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Wavelength‐Multiplexed PUFs Through Single‐Host Multicolor Switching in Cs ₂ NaTbCl ₆ : Eu ³⁺ Double Perovskites

ABSTRACT Physical unclonable functions (PUFs) based on multi‐wavelength emission hold significant promise for advancing high‐capacity hardware security by harnessing intrinsic physical randomness. However, achieving spectrally isolated multi‐channel emission within a single matrix remains a daunting challenge. Herein, we demonstrate a single matrix platform using Cs 2 NaTbCl 6 : Eu 3+ double perovskite that enables excitation‐programmable multicolor switching through orthogonal optical activation of Tb 3+ and Eu 3+ centers. This monolithic system exhibits dominant green emission (Tb 3+ : 5 D 4 → 7 F 5, 6 ) under 275 nm excitation, while selective red emission (Eu 3+ : 5 D 0 → 7 F 1, 2 ) under 310 nm excitation, and distinct yellow emission under 275/310 nm co‐stimulation. This unique behavior arises from well‐separated excitation pathways, weak interionic interactions, and suppressed concentration quenching via the large Spacing of rare earth ions and low phonon energy. Leveraging this unique single‐host multiplexing capability, we develop a wavelength‐division multiplexing PUF (WDM‐PUF) featuring simplified information carriers, unprecedented encoding dimensions, and a near‐zero false negative rate through RGY/octal spectral‐channel encoding. Its flexible encoding method and operational simplicity enable its application in color image encryption and programmable information transmission, along with smartphone‐compatible authentication functionality. Our work establishes a new paradigm in optical encryption with wavelength‐multiplexed capacity in a single emissive platform, opening avenues for ultra‐secure anti‐counterfeiting technologies.

Engineering the Local Electronic Microenvironment via Interfacial Chelation for Efficient CO ₂ Photoreduction Toward CH ₄

ABSTRACT The photocatalytic conversion of CO 2 into hydrocarbons using sustainable solar energy offers a promising strategy to address the global energy crisis and achieve carbon neutrality. However, conventional p‐block photocatalysts are often limited by inefficient electron transfer, which restricts the reaction to a two‐electron reduction pathway, primarily yielding CO and impeding the formation of high‐value hydrocarbons like CH 4 . Herein, we construct a novel BiOCl–BiO(HCOO) heterostructure (denoted as BiOCH), which features interfacial chelating interactions between the [Bi 2 O 2 ] 2 + and [HCOO] − layers within the BiO(HCOO) component, for efficient photocatalytic CO 2 reduction to CH 4 . This unique heterostructure broadens the light absorption spectrum and facilitates the separation of photoinduced charges. More importantly, the interfacial Bi─O chelation in BiO(HCOO) modulates the local electronic microenvironment of Bi sites. Mechanistic studies reveal that this modulation enhances the coupling between the C‐2p orbital of the * CHO intermediate and the Bi‐p orbital, thereby lowering the Gibbs free energy barrier for the critical * CO‐to‐ * CHO step and promoting CH 4 generation. Consequently, the optimized BiOCH catalyst achieves a remarkable CH 4 production rate of 42.95 µmol·g − 1 ·h − 1 with a high electron selectivity of 95.38%. This work provides a novel design strategy of organic–inorganic hybrid layered structures for steering photocatalytic CO 2 reduction toward value‐added hydrocarbons.

Palmitic acid induces UCP1-independent mitochondrial depolarization specifically in brown adipose tissue

LUNAR: Safety and efficacy evaluation of nadofaragene firadenovec instilled into the renal pelvis in subjects with low-grade upper tract urothelial carcinoma—A single-arm, open-label phase 1/2 trial.

TPS906 Background: Recommended treatment options for low-grade upper tract urothelial carcinoma (LG-UTUC) include kidney-sparing surgery and radical nephroureterectomy. Kidney-sparing surgery, such as endoscopic ablation, allows the preservation of the ipsilateral kidney, but is associated with high local recurrence rates. Mitomycin gel, the first Food and Drug Administration (FDA)-approved non-surgical treatment for LG-UTUC, is associated with a risk for ureteral strictures. Therefore, there is an unmet need for an alternative well tolerated and effective localized non-surgical treatment option for subjects with LG-UTUC. Nadofaragene firadenovec is a replication-deficient adenoviral vector carrying the interferon alpha-2b (IFNα2b) transgene. It is an effective and well tolerated intravesical bladder-sparing gene therapy approved by the FDA for the treatment of adults with high-risk Bacillus Calmette Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors. The primary objectives of the LUNAR trial are to evaluate the safety and efficacy of nadofaragene firadenovec instilled into the renal pelvis in subjects with LG-UTUC. Methods: Twenty subjects with biopsy-proven LG-UTUC and ≥ 1 measurable papillary low-grade tumor (5-15 mm diameter) above the ureteropelvic junction will be included in this marker-lesion trial. The trial will start with a safety lead-in period in a cohort of 6 subjects, before enrolment of the remaining 14 subjects. During the treatment period, subjects will participate in disease evaluation visits scheduled every 3 months, including ureteroscopy, selective urine cytology, and for-cause biopsy. The primary efficacy endpoint is complete response at 3 or 6 months, defined as the absence of any UTUC in the renal pelvis, indicated by negative urine cytology for high-grade urothelial carcinoma, and either no suspicious lesions on ureteroscopy or a negative for-cause biopsy. Secondary efficacy endpoints include duration of response and urinary excretion of IFN-α2b protein. Results from this trial are expected in 2029. Clinical trial information: NCT06668493 .

