Browse Articles

Second-line therapy after ipilimumab and nivolumab in advanced renal cell carcinoma: A multicenter real-world study (GUARDIANS).

437 Background: Ipilimumab plus nivolumab is a standard first-line therapy for intermediate and poor-risk patients with metastatic or advanced renal cell carcinoma (aRCC). However, data guiding the optimal second-line treatment after progression on this regimen remain limited. In this study real-world outcomes following second line treatment in this setting were analyzed. Methods: We retrospectively evaluated the efficacy and safety of second line therapies in 356 real-world patients with advanced renal cell carcinoma who experienced disease progression on first-line ipilimumab plus nivolumab across 17 tertiary centers in Germany and Switzerland. Results: Median age was 64 years, most patients were male (69.1 %) and had a clear cell histology (74.1 %). ECOG PS was ≥ 2 in 14.3 %. IMDC risk was intermediate in 61.8 % and poor in 28.7 %. Cabozantinib was most frequently administered as subsequent therapy and showed superior median OS and PFS compared to other second-line options. Median OS was 38 months (95 %CI 20.7-55.3) and median PFS 15 months (95 %CI 8.2-21.9) with cabozantinib in second-line setting compared to a median OS of 16 months (95 %CI 10.1-21.9, p = 0.003 ) and median PFS of 7 months (95 %CI 5.1-8.9, p = 0.013 ) in the heterogeneous comparison group including sunitinib (11.3 %), axitinib, pazopanib (both 4.3 %), lenvatinib plus everolimus (3.2 %), tivozanib (2.2 %) and different IO/TKI combinations or study medication (e.g. belzutifan). Comparison of time-to-event data between the two groups revealed a hazard ratio (HR) for death of 0.515 (95% CI, 0.328–0.807; p = 0.004 ) and for disease progression of 0.608 (95% CI, 0.406–0.912; p = 0.016 ) in favor of cabozantinib. Conclusions: Our real-world data support the use of cabozantinib after disease progression on ipilimumab and nivolumab as first-line therapy of aRCC with robust efficacy. Updated results on response rate, survival data and safety will be available for ASCO GU 2026.

Predicting small-molecule–RNA interactions

First results of a dose-escalation study evaluating <i>Clostridium butyricum</i> MIYAIRI 588 (CBM588) with nivolumab/ipilimumab (nivo/ipi) in metastatic renal cell carcinoma (mRCC).

503 Background: CBM588 has shown potential to improve clinical outcomes when combined with immune checkpoint inhibitors (ICIs) in untreated mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). Since no significant treatment-related adverse events were related to CBM588 in previous studies, we sought to determine if CBM588 capsules, a novel formulation of this live biotherapeutic, designated MO-03, could be delivered at higher doses with similar tolerability and greater biologic effect. Methods: Patients (pts) with treatment-naïve mRCC and any international mRCC Database Consortium (IMDC) risk were treated with nivo (3 mg/kg q3w ×4, then 480 mg q4w) and ipi (1 mg/kg q3w ×4) plus CBM588 at one of three dose levels (4 × 10⁸, 1.2 × 10⁹, or 4 × 10⁹ CFU BID) in a 3+3 dose-escalation design. The primary endpoint was safety, with secondary endpoints including response rate and progression-free survival. Stool samples collected at baseline and Week 13 were analyzed by metagenomic sequencing to assess microbial composition across CBM588 dose levels. Plasma samples collected at baseline and Cycle 3 were analyzed for soluble mucosal addressin cell adhesion molecule-1 (sMAdCAM-1), a biomarker associated with dysbiosis (Fidelle et al Science 2023). Results: Twelve pts were treated between 6/26/2024 and 9/15/2025. Median age was 69 (range 48-80). All had clear cell histology without sarcomatoid features; two had rhabdoid features. Half the cohort had ≥3 metastatic sites, most commonly involving the lung, lymph nodes, and contralateral kidney. Most patients had favorable (50%) or intermediate (42%) IMDC risk. No dose-limiting toxicities (DLTs) were observed at any dose level, and no dose-dependent increase in immune-related toxicity was noted with CBM588 escalation. Notably, Bacteroides thetaiotaomicron showed a dose-dependent increase in relative abundance across escalating CBM588 levels (P = 0.0043 for Level 3 vs Level 1 and P = 0.0047 for Level 3 vs Level 2, Mann–Whitney U), suggesting a selective modulation of gut microbial composition. Among 11 pts with evaluable disease, 3 were responders (1 complete response, 2 partial responses), 6 had stable disease, and 2 had progressive disease. Baseline sMAdCAM-1 levels were similar between responders (Rs) and non-responders (NRs) (median: 205,196 vs. 206,462 pg/mL). However, percent change from baseline to Cycle 3 demonstrated a diverging pattern, with an early increase in Rs and relative stabilization in NRs (median: +8.2% vs –0.1%). Conclusions: No DLTs were encountered with CBM588 capsules at the highest dose level (MO-03) in combination with nivo/ipi, supporting the dosing strategy in the upcoming phase III SWOG study S2419 (BioFront). Translational studies indicate a dose effect upon microbiome composition, and sMAdCAM-1 dynamics suggest a potential association with response. Clinical trial information: NCT06399419 .

