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A missense mutation in acyl-CoA synthetase ACSL4 reveals essential residues for catalytic activity in ferroptosis

External validation of a digital pathology-based multimodal artificial intelligence (MMAI)-derived prognostic biomarker in the randomised phase III CHHiP trial.

308 Background: Risk stratification in localised prostate cancer (PCa) based on clinicopathological parameters is inadequate, leading to under- and over-treatment. We used CHHiP trial data to externally validate a previously-developed MMAI prognostic model with potential for cost-effective improved treatment personalisation. Methods: H&E slides from CHHiP translational substudy patients were centrally reviewed by a uro-pathologist between 2013 and 2015, with Gleason grade group (GGG) rescored using contemporary guidelines. GGG was reassigned in 52% of cases. We evaluated the locked ArteraAI prostate MMAI algorithm v1.2 which combines age, T-stage, and PSA with digital prostate biopsy H&E images. Multivariable cox regression analysis of biochemical/clinical recurrence (BCR; trial primary endpoint) and development of distant metastases (DM) were performed with models including age and MMAI as continuous (per 0.1 increase) and categorical (ArteraAI pre-validated 3-tier risk groups) variables. The additional prognostic value of MMAI beyond UK-recommended Cambridge Prognostic Group (CPG) and NCCN risk group models was assessed by change in Concordance Index and Likelihood Ratio Test (LRT). Results: Of 1854 patients with centrally-reviewed pathology, 1797 (97%) had clinical data and H&E with sufficient tumour for MMAI analysis. Median follow up was 14.3 years. Patients were classified as MMAI High (129, 7.2%), Intermediate (885, 49.2%) or Low (783, 43.6%). In univariable analysis, high MMAI score was significantly associated with increased BCR risk, as both a categorical variable (MMAI High risk hazard ratio (HR) = 5.07, 95%CI = 3.77-6.81, p=<0.001, MMAI Intermediate-risk HR = 1.90, 1.52-2.36, p=<0.001), and continuous variable (MMAI raw score HR = 1.55, 1.44-1.67, p=<0.001). MMAI was also significantly associated with DM. Addition of MMAI to CPG and NCCN multivariable models significantly improves discrimination (C-index) and overall fit (change in LRT) for BCR and DM (Table 1). Conclusions: ArteraAI MMAI improves prediction of BCR and DM in CHHiP over standard criteria. This first large-scale external validation in a contemporary UK cohort of localised PCa with rigorously standardized care will inform future prospective trials of MMAI biomarker-guided PCa treatment selection. Endpoint Model C index (MMAI risk group) ΔLRT χ² (p) C index (MMAI raw score) ΔLRT χ² (p) BCR CPG + ageCPG + age + MMAI 0.620.65+0.03 p=<0.001 55.6 p=<0.001 0.620.67+0.05 p=<0.001 67.5 p=<0.001 BCR NCCN + ageNCCN + age + MMAI 0.590.64+0.05 p=<0.001 67.2 p=<0.001 0.590.66+0.07 p=<0.001 80.9 p=<0.001 DM CPG + ageCPG + age + MMAI 0.650.71+0.06 p=0.001 35.3 p=<0.001 0.650.73+0.08p=<0.001 47.0 p=<0.001 DM NCCN + ageNCCN + age + MMAI 0.610.70+0.09 p=<0.001 43.4 p=<0.001 0.610.72+0.11 p=<0.001 55.8 p=<0.001 Total, n=1794. Events BCR, n = 426 (23.7%), DM, n = 121 (6.7%).

Impact of pre-visit educational videos on clinic efficiency for prostate cancer radiation oncology consultations.

332 Background: In 2023, there were roughly 175,000 radiation oncology consultations for prostate cancer, with the average consult taking 35 minutes. The growing demand for prostate cancer consults with radiation oncologists warrants improved clinical efficiency while maintaining a high level of patient satisfaction and patient education. One modality of addressing similar concerns that has been gaining popularity is patient education videos. The goal of this study is to evaluate whether similar provider-developed educational videos decrease the amount of time radiation oncology doctors, residents, and nurses spend with patients for prostate cancer consults, ultimately increasing clinic efficiency. Methods: This prospective, nonrandomized observational study included 205 adult males with prostate adenocarcinoma presenting for a radiation oncology consultation. Eligible participants were undergoing evaluation for radiation therapy; those with prior curative-intent prostate radiation or variant histology were excluded. The educational videos, consisting of 3-4 short videos, were privately shown on the patient’s portal and were made available prior to the scheduled consultations. Videos included briefings on prostate anatomy and physiology, pathophysiology of cancer, staging of the patient’s specific cancer, and a short introduction to treatment options. Measurement of outcomes was done using a clinic time sheet. Analysis was done on patient time with nurses, residents, physicians, and total medical provider time. Two-sample t-tests were performed between patients who did and did not watch the videos. Statistical significance was set at p-value < 0.05 . Findings are from a preliminary analysis to assess for feasibility and early insights. Results: 135 (65.85%) patients did not watch the educational videos, and 70 (34.15%) patients did. The mean amount of time the non-video watching group spent with the provider was 41.533 minutes, and 51.171 minutes for the video watching group. Two-sample t-test revealed statistical significance with p = 0.015 (pooled) and p = 0.019 (Satterthwaite). Time spent in the room, with a nurse, or with a resident was statistically similar between groups. Conclusions: Preliminary results highlight why videos alone, without a change in provider approach, may not be sufficient to increase clinic efficiency. Educational videos may give patients more time to develop questions before the visit. If providers continue their usual discussion routine, this added engagement may lead to longer clinic visits. Future work should evaluate integration of such tools alongside adapted provider communication strategies to optimize both efficiency and patient experience