Incidence of symptomatic hypoxia in a high-altitude cohort of patients with renal cell carcinoma (RCC) treated with belzutifan.

488 Background: Hypoxia-Inducible Factor (HIF-2α) is a transcription factor that allows for adaptation to environments with decreased oxygen availability. It is also dysregulated in RCC. The FDA has recently approved belzutifan, a HIF-2α inhibitor, for the treatment of metastatic RCC (mRCC) following the results of the LITESPARK-005 trial (NCT04195750). However, oxygen availability decreases with altitude, and it’s estimated that 943 million people worldwide live above 1000 meters in elevation. The effect of altitude on belzutifan treatment has not yet been reported. Here, for the first time, we present detailed safety data on a high-altitude cohort of patients with mRCC treated with belzutifan. Methods: In this IRB approved retrospective study, the inclusion criteria were diagnosis of mRCC and treatment with belzutifan. Patients with germline VHL syndrome were excluded. An SpO 2 of <92% was defined as grade 1 hypoxia (in accordance with LITESPARK-005) and all other adverse events were graded according to CTCAE version 5. Patient residential altitude was estimated using US Geologic Survey (usgs.gov) data. Results: Overall, 34 sequential patients with mRCC met eligibility criteria and were included in the analysis. 31 (91%) were male, 28 (82%) were White, 22 (65%) were never smokers, and 22 (65%) had lung metastases at baseline. 3 (10%) were concomitantly treated with a tyrosine kinase inhibitor, and 5 (17%) started at a dose of 200 mg. All had an ECOG of ≤1 and were not on supplemental O 2 prior to start of therapy. The average residential altitude of this cohort was 1457 m (range: 1288 - 1945). Overall, 30 (88%) experienced grade ≥1 hypoxia, with grade 3 being the most common experienced by 16 (47%) patients. At-home supplemental O 2 was required by 28 (82%) and was prescribed at a median of 55.5 days (IQR: 29.3 - 106.5) after starting belzutifan. Grade ≥2 anemia was seen in 27 (79%) patients. Conclusions: The high incidence of hypoxia and use of supplemental oxygen among our high-altitude patient population is in stark contrast to what was expected based on the LITESPARK-005 trial data. In that trial, the rate of hypoxia of any grade was only 14.5% with 10.2% needing supplemental O 2 . By comparing the LITESPARK-005 patient enrollment numbers to the altitude of their recruiting institutions, we can estimate that the weighted average altitude of the patient’s trial site was 201 m, which is much lower than our institutional cohorts' altitude. Upon external validation, these findings may support future guidelines on closer monitoring and earlier intervention for patients with mRCC receiving belzutifan who reside at high altitudes. Observed adverse events seen in patients with mRCC treated with belzutifan. Hypoxia (n) Anemia (n) Grade 1 2 7 Grade 2 10 14 Grade 3 16 13 Grade 4 2 0

Longitudinal assessment of patient-reported quality of life and mental health during active surveillance for low-grade NMIBC.

727 Background: While transurethral resection of bladder tumor (TURBT) remains the gold-standard treatment for non–muscle-invasive bladder cancer (NMIBC), there is growing interest in de-intensification strategies aimed at reducing the patient burden of repeated procedures and the overall economic impact of the disease. Active Surveillance (AS) has been proposed as a potential alternative to TURBT in selected cases of recurrent low-grade (LG) NMIBC, with promising oncologic outcomes. However, the impact of AS on patients’ quality of life (QoL) remains largely unexplored. This study aimed to evaluate longitudinal changes in QoL during AS for LG NMIBC, with a secondary objective of identifying patient subgroups at increased risk of QoL deterioration. Methods: Prospective data were collected from patients enrolled in the Bladder Cancer Italian Active Surveillance (BIAS) project, an ongoing AS protocol initiated at our institution in January 2013, which has included a total of 231 individuals to date. Overall, 48 patients had at least 12 months of follow-up and complete paired QoL data. QoL was assessed at baseline and at 12 months using the EORTC QLQ-C30, EORTC QLQ-NMIBC24, and EQ-5D-5L questionnaires. Paired t-tests compared baseline and 12-month scores, while subgroup analyses by age ( < 70 vs ≥70 years) and sex were performed using Mann–Whitney U tests. Results: Median age was 66 years (IQR 59–77); 18 patients (38%) were female. Median follow-up was 16 months (IQR 14–24). Global health status and domain-specific QoL scores remained stable over time across all instruments. Median EORTC QLQ-C30 global health scores were 97 (IQR 95–99) at baseline and 93 (IQR 88–95) at 12 months. Median EQ-5D-5L index values were 0.92 (IQR 0.88–1.00) and 0.89 (IQR 0.85–0.95), respectively. No statistically significant differences were observed in overall QoL scores or in subgroup analyses by sex or age group (all p > 0.05). Patients aged ≥70 years showed a non-significant trend toward higher depressive symptom scores, likely reflecting age-related health decline rather than cancer-related distress. Median EORTC QLQ-NMIBC24 scores demonstrated overall stability between baseline and 12 months, with no significant changes across any domains. No patients discontinued active surveillance during follow-up. Conclusions: This is the first study specifically assessing QoL in patients undergoing AS for recurrent LG NMIBC. Our data suggest that AS preserves overall QoL and psychological well-being over at least 12 months of follow-up. These findings support AS as a safe and well-tolerated management strategy for appropriately selected patients, with no evidence of QoL deterioration over time. Further efforts are warranted to identify individuals who are at risk of psychological distress, to ensure timely and appropriate supportive interventions aimed at preserving overall well-being.