Noninvasive fragmentomic profiling of plasma cell-free DNA (cfDNA) in metastatic prostate cancer (mPC): Associations with transcriptomic phenotypes and disease states.

260 Background: Current liquid biopsy assays yield few clinically actionable insights, because they measure discrete genomic alterations rather than the actual gene expression pathways that drive cancer resistance and progression. This is because cfDNA is stable whereas circulating RNA is degradable and difficult to analyze. To address this challenge, fragmentomic analysis has been developed, which measures the variability of cfDNA fragments at promoter regions (promoter fragment entropy, PFE) to infer tumor gene expression. Here, we developed PC-FragSeq, a PC-specific fragmentomic sequencing panel targeting 590 genes linked to mPC progression, resistance, and clinical outcome. Methods: We assembled the panel through meta-analysis of publicly available gene expression datasets of aggressive, treatment-resistant mPC. Active promoter regions of dominant transcript isoforms were identified, and a custom hybrid capture panel was designed for optimal on-target enrichment at &gt;500X coverage. Corresponding exonic regions were included for parallel genomic analysis. With IRB approval, we analyzed plasma from 48 patients enrolled in a prospective, clinically annotated institutional biorepository. Of these, 20 had metastatic hormone sensitive PC (mHSPC) and 28 had metastatic castration resistant PC (mCRPC), some at multiple time points. Extracted cfDNA was analyzed by low-pass whole genome sequencing (LP-WGS) followed by PC-FragSeq to generate PFEs. These inferred gene expression values were assessed for associations with clinical states and genomic profiles. Results: PC-FragSeq achieved &gt;85% probe coverage at &gt;500X depth across targeted regions. PFE-based analysis robustly distinguished mHSPC from mCRPC, revealing differential gene expression signatures consistent with known transcriptional reprogramming during progression to castration resistance. Additional expression phenotypes were identified in patients with mCRPC progressing through later lines of therapy, including androgen receptor pathway inhibitors, taxane chemotherapy, poly (ADP-ribose) polymerase inhibitors, and radioligand therapy. PC-FragSeq exonic sequence data and LP-WGS from the same cfDNA samples yielded PC-relevant genomic alterations, including AR amplification and TMPRSS2:ERG fusion, which correlated with matched transcriptional shifts. Conclusions: PC-FragSeq enables high-resolution, repeatable assessment of PC gene expression profiles from a simple blood draw. This minimally invasive approach has the potential to enable longitudinal monitoring of disease progression and resistance pathways for discovery of actionable biomarkers and novel therapeutic targets.

Description and management strategies of prespecified treatment emergent adverse events (TEAEs) amongst patients (pts) treated with 1L enfortumab vedotin (EV) + pembrolizumab (P) for la/mUC in a real-world setting.

671 Background: Based on EV-302 study results, EV+P is considered the standard of care therapy for 1L la/mUC. In EV-302, the most common Grade (G) ≥3 TEAEs of special interest for EV in the EV+P arm were skin reactions, peripheral neuropathy, and hyperglycemia. This real-world study aimed to describe prespecified G2 and G≥3 TEAEs and management strategies in pts who experienced these TEAEs during EV+P treatment for 1L la/mUC. Methods: This chart review study used the Cardinal Health OPEN oncology network in the US. Eligible adult pts had la/mUC, initiated 1L EV+P on/after 22-Oct-2023, experienced ≥1 prespecified TEAE, and had ≥6 mo of follow-up data. Prespecified TEAEs were selected due to being common with EV+P treatment and included non-hematologic TEAEs with dose modification recommendations in the USPI. TEAE management strategies were abstracted by treating physicians. Pts may have experienced ≥1 prespecified TEAE and ≥1 management strategy may have been implemented per TEAE. Results: In this cohort of pts (N=225), all of whom had ≥1 prespecified G≥2 TEAE, baseline characteristics included median (Q1–Q3) age of 69 (63–74) y, 69% male, 69% White, and 80% ECOG PS 0–1. At data cutoff, 41.8% of pts receiving 1L EV+P (n=94/225) had discontinued EV treatment, while 58.2% (n=131/225) remained on therapy. The reasons for EV discontinuations (n=94) were AE(s)/toxicity (n=38; 40.4%), disease progression (n=32; 34.0%), pt choice (n=14; 14.9%), physician decision (n=5; 5.3%), and/or death (n=4; 4.3%). Among all pts, first EV dose reductions and first delays/interruptions due to any TEAE occurred in 91 (40.4%) and 61 (27.1%) pts, respectively, with a median (Q1–Q3) time from EV initiation to dose reduction or delay/interruption of 67 (26–123) and 59 (29–106) days, respectively. Table shows rates of prespecified TEAEs and associated first dose reductions and/or delays/interruptions by TEAE/grade. Conclusions: EV dose modifications were frequently used to manage TEAEs in this real-world cohort; further data on management will be presented. Prespecified TEAEs, n (%) G2 G≥3 First EV dose reduction (G2 a / G≥3 b ) First EV dose delay/interruption (G2 a / G≥3 b ) Fatigue - c 36 (16.0) - / 13 (36.1) - / 1 (2.8) Diarrhea - c 29 (12.9) - / 7 (24.1) - / 10 (34.5) Decreased appetite - c 24 (10.7) - / 7 (29.2) - / 1 (4.2) Peripheral neuropathy 58 (25.8) 7 (3.1) 30 (51.7) / 3 (27.3) 17 (29.3) / 5 (45.5) Rash 37 (16.4) 4 (1.8) 18 (48.6) / 2 (50.0) 10 (27.0) / 2 (50.0) Hyperglycemia 34 (15.1) 4 (1.8) 8 (22.9) / 1 (16.7) 7 (20.0) / 5 (83.3) Dry skin 30 (13.3) 6 (2.7) 2 (6.5) / 0 3 (9.7) / 0 Pruritus 13 (5.8) 6 (2.7) 1 (7.7) / 1 (14.3) 4 (30.8) / 2 (28.6) Pneumonitis 6 (2.7) 3 (1.3) 1 (16.7) / 1 (33.3) 1 (16.7) / 1 (33.3) a % based on pts with G2 prespecified TEAEs. b % based on pts with G≥3 prespecified TEAEs; c Only prespecified as G≥3 TEAE.