Optimal duration of immune checkpoint inhibitor therapy in genitourinary cancers: A systematic review and meta-analysis of real-world studies.

470 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of genitourinary (GU) malignancies, producing durable responses in renal cell carcinoma (RCC) and urothelial carcinoma (UC). However, the optimal duration of ICI therapy and the durability of response after discontinuation remain uncertain. In clinical practice, decisions to stop ICIs are often individualized, based on response or toxicity, with no standardized approach. This systematic review is to evaluate real-world outcomes—including treatment-free survival (TFS), overall survival (OS), and progression-free survival (PFS)—after ICI discontinuation in patients with GU cancers. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was conducted to identify real-world studies reporting outcomes following ICI discontinuation in RCC and UC. Eligible studies included patients who discontinued therapy after achieving an objective response (complete response [CR], partial response [PR], or stable disease [SD]) or due to treatment-related adverse events (TRAEs). Data on TFS, OS, PFS, and duration of ICI therapy were extracted and analyzed descriptively. Studies lacking survival endpoints were excluded from the pooled analysis. Results: Twenty retrospective studies met the inclusion criteria, comprising 611 patients with GU cancers. Among these, 253 (41.4%) discontinued ICIs for TRAEs, and 191 (31.3%) underwent elective discontinuation. Overall, 262 patients (58%) achieved an objective response (CR/PR) and 114 (25.4%) achieved SD. Ten studies were excluded from the pooled analysis due to inconsistent endpoints or incomplete TFS data. Ten studies were included in the pooled analysis. Of these, five studies (127 patients) reported median OS, five studies (126 patients) reported median PFS, and six studies (126 patients) reported median TFS. The median duration of ICI therapy was 6.1 months. Pooled analysis revealed a median TFS of 13.3 months (95% CI: 8.6–18.0), median PFS of 7.4 months (95% CI: 1.8–13.0), and median OS of 19.0 months (95% CI: 2.1–35.0). Conclusions: This systematic review highlights the durability of disease control after ICI discontinuation in advanced GU cancers. Many patients maintained prolonged responses off therapy, suggesting potential for finite-duration immunotherapy in selected responders. However, the wide confidence intervals and study heterogeneity underscore the need for larger, prospective studies to define the optimal duration of ICI therapy and identify predictors of sustained benefit.

Cost effectiveness of eight first-line regimens in metastatic hormone-sensitive prostate cancer (mHSPC) including niraparib + abiraterone acetate/prednisone.

47 Background: An increase in radiographic progression-free survival (PFS) was observed in the AMPLITUDE trial combining androgen deprivation therapy (ADT) with niraparib + abiraterone acetate/prednisone (NAAP) for HRR-deficient metastatic hormone-sensitive prostate cancer (mHSPC) patients (pts). We conducted a cost-effectiveness analysis from a U.S. public-payer perspective comparing NAAP with seven established first-line options for mHSPC of ADT alone and added to ADT; docetaxel (DA); abiraterone (AAP); apalutamide (AAT); enzalutamide (ET); darolutamide + docetaxel (DAD); enzalutamide + docetaxel (EAD). Methods: A partitioned-survival model with monthly cycles over a lifetime horizon (progression-free, post-progression, death) incorporated overall survival (OS) and PFS data derived from survival curves. Drug acquisition costs were from 2025 Federal Supply Schedule (FSS). Administration, subsequent-therapy, and adverse event costs and utilities were obtained from published literature. Costs and outcomes were discounted at 3% annually. Incremental cost-effectiveness ratio (ICER) was estimated at a willingness-to-pay (WTP) threshold of $150,000-$200,000/QALY. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty. Results: Across eight treatment strategies (N= 9,027 pts) lifetime costs ranged from $41K (ADT) to $730K (DAD) and Quality of Life Years (QALYs) from 3.25 to 4.29. ET, EAD, AAT, DAD, and NAAP regimens were more costly and less effective than alternatives. Among non-dominated options, DA had an ICER of $35,505/QALY vs ADT, and AAP yielded $189,589/QALY. Although DAD achieved the highest lifetime QALYs (4.29), its incremental cost was large (ICER $1.43M/QALY). Conclusions: From a U.S. public-payer perspective, ADT remains the least costly option, but DA is consistently cost-effective, and AAP may be considered cost-effective at higher WTP thresholds. The addition of NAAP offered incremental benefit for patients with HRR-positive mHSPC; however, the ICER using niraparib’s current FSS pricing, derived from the mCRPC setting may limit its overall cost-effectiveness. These findings describe relative economic profiles rather than direct head-to-head comparisons. Cost-effectiveness results (in 2025 US dollars). Regimen Cost ($) Effectiveness (QALYs) ICER (US$/QALY) ADT $41,287 3.25 DA+ADT $60,334 3.79 $35,505 AAP+ADT $67,585 3.83 $189,589 NAAP+ADT $116,712 3.45 Dominated 1 AAT+ADT $361,699 2.43 Dominated 1 ET+ADT $491,283 3.99 Dominated 2 EAD+ADT $562,151 4.16 Dominated 2 DAD+ADT $729,270 4.29 $1,432,592 1 More costly and less effective than another treatment strategy (ie, absolute dominance). 2 More costly and less effective than a linear combination of other treatment strategies (ie, extended dominance).