Gut microbiome (GMB) biomarkers in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair alterations (HRRm) treated with PARP inhibitor (PARPi) therapy.

248 Background: As PARPi redefines treatment for HRRm mCRPC, identifying patients most likely to benefit remains a clinical priority. With predictive and prognostic biomarkers evolving, GMB composition has emerged as a potential modifier, influencing oncogenesis and PARPi response through metabolic and immune pathways. We investigated associations between GMB composition and PARPi outcomes in patients with HRRm mCRPC. Methods: Pre-treatment fecal samples were collected from pts with HRRm mCRPC. GMB composition was profiled using shotgun metagenomic sequencing (Illumina NextSeq) and analyzed with inhouse computational pipeline. GMB association with two specific response criteria were assessed independently - radiographic (RECIST v1.1) and by PSA reduction. Radiographic response (R-R) was defined as stable disease or partial response and non-response (R-NR) as progressive disease. PSA response (PSA-R) was defined as a PSA reduction of ≥30% from baseline, non-response (PSA-NR) as PSA reduction < 30%. Paired α diversity (Shannon, Simpson, Chao; Wilcoxon), between-group delta tests (Mann-Whitney (MW)), and β diversity (PERMANOVA) (Bray-Curtis, Jaccard, Euclidean) were calculated. Differential abundance at species level was assessed between response groups using MW-U and effect sizes (Cliff’s δ, Cohen’s d). Results: Median age of total 30 pts cohort at diagnosis was 64 yrs, and 40% had high-volume disease, median PSA of 8.0 ug/L at transition to CRPC. Among 1,913 species, 27 taxa were linked to response (p<0.05, |δ|≥0.33). 70% (21/30) were R-R and 47% (14/30) PSA-R. While overall microbial diversity did not differ significantly between responders and non-responders, species-level differential analysis revealed microbial signatures. Notably, Gordonibacter urolithinfaciens were enriched in R-NR and PSA-NR across endpoints (δ=0.3, p=0.03 and δ=0.29, p=0.027, respectively), indicating a consistent detrimental association. Enterocloster lavalensis (δ=0.59; p=0.009) and a previously uncharacterized Egerieimonas species (δ=0.57; p=0.0019) were more prevalent in R-NR, whereas a different Enterocloster species (δ=–0.47; p=0.038) and Alistipes onderdonkii (δ=–0.47; p=0.047) were more prevalent in among R-R. Bifidobacterium dentium (δ=0.51; d=0.63; p=0.004) and Bacteroides fragilis (δ=-0.46; p=0.027) were more prevalent among PSA-NR, while PSA-R showed higher prevalence of Faecalibacterium prausnitzii (δ=-0.42; p=0.04). Conclusions: This is the first analysis linking species-level GMB signatures to PARPi response in HRRm mCRPC. Given G. urolithinfaciens ’s role in urolithin production affecting DNA-damage/epigenetic pathways, these exploratory findings support further study of GMB and metabolites (i.e. urolithin) as potential PARPi biomarker in HRRm mCRPC.

Functional Biomaterials Through Biocooperation

ABSTRACT There is a growing need to develop materials that can recreate the inherent structural and functional complexity of living systems. These environments are increasingly needed both in vitro to better screen drugs and therapies, and in vivo to overcome key challenges of regenerative medicine that continue to limit broad impact in the clinic. In this perspective, we argue that it is time to go beyond bioinspiration and design materials by working with biological and regenerative mechanisms that Nature has evolved and established. In this biocooperative approach, biology is not seen as a template to copy, but rather as a partner to engage with, by harnessing biomolecules and biological mechanisms as building‐blocks and fabrication processes of materials. The manuscript also summarizes studies describing the use of recombinant technologies to produce biomolecules as material building‐blocks, incorporating living systems within synthetic matrices to create engineered living biomaterials, and integrating synthetic building blocks with cellular processes to produce regenerative materials. These examples illustrate the potential for a new biocooperative material paradigm, opening the door for more accessible and functional personalized biomaterials.