Mapping covalent drug targets

Seconds‐Integrated Monolithic System of Zn‐Ion Micro‐Battery and Multi‐Functional Sensors for Robotic Autonomous Tactile Sensing

ABSTRACT Highly integrated devices that combine energy storage with multi‐functional sensing capabilities are pivotal for advancing the practical implementation of intelligent microsystems. However, their development is often hindered by inefficient manufacturing, reliability degradation stemming from interfacial mismatches, and challenges in achieving high‐performance, interference‐free operation. Herein, we demonstrate an ultrafast and efficient strategy to construct a monolithic multifunctional sensing and energy storage system via the Joule heating effect. This strategy enables seamless integration of all components within 8 s, intrinsically mitigating interfacial incompatibility and signal interference. Through the instantaneous thermal activation, the energy storage unit of anode‐free Zn‐ion micro‐battery delivers a capacity of 850 µAh cm −2 and energy density of 1060 µWh cm −2 , superior to most reported aqueous Zn‐based micro‐batteries. With a rapid charging time of 150 s, it powers the integrated device for over 6 h, achieving an impressive 24–h standby under low‐current conditions after full charge. Furthermore, this flexible monolithic system can be directly integrated into unmanned systems such as robotic arms, enabling autonomous environmental perception and adaptive decision‐making via machine learning, with object identification and classification accuracy exceeding 99%. This work paves the way for next‐generation autonomous microrobots, smart healthcare, and human‐machine interfaces.

Epigenetic Metal‐Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective Chemo‐Metalloimmunotherapy in Platinum‐Resistant Ovarian Cancer

ABSTRACT Platinum‐resistant ovarian cancer (PROC) responds poorly to platinum chemotherapy and evades immune surveillance by suppressing the cGAS‐STING pathway, leading to poor outcomes. Herein, we developed an epigenetic metal‐organic framework (MOF) nanoagonist (CMZ‐Pt‐SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn‐ZIF‐8 encapsulating CaO 2 and co‐loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ‐Pt‐SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO 2 triggers calcium overload and oxygen release, and Mn 2+ /Zn 2+ enhances oxidative stress and STING signaling, collectively strengthening chemo‐metalloimmunotherapy. These mechanisms intensify CisPt‐induced DNA damage and stimulate immune activation. CMZ‐Pt‐SA@HA applies a three‐step “POP” strategy to overcome PROC's triple defenses: (I) Pre‐targeting to enhance DNA‐CisPt adducts; (II) On‐targeting to block DNA repair; and (III) Post‐targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS‐STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient‐derived xenograft mouse models, or combined with anti‐PD‐L1 therapy in ascites metastasis models, CMZ‐Pt‐SA@HA consistently showed strong therapeutic efficacy. Its Mn 2+ ‐based magnetic resonance imaging (MRI) capability further supports image‐guided therapy and clinical translation.

Real-world utilization of tissue-free ctDNA monitoring in patients with prostate cancer.