Ultrathin Mesoporous Ionic Brushes Separator Enables Fast and Durable Zinc‐Metal Aqueous Batteries

ABSTRACT Zinc metal aqueous batteries (ZnABs) emerge as promising candidates for grid‐scale energy storage, yet severe Zn dendrite formation and anode side reactions degrade cycle life and hinder practical application. Herein, we report an ultrathin (27 µm) mesoporous ionic brushes (MiB) separator based on sulfonic grafted ordered mesoporous silica nanosheets for stable ZnABs. The well‐ordered perforative mesopores architecture functions as an ion rectifier that achieves enhanced transfer kinetics and a homogeneous concentration field, thereby promoting dendrite‐free deposition, as verified by in situ digital holography and kinetic analyses. Moreover, ionic brushes confined within nanochannels selectively capture water molecules from the primary solvation shell of Zn 2+ , facilitating desolvation and constructing a localized water‐lean interfacial environment, which effectively suppresses water‐related side reactions, as evidenced by various in situ spectroscopy, electrochemical analyses, and theoretical calculations. Consequently, the MiB separator enables the Zn anode to achieve a high Coulombic efficiency of 99.7%, ultralong lifespan over 4300 h, fast plating kinetics of 20 mA cm −2 , and high Zn utilization rate of 51.6%. Furthermore, Zn‐V 2 O 5 cells achieve perdurable capacity retention of 91.5% after 3500 cycles. This work presents a rational mesoporous separator design that synchronously regulates ion transport and interfacial solvation chemistry for highly reversible ZnABs.

An Integrated Stainless Steel‐Based Electrode for Durable Direct Natural Seawater Electrolysis

ABSTRACT Direct seawater electrolysis for hydrogen production is hindered by severe catalyst inactivation and material corrosion caused by the complex composition of natural seawater. In this work, we demonstrate a multistage structure on a stainless steel (SS) substrate by integrating Pt atomic clusters (0.044 wt%) with a dense NiFe layer double hydroxides (NiFe‐LDH) anticorrosive coating. The assembled seawater electrolyzer maintains durable operation for 600 h at a current density of 400 mA cm −2 (∼2.04 V) and for 1000 h at 200 mA cm −2 (∼1.78 V), while simultaneously achieving a cost reduction of more than 40% and ultralow energy consumption of 4.26 kWh Nm −3 H 2 . Multiple in situ characterization results reveal that the adsorbed H 2 O molecules between the interface of Pt atomic clusters and NiFe‐LDH could initiate a potential‐driven dynamic transformation process from a 4 hydrogen‐bond to a 0 hydrogen‐bond coordination of H 2 O, thereby promoting their dissociation. Pt atomic cluster induces a configuration transformation of interfacial water from two‐H down to two‐H up and differentiates the adsorption energies between H 2 O and chloride ions, further optimizing selectivity. This work fully demonstrates the integrated design of catalysts, anti‐corrosion coating, and porous transport layer, thereby offering an innovative and practical approach to direct seawater electrolysis.

Cytosolic nucleic acid sensing triggers type I interferon activation via the Hippo kinase LATS1

Inherited risk for prostate cancer (PCa): Following the natural history of men with increased genetic risk using multiparametric MRI (mpMRI).