A Bilayer Electrode Architecture Enabling SnO ₂ ‐Induced Spatial‐Controllable Zinc Deposition for Ultra‐High‐Areal‐Capacity Zinc‐Based Flow Batteries

ABSTRACT Aqueous zinc‐based flow batteries (ZFBs) show great promise for large‐scale energy storage. However, the practical deployment of ZFBs is hindered by a limited areal capacity, due to uncontrolled zinc deposition and low utilization of electrode volume. Herein, we propose a spatially controllable deposition strategy enabled by a bilayer electrode architecture, featuring a SnO 2 ‐functionalized carbon felt (CF) as the bottom layer and a pristine CF as the top layer. This architecture introduces a steep gradient in nucleation overpotential and zincate affinity that counteracts the ionic migration trend, reversing the deposition behavior from surface‐clogging mode to internal‐to‐external filling. This unique mechanism enables an ultrahigh areal capacity of 330 mAh cm −2 and an ultrahigh volumetric capacity of 1100 mAh cm −3 , representing a 65% improvement over conventional electrodes. Even under a harsh condition of 100% state of charge and 100% depth of discharge at 240 mAh cm −2 , the battery demonstrates exceptional durability over 175 cycles. This work significantly expands volume utilization for zinc deposition via a bilayer electrode design, providing a robust strategy for regulating spatial deposition behavior and paving the way for practical high‐areal‐capacity ZFBs.

Preferential use of alkyl-acyl phosphatidylinositol for GPI biosynthesis and diagnostic potential of lipidomics for inherited GPI deficiencies

Any regression of tumor (ART) to discriminate improvement in overall survival (OS) in patients with metastatic urothelial carcinoma (mUC) receiving PD1/L1 inhibitors who exhibit stable disease (SD) by RECIST1.1.

653 Background: Response to PD1/L1 inhibitors per RECIST 1.1 or immune-related (ir)-RECIST is associated with improved overall survival (OS). Patients (Pts) with stable disease (SD)> 6 months has been proposed to capture benefit; however, SD constitutes a heterogeneous group impacted by pace of disease progression and intervals between radiographic imaging. In contrast, minor tumor regressions that are <partial response (PR) by RECIST1.1 are discerned without formal radiology review and may reflect the activity of immunotherapy, which is known to be durable compared to other therapies. We previously reported that any regression of tumor (ART) on PD1/L1 inhibitor therapy in 1216 patients across solid tumors showed significant association with improved OS and facilitated the discrimination of SD patients with better OS (El Zarif T, ESMO Congress Sep 2022). We aimed to further investigate and validate the association of ART with OS in mUC pts receiving PD1/L1 inhibitors who exhibited SD. Methods: Deidentified data from mUC pts treated with PD1/L1 inhibitors at AdventHealth institutions in the USA were reviewed retrospectively. Demographic data (age, sex), setting (untreated vs. post-therapy), sites of metastasis, performance status (PS) and prior therapy were collected. We assessed the association of overall ART (complete response [CR] + partial response [PR] + those with SD and ART) and ART among those with SD by RECIST 1.1 with OS. Kaplan Meier curves were used to estimate OS with 95% intervals, and log rank tests were used to compare survival distributions between groups. Results: A total of 66 patients were evaluable. The median age was 69.5 years, 48 (72.7%) were male and 32 (48.5%) were therapy naive. Overall, ART (CR+PR+SD with ART) and SD as best response were seen in 38 (57.6%) and 27 (40.9%) pts, respectively. Among pts with SD, ART was seen in 14 pts. Median OS was 22.1 months (95% CI: 15.7–33.2) in the overall group of pts with ART vs 4.6 months (95% CI 1.7–12.9) in the absence of ART (p < 0.001). Among SD patients, median OS was 31 months (95% CI: 18.2–52.3) in patients with ART and 3.6 months (0.4–15.6) in the absence of ART (p ≈ 0.023). When examining the groups by RECIST1.1, the PD+SD group had a median OS of 7.2 months (95% CI: 3.6-18.2) and the PR+CR group exhibited a median OS of 22.1 months (14.0–34.0) (p ≈ 0.024). When examining the outlier groups by RECIST1.1, the PD group had a median OS of 9.8 months (95% CI: 1.2–13.4) and the PR+CR group exhibited a median OS of 22.1 months (14.0–34.0) (p ≈ 0.008). Conclusions: ART was validated to be associated with improved OS in patients with mUC receiving PD1/L1 inhibitor therapy. ART is a readily determined intermediate endpoint capturing OS benefit in pts with advanced solid tumors including mUC and facilitates the discrimination of OS benefit among SD patients.

Is there an opportunity for checkpoint inhibition in MYC amplified castration resistant prostate cancer?

