatment intensification and counseling on the likely need for salvage therapy. Anatomical location of radiographic recurrence on PSMA-PET scan by most distant site of recurrence. Recurrence location by most distant site N = 33 Periprostatic 3 (9%) Pelvic lymph nodes, within ePLND* template 10 (30%) Pelvic lymph nodes, outside of ePLND template 4 (12%) Distant † 16 (48%) *Extended pelvic lymph node dissection. †Includes recurrences in non-regional lymph nodes outside of true pelvis, bones, and visceral organs.

Survival outcomes in metastatic bladder cancer patients in the United States.

675 Background: Bladder cancer is the 10 th leading cause of cancer-related death in the United States. Over the last 15 years, multiple agents have been approved for metastatic bladder cancer. The main objective of our study was to evaluate trends and predictors of survival outcomes among patients diagnosed with metastatic disease in the U.S. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program (~48% of the U.S. population). Adults diagnosed with metastatic bladder cancer (ICD-10: C67.0-C67.9) between 2010 and 2021 were included. Follow-up continued until death or December 2021. Kaplan-Meier methods estimated overall survival (OS) and cancer-specific survival (CSS), with median and 5-year survival rates reported. Cox proportional hazards models identified predictors of survival. Results: A total of 6,601 patients were included; 54% were diagnosed in 2017 or later. Mean age was 69 years; 65% were ≥65 years. Most were male (70%), had transitional cell carcinoma (82%), and underwent prior bladder surgery (78%). Liver or lung metastases were present in 46%. Median OS was 7 months, with a 5-year OS rate of 7%; median CSS was 8 months, with a 5-year CSS rate of 10%. In patients <65 years (n= 2,306), median OS and CSS were 9 months, with 5-year rates of 9% and 11%, respectively. In patients ≥65 years (n=4,295), median OS and CSS were 6 and 7 months, respectively, with 5-year survival rates of 7% and 10%. Five-year relative survival improved from 6% among patients diagnosed in 2010 (n=473) to 9% among patients diagnosed in 2015 (n=584) and 12% among patients diagnosed in 2021 (n=653). Age, race, gender, histology, and absence of prior surgery were significant predictors of OS and CSS (p < 0.05). Conclusions: Gains in long-term survival suggest incremental benefits from newer therapies. While clinically meaningful strides have been made in the treatment of metastatic bladder cancer over the past decade, there remains opportunity to further advance treatment. Continued development of novel agents, especially for subgroups with poor prognosis, is needed to achieve more meaningful improvements. Median and 5-year survival rates among patients with metastatic bladder cancer. Parameter Population Median (Q1, Q3)(months) 5-year survival (%) 5-year relative survival (%) 2010 2015 2021 OS Overall 7.0 (3.0, 16.0) 7.4 (6.6 – 8.2) 6 9 12 < 65 years 9.0 (4.0, 19.0) 8.9 (7.7 – 10.5) 7 9 13 ≥ 65 years 6.0 (2.0, 14.0) 6.5 (5.7 – 7.5) 6 8 12 CSS Overall 8.0 (3.0, 18.0) 10.2 (9.3 – 11.2) NA NA NA <65 years 9.0 (4.0, 21.0) 11.2 (9.7 – 13.0) NA NA NA ≥ 65 years 7.0 (3.0, 17.0) 9.6 (8.5 – 10.9) NA NA NA NA: Not applicable.

Impact of positive ureteral margin on upper tract recurrence after radical cystectomy for bladder cancer.

872 Background: A positive ureteral margin has been considered a key risk factor for upper tract recurrence (UTR) following radical cystectomy (RC) for bladder cancer, supporting intraoperative frozen section analysis to ensure negative margins. This study evaluated the impact of positive ureteral margins on UTR among patients with bladder cancer who underwent RC. Methods: Using our IRB-approved RC database, we identified all patients who underwent RC between 1984 and 2024. Patients with pathology-confirmed UTRs were identified. Cox regression was used to identify the predictive factors for UTR. Results: A total of 3544 patients, mostly male (n=2827, 79.8%) with a median age of 69 (IQR: 61-75) years, were included (Table 1). A total of 258 (7.3%) patients had positive surgical margins on permanent pathology, including 69 (2.0%) with positive ureteral margins. UTRs were identified in 55 (1.5%) patients at a median time of 37.4 (IQR: 14.0 – 65.7) months. Only 2 of the 69 (2.9%) patients with a positive ureteral margin at the time of RC developed UTR – one at 4.2 and the other at 43.8 months. Cox regressions confirmed that neither positive ureteral margin (HR: 2.6, 95%CI: 0.6 – 10.8, p = 0.180), nor overall surgical margin (HR: 1.9, 95%CI: 0.7 – 5.4, p = 0.205) were associated with higher risk of UTR. Hydronephrosis was the only significant predictor of UTR in univariate analysis and remained significant after adjusting for positive ureteral margin in a multivariate analysis (HR: 3.1, 95%CI: 1.8 – 5.4, p < 0.001). Conclusions: UTR occurred in only 1.5% of patients following RC, corresponding to less than 5% of patients with positive ureteral margins. These findings suggest that the necessity of routine frozen section during RC may warrant reconsideration. Larger multi-institutional studies are warranted to validate these results. Baseline characteristics. Charleson Comorbidity Index 0 1024 (29.3%) 1 1017 (29.0%) > 2 1461 (41.7%) Presence of hydronephrosis 837 (23.6%) History of Neoadjuvant Chemotherapy 696 (19.6%) Pathologic Stage < pT2N0 2087 (58.9%) > pT2N0 635 (17.9%) pN+ 822 (23.2%) Histology (Pure Urothelial) 2667 (75.2%) History of Adjuvant Chemotherapy 539 (15.2%)

Preliminary phase 1 dose escalation results of VIR-5500 (AMX-500), a dual-masked PRO-XTEN T-cell engager, in metastatic castration resistant prostate cancer (mCRPC).