315 Background: PCa has substantial inherited predisposition and certain germline variants like BRCA1/2 , ATM , HOXB13 , and DNA mismatch repair (MMR) genes are associated with an increased risk of PCa. This study follows men without a diagnosis of PCa, with known germline pathogenic/likely pathogenic variant (PV) in BRCA1/2 , DNA MMR genes associated with Lynch syndrome ( MLH1/PMS2 , MSH2 / MSH6 , EPCAM ), HOXB13 , ATM , CHEK2 , PALB2 , TP53 , NBN , RAD51C/D , BRIP1 , and FANCA-FANCM (NCT03805919). Methods: Up to 500 men, ages 30-75 years old (y/o) with a documented PV will enroll. Men undergo biennial mpMRI and annual PSA. Indication for prostate biopsy includes clinical, PSA, and/or MRI findings. Patients are followed at 12-month intervals to determine PSA, PCa diagnosis, and disease/survival status until death. Results: To date, 378 evaluable patients have enrolled: 353 (93%) Caucasian, 11 (3%) Hispanic, 7 (2%) Asian, 4 (1%) African-American, 2 (1%) bi-ethnic. 1 Indian-Asian. Median age was 47 y/o. The most common PV were: 180 (48%) BRCA2 , 94 (25%) BRCA1 , 22 (6%) CHEK2 , and 18 (5%) ATM . PVs in MLH1 / PMS2 , MSH2 / MSH6 , PALB2 , HOXB13 , TP53 , BRIP1 , RAD51D , EPCAM , NBN , and FANCA are <4%. Eight patients carried more than one PV. A total of 782 MRIs were performed: 378 baselines, 228 at year 2, 121 at year 4, 30 at year 6, and 25 clinical. Indication for biopsy was present in 89 (24%) patients with 37 (10%) diagnosed with PCa. Of the 90 biopsies indicated, 1 refused and withdrew and 3 are still pending. Of those with PCa, 22 had BRCA1/2 PVs, 5 had MMR PVs, and 10 had non-MMR PVs. Median age at diagnosis was 62. 24 patients were diagnosed with Grade Group (GG) 1, 8 patients with GG2, 1 patient with GG3, 3 patients with GG4, 1 patient with GG5. 21 opted for active surveillance (AS), 10 opted for prostatectomy, 6 opted for radiation therapy. 5 patients on AS converted to definitive treatment after progression was noted at 1-year follow-up. Conclusions: mpMRI screening in men with PVs is feasible and can be used for early diagnosis, PCa monitoring, and facilitates PCa diagnosis at PSA levels below conventional thresholds. Correlative studies including cfDNA, PBMCs and PRS, are ongoing. Clinical trial information: NCT03805919 . Indication for biopsy. BiopsyPositive BiopsyNegative Biopsy Pending, Refused Total = 89 PSA WNL PSA Elevated PSA WNL PSA Elevated PSA WNL PSA Elevated PIRADS 1 13 0 4 0 9 0 0 PIRADS 2 15 1 3 5 6 0 0 PIRADS 3 23 5 1 11 3 2 1 PIRADS 4 34 10 9 13 2 0 0 PIRADS 5 4 1 3 0 0 0 0

Response to primary chemoablation with UGN-102 in different EOTRC risk groups.

733 Background: The ENVISION phase 3 study (NCT05243550) treated patients with recurrent low-grade intermediate-risk non-muscle-invasive bladder cancer (LG-IR-NMIBC) with UGN-102, a reverse thermal hydrogel administered intravesically containing 75 mg mitomycin. Complete response (CR) rate at 3 months was 79.6% (95% confidence interval [CI]: 73.9, 84.5) with a 72.2% (95% CI: 64.1, 78.8) 1 probability of remaining in response (DoR) 24 months later. The European Organization for Research and Treatment of Cancer (EORTC) recurrence score tables provide estimates of recurrence based on baseline prognostic factors. We conducted a post-hoc analysis of CR and DoR by EORTC recurrence score subgroup. Methods: 240 patients with recurrent LG-IR-NMIBC received ≥1 dose of UGN-102. CR was assessed at 3 months using cystoscopy, urine cytology testing, and for-cause biopsy. Patients achieving CR entered the follow-up period and are being assessed for recurrence or progression for up to 5 years. CR at 3 months and probability of maintaining CR at 24 months (DoR) in patients with EORTC recurrence scores of 1-4, 5-9 and 10-17 were calculated. DoR was calculated using the Kaplan–Meier (KM) estimation method. Results: The median (range) EORTC recurrence score was 7 (2-13). CR rate at 3 months was 83.9%, 81.2% and 60% for patients with recurrence scores of 1-4 (n=31), 5-9 (n=191) and 10-17 (n=15), respectively. Of the patients with CR at 3 months, 26.9%, 23.9% and 33.3% (for recurrence scores of 1-4, 5-9 and 10-17) experienced recurrence of LG disease, progression (either in stage or grade), or death by 24 months. The KM estimate of median DoR was not estimable for any group due to the low event rates. Conclusions: UGN-102 demonstrated robust complete response rates across all EORTC recurrence score subgroups, including patients with higher baseline recurrence risk. The majority of patients remained recurrence-free at 24 months. Despite the post-hoc design and small subgroup sizes, these findings suggest UGN-102 provides durable and clinically meaningful disease control in recurrent LG-IR-NMIBC. Clinical trial information: NCT05243550 . EORTC recurrence score group 1-4 N=31 5-9 N=191 10-17 (N=15) CR at 3 months, n (%) 26/31 (83.9) 155/191 (81.2) 9/15 (60) CRR (95% CI) 83.9 (66.3-94.5) 81.2 (74.9-86.4) 60.0 (32.3, 83.7) Recurrence 24 months*, n (%)Recurrence of LG diseaseProgressionDeath 7/26 (26.9) 5/26 (19.2) 0 2/26 (7.7) 37/155 (23.9) 27/155 (17.4) 7/155 (4.5) 3/155 (1.9) 3/9 (33.3) 3/9 (33.3) 0 0 Probability of remaining in response at 24 months, %, 95% CI** 67.4 (43.2-83.1) 73.7 (64.6-80.8) 66.7 (28.2-87.8) Median duration of follow up, months, 95% CI*** 23.29 (23.03-23.92) 23.72 (23.66-23.92) 23.90 (23.72-NE) *24 months after 3-month CR. **Calculated using the KM method, with Brookmeyer–Crowley CIs. *** Estimated using reverse KM method. CI, confidence interval; CRR, complete response rate. 1. Prasad SM, et al. J Urol. 2025;213:205–16.