393 Background: The paradigm of prostate cancer (PCa) management continues to expand with the advent of newer therapies. Unfortunately, checkpoint inhibitors (CPIs) have not been very effective in PCa. It has become increasingly apparent that leveraging the PCa tumor immune microenvironment (TiME) is crucial to maximizing therapeutic benefit. Methods: We examined a cohort of 77 radical prostatectomy specimens - 37 received neoadjuvant androgen deprivation therapy (nADT) +/- bicalutamide, and 40 did not receive any presurgical therapy (stage/grade matched as controls). Tumors were evaluated for tumor and immune cell abundance, somatic and germline genomic alterations. We conducted correlation analyses followed by simple and multiple linear regression analyses using the Data Analysis ToolPak on Microsoft excel to evaluate the relationship between genomic profiles and TiME while adjusting for co-occurring alterations and receipt of nADT. Results: These Genomic alterations included Tumor mutational burden (TMB - ranging from 3 to 189), PTEN alterations (PTEN = 8), MYC amplification (MYCa = 20) and Fusions (including ERG, ETV1, MRPS18C, NBEAL1). Among the 20 MYCa patients, 7 received nADT +/- bicalutamide and 13 were controls. We conducted a correlation analysis between PTEN, MYCa, TMB and fusions with the immune cells including M1 and M2 macrophages, T- helper cells (Th), T regulatory (Treg) cells and cytotoxic T lymphocytes (CTL) (Table). MYCa demonstrated correlation coefficients of -0.26 with M1 and -0.27 with M2. Simple linear regression analyses for MYCa with M1 and M2 revealed coefficients (c) -0.4 (p= 0.048), -1.9 (p=0.02) respectively. Multiple regression analyses including MYCa, PTEN, TMB, Fusions, nADT as independent variables were conducted to assess for effect on M1 and M2. For M1 abundance, the model fits well (p = 0.018) with adjusted R 2 0.11, likely due to the low sample size. The M1 coefficient (c) for MYCa was -0.29 (p value 0.14), and for nADT was 0.51 (p = 0.006). For M2 abundance, the model demonstrates a good fit (p value 0.0003) with adjusted R 2 0.23. The M2 c for MYCa was -1.45 with p value approaching statistical significance at 0.06, while nADT was 2.89 (p = 0.00007). Conclusions: MYCa in PCa is likely associated with M2 exclusion (p value 0.06) from the PCa TiME. In a hormone sensitive tumor, the effect of nADT is dominant and overcomes this effect. These data suggest castration resistant PCa may be more susceptible to M2 exclusion due to MYCa. Thus, MYCa tumors may have reduced immunosuppression, enabling successful application of CPIs. Further studies with larger samples and a comprehensive TiME evaluation may assist with therapeutic guidance. Correlation coefficient for genomic alterations and immunophenotype. Correlation coefficient PTEN aMYC TMB Fusions Treg 0.02 -0.14 -0.04 -0.09 M2 0.07 -0.27 -0.03 -0.11 CTL -0.13 -0.14 -0.09 0.06 M1 0.09 -0.26 0.15 -0.08 Th -0.07 -0.19 -0.06 -0.01

Incidence of adolescent and young adult renal cell carcinoma in the modern era.

568 Background: The incidence of solid tumors in adolescents and young adults (AYA) has been reported to be increasing, but contemporary patterns in renal cell carcinoma (RCC) remain underexplored. We hypothesized that the incidence of RCC would be increasing over time. Methods: Using the National Cancer Database, we assessed patients under 30 years old diagnosed with RCC between 2004–2018. We excluded Wilms tumor and retroperitoneal sarcoma diagnoses. We examined the incidence of AYA RCC over time. Multivariable logistic regression was performed to evaluate differences in demographics, tumor characteristics, and treatments across age groups (0–14, 15–21, and 22–30 years) and time periods (2004–2010 vs. 2011–2018). Results: We found 5,172 AYA patients diagnosed with RCC from 2004–2018. The incidence of RCC increased over time with 2,007 patients diagnosed between 2004–2010 and 3,165 patients diagnosed between 2011–2018. The most common AYA RCC histology was clear cell RCC (ccRCC) (46.7%), which increased by 9.8% between the two time periods. Other histologies included RCC not otherwise specified (NOS) (31.9%), chromophobe (11.0%), and papillary (10.4%). The incidence of RCC was highest in the 22–30 age group and they were more likely to have a diagnosis of ccRCC than younger patients. Patients aged 0-14 years were more likely present with papillary (22.0%) or RCC NOS (61.3%) histologies and at higher clinical stages (cT2b: 8.2%, cT3: 20%, and cT4: 5.9%) as compared to older age groups (age 15–21 papillary 15.2%, NOS 43.9% | cT2b: 5.9%, cT3: 7.5%, and cT4: 3%; age 22–30, papillary 9.4%, NOS 29.2% | cT2b: 4%, cT3: 4.6%, and cT4: 1.4%). Tumor size was also larger in 0–14 year olds as compared to those who are aged 15–21 and 22–30 (6.0cm vs 4.1cm vs 3.3cm, respectively). Patients aged 0–14 were more likely to present with node positive disease (33.7% of 0–14, 8.1% of 15–21, and 4.7% of 22–30 year olds) compared to other age groups. Rates of surgical management as first-line therapy remained consistent across age groups and over time (2004–2010: 0–14 (91.8%), 15–21 (83.0%), and 22–30 (92.1%) vs. 2011–2018: 0–14 (91.4%), 15–21 (86.6%), and 22–30 (90.0%). Conclusions: AYA RCC is rare but increasing, with the greatest burden in young adults aged 22–30. Clear cell histology predominates in this group, while younger patients are more likely to present with non–clear cell and NOS variants. Despite differences in stage and histology, rates of surgical management have remained consistent across age groups. These findings highlight the need for a high index of suspicion when evaluating AYA patients and the need to develop age-specific considerations in RCC treatment and surveillance strategies.

Tobacco use and survival among veterans with metastatic prostate cancer.