98 Background: Circulating tumor DNA (ctDNA) monitoring provides an additional clinical tool for assessing treatment response and emerging resistance. We evaluated the real-world (RW) use and results of FoundationOne Monitor (F1Monitor), a tissue-free ctDNA monitoring assay, in patients (pts) with prostate cancer (PCa). Methods: The clinical laboratory developed test, F1Monitor, was available to physicians in a limited pilot with full discretion of test eligibility, timing, and frequency. Therapy type was a non-mandatory field on the order form. CtDNA was detected and quantified by ctDNA tumor fraction (TF); variants were tracked with variant allele frequency (VAF), and the origin [tumor somatic (TS), germline, or clonal hematopoiesis (CH)] was predicted algorithmically. Results: F1Monitor was ordered by 28 physicians for 215 pts with PCa. Therapy data were known for 156 pts: ADT+ androgen receptor pathway inhibitor (ARPI, N = 69/156 pts, 44%), ADT alone (N = 32, 21%), ADT + chemotherapy (chemo, N = 20,13%), ADT + radioligand therapy (RLT, N = 17, 11%), and others (N = 18). Median follow-up was 188 days. Longitudinal testing (≥2 tests) occurred in 64 pts, often (N = 37) when the first test was ctDNA TF positive (+). Median cadence for serial testing (≥3 tests, N = 31) was 42 days (IQR: 35, 59). ctDNA TF was + at any timepoint in 50% (107/215) of pts overall and 53% (82/156) of pts known to be on therapy, trending higher in pts on ADT+chemo (80%) and ADT+RLT (65%). Median and maximum ctDNA TF values were 11% (IQR: 0.9,37.8%) and 89% respectively. Lowest ctDNA TF and reportable TS VAF quantified were 0.13% and 0.04%, respectively. ctDNA TF longitudinal changes were observed in 67% (43/64) of pts: 92% of pts on ADT+chemo, 69% on ADT+RLT, 59% on ADT+ARPI, and 38% of pts on ADT alone. Among pts with ≥2 tests, 39% (25/64) had ctDNA TF increase, including 6/27 (22%) pts that were ctDNA TF negative (-) on the first test. Of pts with ≥2 tests and any ctDNA TF+ result, 35% cleared ctDNA TF in later tests. 33% of pts were persistently ctDNA TF -. Each test reported an average of 5 alterations: ~2 TS short variants, copy number variants, or rearrangements, and ~2 predicted CH variants. HRR variants were detected in 37% (80/215) of pts (31 with ≥2 tests) : persistent in 20 pts, cleared in 7, and newly emerging in 14. At least 50% of alterations in CHEK2 and ATM were predicted CH. Alterations in PI3K pathway genes were detected in 20% (43/215) of pts: (16 with ≥2 tests) persistent in 6 pts, cleared in 5, and newly emerging in 5. Conclusions: In this RW pilot of tissue-free ctDNA monitoring in PCa, F1Monitor demonstrated high sensitivity in clinical practice, detecting ctDNA TF as low as 0.13% and TS VAF as low as 0.04% while distinguishing tumor-derived from predicted CH variants. Importantly, ctDNA TF was + in 53% of pts while on therapy with observed longitudinal changes for 67% of pts, supporting potential utility of ctDNA for monitoring treatment response and emerging resistance.

Discrepancies in the administration of sequential therapies for metastatic renal cell carcinoma: Real-world practice versus randomized controlled trials.

481 Background: While randomized controlled trials (RCTs) have established first-line standards for metastatic renal cell carcinoma (mRCC), real-world practice often differs. The use of sequential therapy after first-line treatment remains underexplored. We conducted this study to compare the administration rates of second-line therapy in mRCC between pivotal RCTs and real-world data, and to evaluate their association with overall survival (OS). Methods: Six phase III RCTs (CheckMate-214, COSMIC-313, JAVELIN Renal-101, KEYNOTE-426, CheckMate-9ER, and CLEAR) were compared with real-world data from the Japanese AGEHA database (n = 518). Patients who discontinued first-line therapy due to progression or adverse events (PD/AE) were assessed for the subsequent use of second-line treatment or best supportive care. Age and IMDC risk differences were also evaluated. Survival analysis was performed based on sequential systemic therapy status. Results: Despite younger age and lower IMDC risk in RCTs, some trials showed lower second-line rates than RW. Immune-oncology (IO)-based regimens in real-world practice achieved 55.4%, exceeding rates in nivolumab+cabozantinib (44.1%) and pembrolizumab+lenvatinib (55.5%) trial arms. In real-world, second-line therapy was associated with longer OS after PD/AE (median 43.5 vs 15.1 mo.; p &lt; 0.001). Limitations include possible selection bias and differences in definitions between datasets. Conclusions: Some RCTs reported lower sequential systemic therapy rates than RW practice despite favorable patient selection. In real-world settings, receiving second-line therapy was strongly associated with improved survival, highlighting the need to bridge this gap in future treatment strategies.

The efficacy and safety of disitamab vedotin plus immunotherapy in locally advanced or metastatic urothelial carcinoma: A systematic review and meta-analysis.