Therapy-resistant subclones as drivers of progression in aggressive variant prostate cancer.

239 Background: Tumor heterogeneity and clonal evolution are key drivers of cancer progression and therapeutic resistance. In metastatic prostate cancer, the aggressive variant prostate cancer (AVPC) phenotype, often defined by concurrent alterations in TP53, RB1, and PTEN, is associated with poor clinical outcomes and rapid progression under standard treatments. However, the evolutionary trajectories that sustain resistance and promote relapse in AVPC remain incompletely characterized. To elucidate the clonal and genomic mechanisms underlying therapeutic failure, we performed a whole-genome analysis of AVPC tumors before and after chemotherapy. Methods: We analyzed 40 AVPC tumors from frozen metastatic biopsy cores collected at baseline in men enrolled in the MDA 2017-0133 (CCOLA) trial. High-depth whole-genome sequencing (~80–120×) was performed on all baseline samples. A longitudinal subset of nine patients also underwent matched post-chemotherapy biopsies after six cycles of carboplatin–cabazitaxel, yielding nine post-treatment tumors; per protocol, post-chemotherapy biopsies were obtained only from patients who progressed on treatment. Somatic mutations, copy number alterations and tumor purity estimates were integrated to reconstruct clonal/subclonal architecture and quantify genomic instability. Results: Concurrent inactivation of ≥2 of TP53, RB1, and PTEN, were frequent and associated with adverse clinical outcomes. Despite chemotherapy, overall clonal diversity persisted, indicating sustained subclonal complexity under treatment pressure. In longitudinal analyses, post-treatment founder clones commonly descended from pre-existing minor subclones that accrued additional mutations during therapy. Progression-specific TP53 mutations were identified in 14/25 (56%) evaluable patients and were also observed in 3/15 (20%) patients with prolonged progression-free survival, underscoring the mechanistic heterogeneity of resistance. The cohort exhibited pronounced genomic instability with extensive subclonal copy number alterations, exceeding prior reports and revealing the underestimated complexity of AVPC. Conclusions: Therapy-resistant subclones emerge from pre-existing tumor lineages that evolve under selective pressure, contributing to progression and resistance in AVPC. The persistence of clonal diversity despite chemotherapy shows that many tumors retain evolutionary capacity, which limits the reliability of single time-point genomic models for prognosis or treatment selection. These findings support earlier, serial detection of emergent resistant lineages and the use of genomic profiling to guide timely, individualized treatment strategies. Clinical trial information: NCT03263650 .

Clinical and cost impact of cabazitaxel versus lutetium-177 vipivotide tetraxetan (Lu-PSMA) for patients with metastatic castration-resistant prostate cancer (mCRPC).

41 Background: The TheraP trial compared cabazitaxel to Lu-PSMA in patients with mCRPC who previously received docetaxel. In TheraP, Lu-PSMA achieved greater PSA responses than cabazitaxel (66% vs 37%; p=0.0016), while OS was similar (HR 0.97, p=0.99; difference –0.5 months [m], p=0.77). Rates of grade 3-4 adverse events (AE) were also similar. We aimed to quantify the direct cost differences and assess the clinical outcomes associated with the use of cabazitaxel compared to Lu-PSMA in this population. Methods: An Excel-based model was developed to assess clinical and economic outcomes at 6, 12, 18, and 24m in a U.S. patient population from the U.S. Medicare payer perspective. Efficacy and safety were informed by the TheraP study, supplemented by literature when data were lacking, and confirmed by a genitourinary oncologist (PB). Drug costs were based on Medicare ASP (or RedBook). Costs of grade 3-4 AE were estimated by weighted inpatient and outpatient management costs. Outcomes included direct costs related to PSMA testing, drug acquisition and administration, supportive care, AE, and end-of-life care. Clinical outcomes included the number of patients in OS, PFS, PSA-PFS, and rPFS. The cost impact was modeled for a cohort of 100 mCRPC patients receiving cabazitaxel or Lu-PSMA. A base case time horizon of 18m was chosen to correspond with available clinical trial follow-up data, provide a balanced assessment of costs and outcomes, and align with a prior published model in third-line mCRPC. Costs were reported in 2025 US dollars. Results: At 18m, total costs for a 100-patient cohort were $9.97M with cabazitaxel versus $29.37M with Lu-PSMA, equating to $19.40M in savings overall. Cabazitaxel costs were about one-third those of Lu-PSMA, driven primarily by drug acquisition ($8.53M vs $27.76M; –$19.23M). Other cost categories contributed smaller differences, ranging from savings with PSMA testing (–$0.15M) to incremental costs associated with adverse event management (+$0.07M). Clinically, at the primary analysis timepoint of 18m, cabazitaxel was modeled to yield 9 fewer deaths, though this numerical advantage favoring cabazitaxel should be interpreted cautiously, as TheraP found no OS difference and reported OS results accounting for non-proportional hazards. Lu-PSMA demonstrated greater disease control, with 8 additional patients free of progression (PFS) and PSA-PFS at 18m, consistent with TheraP findings. Cabazitaxel was associated with consistent and substantial cost savings across all timepoints. Lu-PSMA conferred greater PFS and PSA benefits, especially during the 12–18m interval. Conclusions: Cabazitaxel is estimated to reduce direct payer costs by approximately $194,000 per patient relative to Lu-PSMA, driven primarily by lower drug acquisition expenses. These savings contrast with Lu-PSMA’s improved PFS and PSA outcomes.