38 Background: Tobacco has been associated with the development of many cancers, but its role in prostate cancer remains unclear. We evaluated the relationship between tobacco use and overall survival among veterans with metastatic prostate cancer, adjusting for clinical and demographic covariates such as age at diagnosis, Body Mass Index (BMI), Prostate-Specific Antigen (PSA), and Charlson Comorbidity Index (CCI). Methods: We conducted a retrospective cohort study of 5,889 veterans with known tobacco use diagnosed with de novo metastatic prostate cancer within the Veterans Health Administration. The primary exposure was tobacco use history (ever vs. never) and baseline characteristics were compared with t-tests or Kruskal-Wallis as appropriate. Survival from time of diagnosis was compared with using the Kaplan-Meier method and Cox proportional hazards models were used to estimate hazard ratios (HRs) for tobacco use, both unadjusted and adjusted for age at diagnosis, BMI, PSA, and CCI. Results: Among 5,889 veterans diagnosed with de novo metastatic prostate cancer, 4,115 were known tobacco users (69.9%). The median age at diagnosis in tobacco-users was 72.5 years vs. 74.7 in non-users (p<0.001). Tobacco use prevalence did not differ significantly by race (White: 69.7%, Black: 70.6%, Other: 63.7%; χ²(2)=2.28, p=0.32). Median BMI was 26.9 in users vs. 27.4 (p<0.001). Median survival was 31.5 months (95% CI 30.2–32.8) in users vs. 35.9 months (95% CI 33.7–38.1) in non-users (log-rank p<0.001). Median PSA was 99.3 ng/dL in users vs. 111.0 (p=0.519). The median CCI was 2 in both groups (p=0.093). In multivariate Cox regression, tobacco use was associated with increased mortality (HR: 1.20; 95% CI: 1.11–1.29; p<0.001). In patients with known race (n=3,886), there were no significant differences in prostate cancer mortality (χ²(2)=1.65, p=0.44) or overall survival (log-rank χ²(2)=1.67, p=0.44). Conclusions: Veterans who used tobacco were diagnosed with metastatic prostate cancer at a younger age and had lower BMI. Although PSA and comorbidities did not differ significantly between ever and never tobacco users, tobacco use was independently associated with worse overall survival after adjusting for clinical covariates. No racial disparities in tobacco use, mortality, or survival were observed. These findings highlight the prognostic value of tobacco-use history and support tobacco cessation strategies into prostate cancer prevention. Baseline characteristics and survival by tobacco use status. Variable Tobacco User (Median) Non-User (Median) p-Value Age at Diagnosis (years) 72.5 74.7 <0.001 BMI 26.9 27.4 <0.001 PSA 99.3 111.0 0.519 CCI 2 2 0.093 Survival Time (months) 31.5 35.9 <0.001

Binder‐Free, Self‐Supporting, and Highly Conductive Sulfide Electrolytes Enabling Superior Anode Stability

Abstract All‐solid‐state batteries (ASSBs) are attracting interest as next‐generation rechargeable batteries, offering the promise of high energy density, high power capability, and superior safety. To practically realize these characteristics, it is essential to develop solid electrolytes (SEs) that exhibit both high ionic conductivity and robust physicochemical stability—an inherently challenging feat. In this paper, the fabrication of a sulfide‐based glass SE layer is reported using a warm isostatic pressing (WIP) technique that enables simultaneous densification and crystallization under elevated temperature and pressure. The results show that the elimination of binders from the SE layer significantly enhances the efficiency of the WIP process, while the incorporation of a glass‐based supporting layer imparts excellent mechanical strength and flexibility to the SE film. The resulting SE layers are compatible with standard ASSB fabrication protocols and can be integrated into 13 mAh‐class laminated cells using nickel‐cobalt‐manganese cathodes and graphite anodes. The assembled cells demonstrate outstanding cycling performance, retaining ≈80% of their initial capacity after 300 cycles at 25 °C under a moderate stack pressure of 20 MPa. This study offers a promising pathway toward the practical implementation of high‐performance ASSBs by addressing key challenges in electrolyte design and process integration.

Mass spectral proteomics checklist

Circulating tumor cell detection and prognostic relevance in patients with metastatic genitourinary cancers.

826 Background: Circulating tumor cells (CTCs) are detectable and quantifiable in the peripheral blood of patients (pts) with certain malignancies and can be assessed by liquid biopsy. The presence and change in quantity of CTCs may correspond to tumor burden and therapeutic response. This study aims to explore the utility of CTC quantification and serial measurement in pts with metastatic GU cancers. Methods: This study is a retrospective pooled analysis of CTCs in metastatic GU cancer pts enrolled on several clinical trials from 7/2016 to 3/2023. Plasma for CTCs was drawn on Cycle (C)1 Day (D)1, C2D1 and C3D1 of treatment and quantified using the EPIC Sciences CTC platform. CTCs >4/mL was considered the threshold for positive detection. The association of CTC values and trends from baseline C1 and on treatment (C2 or C3) with PFS and OS was assessed using Cox-proportional Hazards Ratios. CTC trend with best response (partial or complete response vs stable disease or progressive disease) was assessed using logistic regression. Results: There were 76 pts with 158 samples (52 with at least 2 paired samples) included in this retrospective study. The median age was 63 years (IQR 55 – 71) and most pts were male (71.6%). Most common histology was urothelial carcinoma (UC) (n = 66). All were metastatic at enrollment, 75% had lymph node involvement, 69.5% had visceral mets, 35.3% had liver mets and 33.8% had osseous mets. Most pts received VEGF TKI with checkpoint inhibition (n = 56), other regimens included IO-cytokine combination (n = 9), chemotherapy (n = 5) and PARP inhibitor (n = 5). CTCs were present in 20 of 71 pts (28.2%) at C1D1, 16 of 47 (34.0%) at C2D1, and 10 of 41 (24.4%) at C3D1. OS and PFS did not differ by CTC presence at C1D1 or on treatment. The absolute value (log2-transformed) of CTCs at C1D1 was associated with OS in all pts (Hazard Ratio (HR) 1.19, 95% CI 1.03 – 1.37, p = 0.017) and in UC pts (HR 1.21, 95% CI 1.05 – 1.40, p = 0.008), but not at C2D1 or C3D1 for either. A decrease in CTCs versus an increase from C1-C2 (up to C2D15) was significantly associated with improved PFS in all pts (HR 0.48, 95% CI 0.24 – 0.98, p = 0.043), and in UC pts (HR 0.42, 95% CI 0.19 – 0.91, p = 0.029) but not OS for all patients (HR = 0.70, 95% CI 0.35 – 1.40, p = 0.308) or UC pts (HR 0.62, 95% CI 0.29 – 1.33, p = 0.220). CTC trend was not significantly associated with achieving objective response in all pts (Odds Ratio (OR) 3.0, 95% CI 0.63-14.37, p = 0.169) and in UC pts (OR 2.8, 95% CI 0.56 – 14.0, p = 0.209). Conclusions: Absolute CTC values prior to treatment were associated with OS while CTC trend after initial treatment was associated with PFS in all patients and in pts with UC. These findings signal the potential utility of CTCs in providing minimally invasive prognostic information. Further work is needed to identify thresholds for CTC quantification and refine on-treatment response monitoring.