774 Background: The combination of disitamab vedotin (DV), a novel human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate, with immunotherapy represents a promising strategy for locally advanced or metastatic solid tumors. However, comprehensive evidence regarding its efficacy and safety in locally advanced or metastatic urothelial carcinoma is lacking. Therefore, this systematic review and meta-analysis aimed to synthesize available data about the combination regimen in this population. Methods: We systematically searched PubMed, Scopus, Embase, and the Cochrane Library for studies published up to September 1, 2025. The primary outcomes were objective response rate (ORR) and treatment-related adverse events (TRAEs). Secondary outcomes included disease control rate (DCR) and median progression-free survival (mPFS). Pooled analyses were performed using a random-effects model. Results: Eleven studies involving 517 patients were included. The pooled ORR was 57% (95% CI: 50%–64%), and the DCR was 86% (95% CI: 80%–90%). The pooled mPFS was 8.2 months (95% CI: 6.7–9.7). Subgroup analyses indicated superior efficacy in HER2-positive tumors, and first-line treatment settings. Any-grade and grade ≥3 TRAEs occurred in 87.5% and 26.4% of patients, respectively, with a toxicity profile dominated by DV-related adverse events such as fatigue, hypoaesthesia, and hematological toxicities. Conclusions: The combination of DV and immunotherapy demonstrates encouraging antitumor activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma, particularly in HER2-expressing populations and when used in the first-line setting. These findings support further investigation of this combination in randomized controlled trials.

Reversible Oxygen Redox in Li‐Rich Mn Based Cathodes Achieved by Regulating the Local Environments of Bulk and Surface Lattice Oxygen

ABSTRACT Lattice‐oxygen redox (L‐OR) has been widely considered a viable approach to attain high‐capacity cathodes for next‐generation batteries. However, achieving highly reversible L ‐ OR remains challenging due to the intrinsic chemical instability of lattice oxygen. As such, stabilizing the lattice oxygen becomes necessary for improving the performance of cathode materials with oxygen redox chemistry. In this study, the distinct properties of both bulk and surface lattice oxygen are systematically studied in a model Li‐rich layered oxide material (LRMO, i.e., Li 1.2 Ni 0.2 Mn 0.6 O 2 ) by employing different techniques. We find that, in the bulk, distortions in octahedral coordination geometry are closely correlated with variations in the electronic structure, and the substitution of Li ions with protons in a subsurface layer enhances the stability of surface lattice oxygen by altering its coordination environment. By jointly regulating the local environments of both bulk and surface lattice oxygen, the initial Coulombic efficiency is remarkably improved from 73.88% to 91.72%. Moreover, the modified LRMO demonstrates an impressive cycle stability, which realizes a capacity retention of 95.9% after 500 cycles at 250 mA g −1 . This work demonstrates that rationally‐designed local environments of lattice oxygen can effectively stabilize the oxygen redox in Li‐rich cathodes.

Development and validation of a computational histology artificial intelligence (CHAI) prognostic biomarker in renal cell carcinoma.

546 Background: Artificial intelligence (AI)–based digital pathology has shown great promise in prostate and bladder cancer, but its application in renal cell carcinoma (RCC) remains limited. We applied the Computational Histology Artificial Intelligence (CHAI) platform, a deep learning-based pathology system, to develop and validate a novel prognostic biomarker for localized RCC. Methods: Hematoxylin and eosin stained whole-slide images from stage I-III RCC cases in The Cancer Genome Atlas (TCGA) were analyzed with CHAI to quantitatively extract histologic features from the tumor and microenvironment. All RCC subtypes within TCGA were included (clear cell, papillary, chromophobe). Cases were divided into development (30%) and validation (70%) cohorts using a stratified random split. In the development cohort, a continuous histologic risk signature for overall survival (OS) was derived and dichotomized into low- and high- risk groups with a 70-30 cutoff. We then tested the locked biomarker and evaluated its performance in the independent validation cohort. Multivariate Cox proportional hazards (CPH) models assessed associations with progression-free survival (PFS), disease-specific survival (DSS), and OS. Results: 801 RCC patients were available (236 in development, 565 in validation). In the validation cohort, the median age was 60 years (IQR 51-70), and 370 (65%) were male. Disease stage was I in 340 (60%), II in 86 (15%), and III in 139 (25%). Histologic subtypes in the validation cohort included clear cell in 307 (54%), papillary in 184 (33%), and chromophobe in 74 (13%). On validation, the biomarker stratified patients into 167 (29%) high-risk and 398 (70%) low-risk. High-risk status was significantly associated with inferior PFS (HR: 2.74 [95%CI: 1.81, 4.15]), DSS (HR: 3.37 [1.89, 6.03]) and OS (HR: 1.92 [1.25, 2.96]), all p&lt;0.05. Associations remained significant after controlling for age, sex, stage, and subtype (p&lt;0.05). At 1 year, high-risk patients demonstrated higher rates of progression (15% vs 4.6%), disease-specific mortality (4.8% vs 1.1%), and overall mortality (7.8% vs 2.9%). Conclusions: We developed and validated an AI-derived digital pathologic biomarker that prognosticates localized RCC by risk of progression, disease-specific death, and overall mortality--independent of histologic subtype. These findings support further investigation of CHAI-based digital biomarkers as tools to refine RCC risk assessment and guide personalized management. Multivariate CPH model of OS. Variable Factor HR (95% CI) p-value Biomarker (ref: Low-Risk) High-Risk 1.90 (1.22, 2.97) &lt;0.01 Age 1.03 (1.01, 1.04) &lt;0.01 Sex (ref: Female) Male 0.71 (0.45, 1.11) 0.12 Stage (ref: Stage I) II 1.61 (0.79, 3.29) 0.19 III 3.93 (2.43, 6.35) &lt;0.01 Subtype (ref: Clear Cell) Papillary 0.74 (0.43, 1.25) 0.26 Chromophobe 0.43 (0.18, 1.02) 0.06