Like water on rock, the microenvironment bends stem cell fate

Heterogeneous Network SLIPS Coating with Soft‐Hard Chain Integration Design for Marine Antifouling Engineering

ABSTRACT Developing durable coatings that sustain long‐term antifouling activity is critical for the reliable operation of ocean monitoring systems in biologically complex marine environments. Here, we report a heterogeneous‐network slippery liquid‐infused porous surface (SLIPS) coating engineered through a molecular design strategy. This design integrates a low‐surface‐energy rigid framework with a dynamic, self‐healing soft network. The rigid framework is formed by a cross‐linked network of thiol‐functionalized polyhedral oligomeric silsesquioxane (POSS‐(SH) 8 ) and fluorinated liquid nitrile rubber (F 13 ‐LNBR). The soft network is based on a three‐arm cross‐linked structure constructed from hexamethylene‐diisocyanate isocyanurate trimer (THDI) and 2‐ureido‐4[1H]‐pyrimidinone (UPy) units. Infused with silicone oil, the coating exhibits robust mechanical strength, demonstrated by an erosion rate of 74.37 nm/s, and autonomous self‐healing capability enabled by multiple hydrogen bonds in both aerial and underwater conditions. Remarkably, the release rate of the silicone oil and the uniformity of surface hydrophobicity are precisely regulated by incorporating UPy units with tailored molecular structures and perfluoroacrylate monomers with varying hydrophobic chain lengths. Owing to these rational design elements, the coating repels a broad spectrum of fouling agents, including bacteria, algae, and highly viscous crude oil, while maintaining excellent flexibility and wear resistance. During a 90‐day field test in real seawater, the coating's transmittance decreased by only 5.8%. This synergistic design addresses key limitations in current SLIPS technologies, offering a viable pathway toward long‐term antifouling performance in challenging marine environments.

BiO(IO ₃ ) with Ultrahigh Effective Atomic Number and Density for Sensitive and Stable Hard X‐Ray Detection

ABSTRACT Bismuth halide perovskites are promising materials for hard X‐ray detection owing to their high effective atomic number (Z eff ) and excellent optoelectronic properties. However, the reported A‐site cations or pseudohalides to address chemical stability issues inevitably reduce material Z eff /density and aggravate electron localization. These changes significantly degrade X‐ray absorption and charge transport, ultimately undermining detection performance. Herein, we chose the oxidized I 5+ to replace I − , and designed 2D BiO(IO 3 ). This substitution yields a significantly more compact crystal lattice while retaining two high‐Z elements (Bi and I), affording the material an ultrahigh Z eff (72.29) and density (7.399 g/cm 3 ), which greatly enhances hard X‐ray absorption. Concurrently, the small effective mass of the material facilitates efficient carrier transport, resulting in a high device sensitivity of 4563 µC Gy air −1  cm −2 for ∼25 keV X‐ray photons. Furthermore, the formation of strong Bi–O and I–O bonds endows the material with excellent stability, leading to a high ion migration activation energy of 0.73 eV. Specifically, polycrystalline wafers with a thickness of 1 mm were successfully fabricated and showed no performance degradation after long time continuous aging test (160 kV X‐ray, high voltage, temperature, etc.). This work provides a promising solution for developing high‐performance hard X‐ray detection materials.

A submission checklist to improve transparency and replicability of functional genomics data analyses

Real-world efficacy of nivolumab plus cabozantinib in metastatic renal cell carcinoma (mRCC) using the IMDC.