Renal outcomes following ¹⁷⁷ Lu-PSMA-617 (LuPSMA) in patients with metastatic castration-resistant prostate cancer (MCRPC).

138 Background: LuPSMA is a PSMA-targeted radiopharmaceutical used to treat mCRPC that may impair kidney function, due to PSMA expression on proximal tubular cells and urinary excretion of the radiopharmaceutical. While a short-term decline in estimated glomerular filtration rate (eGFR) has been reported, the incidence of long-term decline, along with clinical and biochemical predictors for decline, has not been well-characterized. Methods: We evaluated consecutive patients with mCRPC treated with ≥3 cycles of LuPSMA at our institution between 6/2022 and 6/2025. Kaplan-Meier and Cox regression models were used to analyze time to eGFR decline, defined as ≥15% decline from baseline eGFR; severity of eGFR decline was further categorized as mild (15-30%), moderate (30-40%), and severe (≥40%). Baseline plasma levels of TNFaR-1, TNFaR-2, YKL-40, MCP-1, and KIM-1 were evaluated in a subset of patients who did (n=23, cases) and did not (n=23, controls) experience ≥15% eGFR decline. Results: 213 patients (median age 72) were included, who received a median of 6 cycles of LuPSMA; median baseline eGFR was 88 mL/min (IQR 73-97). At a median follow-up of 7.1 months (range <0.1-29) after cycle 3, 92 patients experienced eGFR decline; the cumulative incidence was 23% (95% CI 18-29), 33% (26-40) and 42% (33-50) at 3, 6, and 9 months after cycle 3, respectively. Renal recovery (to eGFR ≤15% from baseline) was seen in 61 patients (66%), with a median time to recovery of 1.8 months (95% CI 1.5-2.5). Among those who experienced eGFR decline by 12 months post-treatment initiation (n=73), 45 (62%), 11 (15%), and 17 (23%) had mild, moderate, and severe impairment, respectively; CKD stage distribution at baseline and 12 months are shown in the Table. Hypertension was the only baseline factor associated with eGFR decline (univariable HR=1.55 [1.01-2.38]). While baseline levels of plasma biomarkers were generally higher in cases compared to controls, these differences were not statistically significant (all p>0.1). Conclusions: eGFR decline after LuPSMA was common but generally transient, with <10% of patients progressing to CKD stage 4 at 12+ months. Longer follow-up and broader evaluation of biomarkers may be helpful in identifying patients at risk for long-term eGFR decline. CKD stage (ml/min) Baseline (n=212), % 12 months (n=68), % 1 (>90) 104 (49) 31 (46) 2 (60–89) 86 (41) 22 (32) 3 (30–59) 22 (10) 12 (18) 4 (15–29) 0 3 (4)

Outcomes in participants (pts) with bacillus Calmette-Guérin (BCG)–unresponsive high-risk non–muscle-invasive bladder cancer (NMIBC) who underwent radical cystectomy (RC) after pembrolizumab (pembro): KEYNOTE-057 cohort A post hoc analysis.