Real-world genomic analysis of chemerin in prostate cancer (PCa) and correlation with markers of immune infiltration and activation.

110 Background: Chemerin, a leukocyte chemoattractant, signals through CMKLR1 on immune cells. Its role in tumor immunology is increasingly recognized. Prior evidence from our group suggests chemerin has tumor-intrinsic and immune effects, recruiting T and NK cells to the tumor microenvironment (TME). We used a real-world clinicogenomic dataset to characterize chemerin and related gene expression in PCa. Methods: The Tempus Lens Platform (Tempus AI, Chicago, IL) was used to derive a cohort of de-identified PCa cases with clinical and genomic data. Data was analyzed in Tempus Workspaces using the tempusverse suite of R packages. In a pre-clinical study, chemerin-overexpressing TRAMP-C1 and vector control tumors were subcutaneously engrafted into mice. Tumor-infiltrating leukocytes (TILs) were analyzed by single-cell RNA sequencing (scRNA-seq). Results: We retrospectively identified 311 men with PCa who underwent standard-of-care tumor genomic analysis, including WT bulk RNAseq. Chemerin expression was lower in metastatic sites (lymph nodes [LNs], bones, soft tissues) relative to primary prostate tumors (p&lt;2.2e-16). Chemerin expression decreased linearly with increasing pathologist-estimated tumor purity (p=5.6e-5). A subset of cases with tumor purity &gt; 70% (n=163) were selected for co-expression analysis. CMKLR1 and genes known to contribute to the coordinated anti-tumoral immune response (eg CD8, GZMB, CD86, etc) were significantly correlated with chemerin expression, as was the tumor suppressor PTEN (see table). In subset analysis of tumors by metastatic site similar correlations held in lung, bone, and LN metastases. Trends towards improved rwOS were seen in subset analyses favoring high chemerin expression though were not significant following risk-set adjustment. In mice, chemerin overexpressing tumors showed increased expression of cytotoxicity, activation, trafficking, and effector genes in TILs by scRNAseq, further corroborating these correlations. Conclusions: We present the first real-world genomic analysis of chemerin in PCa. Chemerin is significantly downregulated in metastatic PCa sites compared to primary tumors. Higher chemerin correlated with a potent effector cell gene pattern, inline with our preclinical evidence of a chemerin-CMKLR1-PTEN tumor suppressive axis. In total, these data further suggest that chemerin is a key determinant of an immunologically “hot” TME in PCa, and may have relevance in clinical outcomes. To this end, a chemerin-based therapeutic for PCa is currently in development by Pixie Bio (St. Louis, MO). Chemerin : Gene 2 Spearman Correlation P-value CMKLR1 0.496 1.19E-11 XCR1 0.389 2.86E-07 CD8A 0.514 &lt;2.2E-16 CD86 0.481 1.12E-10 GZMB 0.331 1.60E-05 GZMA 0.473 2.67E-10 PDCD1 0.383 5.68E-07 CD3D 0.455 1.52E-09 PTEN 0.196 0.012 All Spearman correlation values represent positive correlations.

Randomized trial of urinary tumor DNA (utDNA) testing-guided cystoscopy in high-risk/very high-risk non-muscle-invasive bladder cancer (NMIBC): TRUCE-LB02.