446 Background: Nivolumab plus Cabozantinib is an established first-line standard of care in mRCC after demonstrating significant improvements over Sunitinib in the phase III CheckMate 9ER trial. However, real-world outcomes with this regimen remain under-reported. Methods: Using the International mRCC Database Consortium (IMDC), we identified all patients treated with Nivolumab plus Cabozantinib between January 1, 2018, and August 31, 2025. Baseline characteristics were described, and median time to next treatment (mTTNT), overall survival (mOS), overall response rate (ORR), and subsequent treatment sequencing and efficacy were evaluated. OS was compared by IMDC risk group using log-rank. Results: 195 patients were identified. Baseline characteristics are summarized in Table 1. With a median follow-up of 18.9 months, the ORR was 41.6% (3.6% CR), mTTNT was 19.4m (95% CI 16.9-26.4) and mOS 44.4m (95% CI 29.6 m-NR). By IMDC risk group, mOS was NR (44.4–NR), 46.9m (26.4–NR), and 18.4m (11.5–NR) for favorable, intermediate, and poor risk, respectively (p<0.0001). At data cutoff, 91 patients were still on treatment, and 58 patients started a 2nd line. The most commonly used second line drugs were Axitinib (27.6%) and Lenvatinib plus Everolimus (17.2%). Others included Sunitinib (6.9%), Pazopanib (6.9%), Tivozanib (6.9%), Pembrolizumab plus Lenvatinib (5.2%) and Belzutifan (3.4%). Among patients treated with second-line Axitinib (n=16), ORR was 33.3%, with a mTTNT of 7.2m (95% CI 5.4–NR) and mOS of 12.3m (95% CI 5.4–NR). Conclusions: In this real-world analysis, Nivolumab plus Cabozantinib achieved TTNT and OS comparable to those reported in CheckMate 9ER, albeit with a somewhat lower ORR (41.6% vs 55.7%), likely influenced by the inclusion of non-clear cell histology. Importantly, 2nd line TKIs demonstrated activity following Cabozantinib exposure, supporting its use in this treatment sequence. Baseline characteristics. Characteristic N=195 (%) Median Age (IQR) 63 (56-71) Male 157 (80.5%) Non-clear cell 54 (27.7%) Nephrectomy 107 (54.9%) Brain metastasis 18 (9.3%) Bone metastasis 97 (49.7%) Liver metastasis 40 (20.5%) More than 1 metastasis site 141 (72.3%) IMDC risk (Fav/Int/Poor) 36 (21.7%) / 81 (48.8%) / 49 (29.5%)

Three-year median follow-up update of BGB-A317-2002-IIT: A phase 2 study of neoadjuvant tislelizumab plus gemcitabine and cisplatin in patients with cT2–T4aN0M0 muscle-invasive bladder cancer.

783 Background: A multicenter phase II trial evaluating neoadjuvant tislelizumab plus gemcitabine/cisplatin for patients with cT2–T4aN0M0 muscle-invasive bladder urothelial carcinoma (MIBC) demonstrated a favorable pathological response and safety. Here, we present the updated survival outcomes with a median follow-up of 3 years. Methods: Cisplatin-eligible patients with cT2–T4aN0M0 MIBC received tislelizumab 200 mg on day 1, cisplatin 70 mg/m 2 on day 2, and gemcitabine 1000 mg/m 2 on days 1 and 8 of a 21-day cycle for four cycles, followed by radical cystectomy (RC). Event-free survival (EFS) and overall survival (OS) were analyzed in the intention-to-treat (ITT) cohort, while recurrence-free survival (RFS) was analyzed among patients who underwent RC. Survival outcomes were estimated using Kaplan–Meier methods and stratified by pathological response (ypT0N0, ypTis/Ta/T1N0, and ≥ ypT2N0), PD-L1 expression, and tumor mutational burden (TMB). Results: From February 2021 to September 2022, 65 patients (12.3% female) were enrolled, and 57 underwent RC. The median follow-up was 42.2 months (IQR: 38.6–47.7). In the ITT population, the 3y-EFS was 73.4% (95% CI: 59.2–83.3%), and the 3y-OS was 82.5% (95% CI: 70.7–89.9%). Pathological response categories were significantly related to RFS (p < 0.0001): 3y-RFS for ypT0N0 responders was 86.9% (95% CI: 62.9–95.8%) vs 92.9% (95% CI: 59.1–99.0%) for ypTis/Ta/T1N0 vs 32.1% (95% CI: 9.5–57.9%) for ≥ ypT2N0. Eight patients who declined RC were alive at data cutoff, including 5 disease-free cases. Survival analysis stratified by TMB (cutoff at 14.8 mutations/Mb) showed significantly better EFS in the TMB-high group (N = 11) versus TMB-low (N = 35; log-rank test p = 0.031). Baseline PD-L1 expression was available for all ITT patients, and the EFS curves did not separate between PD-L1–high (N = 19) and PD-L1–low (N = 46) groups (log-rank test p = 0.599). Conclusions: Neoadjuvant tislelizumab plus gemcitabine/cisplatin demonstrated durable clinical benefit with sustained 3-year survival outcomes in patients with MIBC. Pathological response remained strongly associated with survival. High TMB, rather than PD-L1 expression, correlated with improved survival. Clinical trial information: ChiCTR2000037670.

Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with genitourinary extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial.