745 Background: Based on results from cohort A of the phase 2 KEYNOTE-057 trial (NCT02625961), pembro monotherapy is a bladder-sparing treatment option for pts with BCG-unresponsive high-risk NMIBC with carcinoma in situ (CIS) with or without papillary disease. A post hoc analysis of KEYNOTE-057 suggested that pembro may provide a clinically meaningful delay in RC. We present updated outcomes of pts in cohort A of KEYNOTE-057 who underwent RC after discontinuing pembro after a median follow-up of 6 years. Methods: Adults in cohort A with histologically confirmed BCG-unresponsive high-risk NMIBC with CIS who were ineligible for or declined RC received pembro 200 mg IV Q3W for ≤2 years. End points of this analysis were to evaluate cystectomy-free survival (CFS) for complete and non–complete responders, time to cystectomy (TTC), pathologic staging at RC, and subsequent therapies/procedures other than RC following pembro discontinuation. CFS was calculated from first dose of pembro until death or RC. TTC was calculated from last dose of pembro. Complete responders were defined as pts with best overall response of CR. Results: Ninety-six pts were enrolled in cohort A; 44 underwent RC after discontinuing pembro (1 additional pt since previous analysis). Median follow-up (May 30, 2023) was 72.6 mo (range, 62.5-83.1). Before undergoing RC, 13/44 pts had initial CR. Median CFS (95% CI) was 56.8 mo (30.9-NR) for pts with CR and 18.5 mo (7.8-36.5) for pts without CR; 12-mo CFS rates were 87.2% and 54.1%, respectively. Median TTC (range) was 15.0 mo (9.0-69.8) for pts with CR and 6.4 mo (4.0-42.2) for pts without CR. Fifteen pts (34.1%; 2 with CR, 13 without) underwent subsequent therapy/procedures following pembro discontinuation. Six pts (13.6%) had upstaging to MIBC at RC (1 additional pt since previous analysis). The subset of pts (n = 3) with ≥pT3 stage, which is associated with higher recurrence risk, underwent RC ≥1 year after last dose of pembro. Conclusions: Long-term results from this post hoc analysis of KEYNOTE-057 continue to suggest that intravenous pembro can offer durable bladder preservation in high-risk BCG-unresponsive NMIBC with CIS, with sustained delays of RC among initial responders and minimal additional upstaging. Pts with CR had > 3-fold longer median CFS than nonresponders. Results suggest pembro can provide durable responses and can delay time to subsequent RC in most pts. Clinical trial information: NCT02625961 . Pts(n=44) Maximumpathologic T stage Pathologic N stage, n Prior CR on pembro, n TTC, median (range), mo NMIBC (n=38) N0/NX/N1/N2 Yes/No  7 pT0 6/1/0/0 5/2 4.5 (2.0-9.3)  4 pTa 4/0/0/0 0/4 5.1 (2.6-27.0)  21 pTis 19/2/0/0 6/15 2.5 (1.4-38.7)  6 pT1 6/0/0/0 0/6 4.4 (1.7-19.0) MIBC (n=6)  3 pT2 2/0/1/0 1/2 24.2 (2.0-46.5) (N0)2.8 (N1)  2 pT3 1/0/1/0 0/2 31.0 (N0)15.0 (N1)  1 pT4 0/0/0/1 1/0 12.7

Intravesical T3011, an IL-12/anti-PD-1 armed oncolytic HSV-1, in BCG-naïve high-risk NMIBC: A phase IIa trial.

762 Background: Intravesical BCG is the standard of care for BCG-naïve high-risk non-muscle-invasive bladder cancer (NMIBC) patients. However, the scarcity of BCG products is a global issue, and coupled with the side effects of BCG therapy itself, approximately 30-40% of patients fail to receive effective BCG treatment. Therefore, it is essential to seek better alternative therapies to BCG in order to meet clinical needs. Herpes Virus T3011 Injection (MVR-T3011) is a clinical-stage oncolytic herpes simplex virus type 1 (HSV-1) developed for cancer immunotherapy. Genetically engineered to replicate selectively in tumors, it enables localized expression of two potent immunomodulators: interleukin-12 (IL-12) and an anti-PD-1 antibody. This study is designed to assess the efficacy and safety of intravesical T3011 in BCG-naïve high-risk NMIBC patients. Methods: BCG-naïve NMIBC patients were enrolled and treated with intravesical MVR-T3011 at two dose levels: 2.0 × 10⁹ PFU and 1.0 × 10¹⁰ PFU in a 50 mL solution. To streamline administration, no bladder prewash was performed. MVR-T3011 was administered QW for 6 weeks in the induction course (with a second induction allowed, if applicable) and Q3W until 2 years in the maintenance course. Patients will be evaluated for recurrence and progression using cystoscopy, cytology, biopsy (if applicable), and CT/MRI (if applicable). The primary efficacy endpoint was 12-month RFS in papillary Ta/T1 without CIS patients. Results: As of October 10, 2025, 16 patients with papillary Ta/T1 have been treated with MVR-T3011 monotherapy (3 received 2×10 9 PFU dose and 13 received 1×10 10 PFU dose), with 8 assessments completed. In the efficacy-evaluable patients, the 3-month (n = 8), 6-month (n = 5), 9-month (n = 3), 12-month(n = 1), and 15-month (n = 1) RFS rates were all 100% respectively. No grade 3 or above TEAEs or SAEs were reported. Grade 1-2 TEAEs included dysuria, hematuria, urinary tract infection, dry mouth, alanine aminotransferase increased, hyperuricemia, breast fibroadenoma, and aspartate aminotransferase increased. Treatment-related adverse events (TRAEs) included urinary tract infection and dry mouth. Conclusions: Oncolytic viruses and BCG both fall within the realm of immunotherapy, with the former possessing scientific attributes to potentially replace BCG in the future. With encouraging preliminary efficacy in papillary Ta/T1 disease, MVR-T3011 shows potential as an effective alternative therapy for BCG-naïve NMIBC, supported by its favorable safety profile.