TPS911 Background: Patients with high-risk or very high-risk non–muscle-invasive bladder cancer (NMIBC) require intensive cystoscopic surveillance after transurethral resection of bladder tumor (TURBT), typically every 3 months for the first 2 years. However, repeated cystoscopy is invasive, costly, and associated with pain, anxiety, and complications such as infection and bleeding. Liquid biopsy has emerged as a promising noninvasive tool for dynamic tumor monitoring. Urinary tumor DNA (utDNA) testing, uniquely suited for urothelial malignancies, offers a sensitive means to detect molecular residual disease and early recurrence. Incorporating utDNA testing to guide cystoscopic surveillance may help optimize follow-up intensity, reduce unnecessary procedures, and improve patient experience. The TRUCE-LB02 trial was initiated and is currently ongoing to evaluate the clinical utility, safety, and cost-effectiveness of utDNA-guided cystoscopy in high-risk/very high-risk NMIBC. Methods: TRUCE-LB02 is an open-label, multicenter, randomized controlled trial assessing the role of utDNA testing in guiding cystoscopic surveillance for NMIBC. Eligible patients are adults (≥18 years) with pathologically confirmed high-risk or very high-risk NMIBC as defined by the 2025 EAU guidelines. Prior to randomization, all patients undergo cystoscopy and urine cytology confirming absence of visible tumor. A total of 360 patients are randomized 1:1 to a utDNA-guided arm or a control arm. In the utDNA-guided arm, patients undergo utDNA testing and cytology every 3 months, with one scheduled cystoscopy per year; additional cystoscopy is performed if utDNA or cytology is positive. A single positive cytology or two consecutive utDNA-positive results with negative cystoscopy trigger computed tomography urography (CTU). In the control arm, patients undergo cystoscopy and cytology every 3 months, with CTU performed if cytology is positive but cystoscopy is negative. The primary endpoints are 2-year recurrence-free survival (RFS) and the mean number of cystoscopies per patient. Secondary endpoints include progression-free survival (PFS) and the diagnostic and prognostic performance of utDNA testing, while exploratory endpoints include patient compliance, cost-effectiveness, and patient-reported outcomes (PROs). All patients receive standard treatment and follow-up per EAU 2025 guidelines. The study is conducted in accordance with the Declaration of Helsinki and ICH-GCP. Patient enrollment is ongoing across multiple centers in China. Clinical trial information: NCT07180212 .

Spatiotemporal in vivo protein degradation

Direct Growth of Wafer‐Scale 2D Semiconductor Transistors via One‐Step PtTe ₂ /2H‐MoTe ₂ Heterophase Formation

ABSTRACT 2D semiconductors offer a promising platform for next‐generation integrated circuits and large‐scale electronic systems. Realizing high‐performance p‐type transistors, however, remains challenging due to Fermi‐level pinning, high contact resistance, and poorly defined interfaces in conventional stepwise fabrication. Here, we demonstrate a single‐step tellurization growth strategy that simultaneously forms PtTe 2 contacts on 2H‐MoTe 2 channels to directly realize 2D semiconductor transistors. This approach forms PtTe 2 /2H‐MoTe 2 metal/semiconductor arrays with precise control of the MoTe 2 phase at the PtTe 2 electrode interface, while providing integrated van der Waals metallic contacts without the need for post‐growth of metal contacts. Using this method, we achieve wafer‐scale heterophase arrays characterized by uniform patterning and well‐controlled 2H/1T' phase transformation dynamics. The heterojunctions display sharp and clean interfaces, as verified by TEM, STEM, and EDS mapping. Transistor arrays fabricated from these heterophase structures show Ohmic contacts with low Schottky barrier heights, delivering on/off ratios up to 5 × 10 4 and consistent mobility of 5–9 cm 2 /Vs across 100 devices, ensuring efficient carrier injection. Our results establish a scalable pathway for the direct growth of 2D semiconductor transistors, overcoming conventional multi‐step device fabrication bottlenecks and providing a promising platform for large‐scale, and reproducible 2D electronics.

Localized Solvent‐Anchored Carboxylate Ester Electrolyte Enables Wide Temperature and Fast Charging Sodium Metal Batteries

ABSTRACT Sodium‐metal batteries (SMBs) have attracted considerable interest due to their abundant raw material supply and high energy density. Nevertheless, realizing fast charging and long‐term cycling stability over a wide temperature range remains a considerable challenge. In this work, we propose a novel strategy that integrates molecular anchoring with weak solvation by modulating the dipole‐dipole interactions between methyl propionate (MP) and fluoroethylene carbonate (FEC). This approach effectively stabilizes the free solvent ratio, suppresses the irregular dendrite formation under low‐temperature and fast‐charging conditions, and minimizes HF generation at elevated temperatures, thereby enhancing electrolyte chemical stability and Na + desolvation kinetics. These synergistic enhancements enable rapid Na + transport and facilitate the formation of a robust interface layer across a broad temperature range. Consequently, Na 3 V 2 (PO 4 ) 3 ||Na cells demonstrate stable operation from −40°C to 70°C and sustain over 10 000 cycles at 80°C, outperforming previous reports on wide‐temperature fast‐charging systems. Notably, the cells achieve a capacity retention of 98.58% after 1200 cycles at −20°C and 85.93% after 1500 cycles at 60°C. Moreover, pouch cells configured with this electrolyte exhibit superior all‐weather adaptability and fast‐charging capability. This work offers valuable insights for developing high‐performance SMBs operable under broad‐ temperature conditions.

Genomic characterization of upper tract urothelial carcinoma (UTUC) with or without sarcomatoid differentiation.