152 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC), including extrapulmonary NECs (epNEC) of a genitourinary (GU) origin. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive tumors. A recent analysis from a Phase I dose-escalation trial of obrixtamig (NCT04429087) showed manageable safety and promising efficacy in patients (pts) with advanced previously treated epNEC (objective response rate [ORR] of 40% and median duration of response [DoR] of 7.9 months in pts with tumors expressing high levels of DLL3 [DLL3-high]). This sub-analysis examined the efficacy and safety of obrixtamig in epNEC GU. Methods: Obrixtamig was given IV in 4 dose-escalation regimens (R): RA (fixed dose q3w), RB1 (fixed dose qw), RB2 (step-up dose, then qw), and RB3 (step-up dose, then qw for 3 weeks, then q3w), until disease progression or unacceptable toxicity. Efficacy was assessed through confirmed ORR and disease control rate (DCR) using RECIST v1.1 (investigator review). Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high or low DLL3, using a threshold of ≥50% of tumor cells with moderate and/or strong (2+/3+) membrane and/or cytoplasmic staining with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 20 pts with epNEC GU were included (prostate: 45%, bladder: 40%, gynecological: 15%); 60% DLL3-high and 40% DLL3-low. Median age: 69 years. Female: 20%. ECOG PS (0/1/missing): 30%/65%/5%. Efficacy data are shown in the Table. In the DLL3-high group ORR/DCR was 50%/75% with responses observed across tumor types (prostate: 60%, bladder: 50%, gynecological: 33%). Median DoR was not reached. Five of 6 responding pts are ongoing. Most treatment-related AEs (TRAEs) were mild to moderate with no cases of grade ≥3 cytokine release syndrome (Table). Conclusions: Obrixtamig showed preliminary efficacy and durable responses in heavily pretreated patients with DLL3-high epNEC GU, with a manageable safety profile. These data support further development of obrixtamig in this setting. Clinical trial information: NCT04429087 . Efficacy/safety parameter Overall (N=20) DLL3-high (n=12) DLL3-low (n=8) ORR, % (95% CI) 30 (15–52) 50 (25–75) 0 (0–32) DCR, % (95% CI) 55 (34–74) 75 (47–91) 25 (7–59) 6-month DoR, %* 100 100 – TRAEs, all/G ≥3, (%) 95/25 100/33 88/13 CRS, all/G ≥3, (%) 65/0 75/0 50/0 Obrixtamig-related potential neurological toxicity † , including ICANS, all/G ≥3, (%) 10/5 17/8 0/0 *Kaplan−Meier estimate. † Evaluated with a customized MedDRA query. CI, confidence interval; ICANS, immune effector cell-associated neurotoxicity syndrome; CRS, cytokine release syndrome; MedDRA, Medical Dictionary for Regulatory Activities.

Quality improvement initiative to increase osteoporosis screening in patients with prostate cancer on long-term androgen deprivation therapy.

51 Background: Long-term androgen deprivation therapy (ADT) for hormone sensitive prostate cancer (HSPC) is associated with increased bone mineral density loss, risk for major osteoporotic fractures and increased morbidity and mortality. Although guidelines recommend baseline bone mineral density (BMD) assessment before starting ADT, national osteoporosis screening rates remain low around 8%. The aim of this quality improvement initiative was to increase osteoporosis screening rates to 20% for HSPC patients on long-term ADT seen at the University of Virginia Cancer Center. Methods: A multidisciplinary team of health care professionals was assembled and completed the ASCO Quality Training Program in 2024. Baseline data on osteoporosis screening among patients with HSPC treated with ADT for longer than 6 months at the University of Virginia Cancer Center between August 2023 and June 2024 was analyzed. After conducting a thorough evaluation of our current osteoporosis screening process, which included a provider survey, process mapping, and a root cause analysis, we implemented two Plan-Do-Study-Act (PDSA) cycles and tracked our outcome measure of completed bone mineral density assessments with a statistical control chart (P-Chart). Results: Between August 2023 and June 2024, an average of 11% of prostate cancer patients underwent BMD assessment with notable screening rate disparities based on the area deprivation index. A provider survey showed agreement in the importance of osteoporosis screening, but providers were hesitant to adopt routine screening protocols. PDSA Cycle 1 involved the standardization of provider practices by implementation of risk-stratified screening criteria. In PDSA Cycle 2, an email notification system was established to alert providers about patients who are eligible and due for osteoporosis screening. Following these interventions, we observed a special cause variation with an increase in the osteoporosis screening rate from 11.4% at baseline to 17.3% (P = 0.001) by July 2025. A review of 63 DEXA scans revealed that 54% of patients were diagnosed with osteopenia and 17.5% with osteoporosis. Barriers to achieving our benchmark for osteoporosis screening included competing clinical priorities, limited time during clinic visits, patient preferences and goals of care. Conclusions: Establishing consensus on risk-stratified osteoporosis screening criteria for HSPC patients on long-term ADT and notification of providers on eligible patients led to increased rates of osteoporosis screening.