17 Background: VIR-5500, a dual-masked, PSMA-targeted bispecific T-cell engager, is designed to be specifically activated in the tumor microenvironment where protease activity is dysregulated relative to healthy tissues, potentially expanding the safety margin and therapeutic index. Methods: VIR-5500 was administered IV weekly (QW) and every 3 weeks (Q3W) at doses of 30 - 4000 ug/kg to eligible participants (pts) with progressive mCRPC after receiving SOC. Objectives were to characterize safety, pharmacokinetics (PK) profiles, anti-tumor activity, and determine the dose(s)/regimen(s) for expansion (NCT05997615). Results: As of 23 September 2025, 51 heavily pretreated mCRPC pts (~95% post-taxane) received ≥ 1 dose of VIR-5500. No dose limiting toxicities (pre-defined toxicities occurring during cycle 1) were reported. The incidence of related Grade ≥ 3 AEs was low and CRS was mostly limited to grade 1 and 2 (see Table). PSA declines were noted in all pts dosed at ≥ 3000 ug/kg Q3W, including clinically significant and deep PSA reductions (91% PSA 50 and 55% PSA 90 ). Preliminary evidence of durable PSA responses lasting over one year was noted in select patients undergoing intrapatient dose escalation. An objective response rate of 67% was observed in 4 out of 6 RECIST-evaluable patients treated at doses ≥ 3000 µg/kg Q3W, including one confirmed partial response and three additional partial responses pending confirmation. PSMA-PET imaging confirmed anti-tumor activity, demonstrating strong concordance with PSA 90 responses. Evidence of T-cell activation and target engagement included increased on-treatment CD3+ T-cell tumor infiltration and serum IFN-γ, including minimal elevation of IL-6 levels, consistent with generally low-grade CRS. Preliminary analyses indicated PK was dose-proportional for VIR-5500, with a half-life of approximately 8-10 days and minimal systemic unmasking to the fully unmasked metabolite. Dose escalation continues with both QW and Q3W regimen, and updated data will be provided at the time of the presentation. Conclusions: Pending further clinical validation, available data are suggestive of a generally favorable safety profile, with evidence of meaningful anti-tumor activity, including RECIST responses, and preliminary evidence of durable benefit in a heavily pretreated population with substantial disease burden. Clinical trial information: NCT05997615 . All Participants(n/N, %) ≥ 3000 ug/kg Q3W(n/N, %) Gr 1 CRS 24/51, 47% 9/15, 60% Gr 2 CRS 4/51, 8% 1/15, 7% Gr ≥ 3 CRS 1/51, 2% 0/15, 0% Related Gr ≥ 3 TEAE 8/51, 16% 3/15, 20% Any PSA Decline 34/45, 76% 11/11, 100% PSA 50 24/45, 53% 10/11, 91% PSA 90 11/45, 24% 6/11, 55% Objective Response Rate 4/22, 18% 4/6, 67%

Bubble Evolution‐Guided Interconnected Hierarchical Macroporous Sponges for Non‐Compressible Hemostasis in Preclinical Models

ABSTRACT Treatment of uncontrolled non‐compressible hemorrhage remains challenging due to complex anatomical constraints and limitations of existing expandable hemostatic materials, which often lack sufficient porosity, mechanical robustness, biocompatibility, and capacity to support tissue regeneration. To address these issues, an injectable self‐expanding hemostatic sponge was developed using a vacuum‐assisted foaming strategy that harnesses bubble evolution to enlarge pores and enhance interconnectivity, with mechanical stability reinforced by a physically‐chemically integrated double‐network matrix. The optimized formulation (IHMS) exhibited hierarchically interconnected macroporous networks with excellent fatigue resistance, retaining 94.2% of peak stress and 92.7% of strain after 100 compression cycles at 80% strain. It outperformed commercial hemostatic sponges in fluid absorption, blood retention, clot formation, and tamponade sealing. Systematic evaluations demonstrated its intrinsic antibacterial activity, favorable biocompatibility, and ability to promote tissue repair. In rat liver perforation and femoral artery transection models, IHMS achieved superior hemostatic efficacy compared with cotton and commercial sponges. In lethal porcine hemorrhage models under normal and anticoagulated conditions, IHMS provided rapid and durable tamponade, outperforming the FDA‐approved XSTAT, and could be easily removed after hemostasis. Its efficacy was further validated in junctional gunshot wound models. These findings advance the design of high‐performance expandable hemostats for life‐threatening non‐compressible hemorrhage.