862 Background: Sarcomatoid variant of UTUC (S-UTUC) is a rare and aggressive malignancy. Due to the paucity of reported literature, the molecular landscape and potentially targetable alterations harbored by these tumors are not well described. We aimed to comprehensively compare the clinical, pathological, and genomic profiles of S-UTUC and conventional UTUC. Methods: We leveraged the Tempus LENS genomic dataset to extract clinical, pathologic, and somatic genomic alteration data from patients with UTUC and S-UTUC. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Chi-square or Fisher’s exact tests for categorical variables, and Student’s t-test or ANOVA for continuous variables, as appropriate. Mutational frequencies and pairwise comparisons were performed to assess significant differences between histological groups. Results: In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had S-UTUC. Patients with S-UTUC were younger at diagnosis, 61 years (IQR 54, 69), compared to UTUC (71 years, IQR 64, 77) (p &lt; 0.001). Compared to UTUC, patients with S-UTUC were more likely to have node-positive (24% vs 10%), pT4 (13% vs 11%), and stage 4 disease (37% vs 0.5%) (all p &lt; 0.05). Patients with S-UTUC were more likely to have visceral metastasis to the lung (44% vs 30%), bone (19% vs 10%), and brain (7% vs 1%) compared to patients with UTUC (all p &lt; 0.05). Among patients with S-UTUC, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among patients with UTUC, the most common genomic alterations were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). S-UTUC group was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p &lt; 0.05), with lower prevalence of FGFR3 (0% vs 8%) and FGFR4 (0% vs 8%) mutations compared to UTUC (both p &lt; 0.05). Alterations in genes with potentially actionable targets were observed in S-UTUC, including NF2 (19%), SETD2 (12%) , PTEN (13%), and PI3KCA (2%). Conclusions: Compared to UTUC, S-UTUC demonstrated a more aggressive clinical and genomic profile, characterized by a younger age at onset, more aggressive metastatic tropism, relative enrichment in NF2, SETD2, PTEN and PI3KCA alterations , and an absence of FGFR- family mutations. These findings underscore the divergent molecular landscape of S-UTUC and highlight potentially targetable genomic alterations to guide precision oncology strategies for this rare disease.

Impact of GLP1 receptor agonists on severity of prostate cancer at diagnosis: A propensity score weighted analysis.

352 Background: Glucagon-like peptide 1 (GLP1) receptor expression in prostate cancer tissue has raised concerns that GLP1 receptor agonists (GLP1A) may influence tumor growth or progression. We compared prostate cancer severity at diagnosis among patients receiving GLP1A versus other glucose lowering therapies. Methods: A retrospective chart review identified patients who received GLP1A or alternative second-line glucose lowering agents (DPP4/SGLT2 inhibitors) and were subsequently diagnosed with prostate cancer. Patients receiving both drug classes were excluded. Baseline demographics (race, ethnicity, age), comorbidities (diabetes, myocardial infarction, peripheral vascular disease) concomitant medications (insulin, metformin, statins), appointments (within past year) and laboratory values (HbA1c, eGFR) at therapy initiation were recorded. Primary outcomes included Gleason grade group and metastatic presentation within three months of diagnosis. Propensity score matching balanced baseline characteristics between groups. Mann-Whitney U tests compared grade groups. Chi-square tests compared metastatic presentation, reporting odds ratios (OR) with 95% confidence intervals (CI). Multivariable logistic regression identified predictors of grade group (low-grade: 1-2; high-grade: ≥3) and metastatic presentation, reporting OR with 95% CI. A p value &lt;0.05 indicated a significant association. Results: Of 260 propensity-matched patients (GLP1A: 130, comparison: 130), 87% were White and 95% were Non-Hispanic/Non-Latino in each group. Median HbA1c was 7% (IQR: 6.4-8) in GLP1A group versus 7.5% (6.2-8.5) in comparison group. Median eGFR was 75mL/min/1.73m 2 (IQR: 61.5-90.0) in GLP1A group versus 60.0 (52.0-80.5) in comparison group. High-grade disease occurred in 33 (25%) GLP1A patients and 37 (29%) comparison patients. Among patients with available imaging (GLP1A: 40; comparison: 32), metastatic presentation occurred in 7 (18%) GLP1A group and 7 (22%) comparison group patients. No significant differences were observed in grade group (GLP1A median: 2; IQR: 1-2 vs. comparison median: 2; 1-3; p=0.44) or metastatic presentation (OR: 1.32; 95%CI: 0.41-4.25; p=0.64) between groups. In multivariable analysis, higher HbA1c was associated with high-grade disease in GLP1A group (OR: 1.83; 95%CI: 1.07-3.35; p=0.03) while higher eGFR was associated with low-grade disease in the comparison group (0.97; 0.93-0.99; p=0.04). Conclusions: GLP1A use was not associated with prostate cancer grade or metastatic presentation at diagnosis compared to alternative glucose-lowering agents. However, the association between elevated HbA1c and high-grade disease in GLP1A patients suggests a potential impact of poor glycemic control on tumor biology. Prospective studies are needed to elucidate the relationship between metabolic dysregulation and prostate cancer severity.