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Synergistic Coupling of Host and Electrolyte Achieving 1270 Wh L <sup>−1</sup> in Anode‐Free Lithium Metal Batteries
Abstract Anode‐free lithium metal batteries (LMBs) represent a promising avenue for maximizing energy density by eliminating excess lithium (Li), yet their practical implementation is impeded by limited Li reversibility and pronounced interfacial instability. Herein, a synergistic coupling strategy is reported that integrates a highly reversible host (RH) with a rationally designed, carbonate‐rich electrolyte (DEL) to concurrently address these fundamental challenges. The RH spontaneously induces the formation of a robust Li 2 O‐ and Li 3 N‐rich solid electrolyte interphase via electron transfer, which effectively accommodates Li volume changes and suppresses dendritic growth. Complementarily, DEL, composed of commercially available salts, solvents, and additives, establishes stable electrode‐electrolyte interphases at both electrodes. Coin‐type anode‐free full cells employing the RH‐DEL configuration achieve an average Coulombic efficiency of 99.6% and 81.9% capacity retention after 100 cycles at 4.6 mAh cm −2 and 2.3 mA cm −2 . Stacked pouch‐type full cells further deliver a record volumetric energy density of 1270 Wh L −1 (including packaging) under lean electrolyte (E/C = 2.5 g Ah −1 ) and a low stack pressure (≈20 kPa). This synergistic approach delineates a practical pathway toward high‐energy, long‐life anode‐free LMBs for advanced energy storage systems.
Circulating tumor DNA (ctDNA) as a real-time biomarker in marker-negative germ cell tumors (GCT): A proof-of-concept study.
619 Background: Traditional GCT biomarkers include AFP, β-HCG, and LDH. Marker-negative GCTs—comprising seminoma, embryonal carcinoma, and teratoma with or without somatic transformation (SM)—pose diagnostic and monitoring challenges. While miRNA assays have shown promise, they are not widely available. ctDNA has emerged as a robust, dynamic biomarker across cancers, but its role in marker-negative GCT remains underexplored. Methods: A prospectively maintained institutional database of patients with GCT and available ctDNA results was analyzed. ctDNA detection was correlated with radiologic and pathologic evidence of disease across four treatment phases: orchiectomy, RPLND, initial chemotherapy, and salvage therapy. Results were considered concordant when ctDNA status matched radiologic or pathologic evidence of disease (positive/positive or negative/negative); all others were classified as discordant. Descriptive statistics were applied. Results: From December 2024 to September 2025, 33 ctDNA samples were obtained from 21 patients: 18 (86%) with testicular primaries and 6 (29%) with stage I disease. Histologies included seminoma (11, 52%), embryonal carcinoma (4, 19%), SM (4, 19%), mature teratoma (1, 5%), and mixed (1, 5%). Across all treatment phases, ctDNA detection showed 100% concordance with disease status. Serial measurements were available for 8 patients, 5 of whom had results before and after interventions (surgery, radiation, or chemotherapy). (See Table) Four patients were monitored serially during surveillance—2 maintained undetectable ctDNA with no relapse, while 2 showed ctDNA re-emergence preceding relapse. In 6 instances with indeterminate imaging, ctDNA provided adjunctive diagnostic clarity: 3/3 patients with detectable ctDNA had subsequent biopsy-proven active disease, whereas 3/3 with undetectable ctDNA remained disease-free on surveillance. Conclusions: This study provides proof-of-concept for ctDNA as a real-time biomarker in marker-negative GCTs. ctDNA trends mirrored treatment response and disease dynamics across all phases and served as a sensitive adjunct when imaging was inconclusive. To our knowledge, this is the first report of ctDNA utility in SM, warranting further exploration in monitoring and early detection of transformed teratoma. Patient Histology Pre-intervention value (MTM/ml) Intervention Post-intervention value (MTM/ml) Current Status 1 Transformed teratoma 83.77 Salvage surgery 0 (No evidence of disease)NED 2 Seminoma 0.2 RPLND 0 NED 3 Transformed teratoma 18.44 Salvage Chemotherapy 0.23 3 contd. 0.23 Salvage Surgery 0 NED 4 Seminoma 7.88 Salvage Radiation 0.24 On treatment 5 Seminoma 0.25 Orchiectomy 0 NED
Feasibility and outcomes of response-adapted and retreatment <sup>177</sup> Lu-PSMA-617 therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
184 Background: The depth and time to response vary among patients with mCRPC receiving Lutetium-177 prostate-specific membrane antigen-617 (Lu-PSMA) and the optimal treatment strategy is yet to be determined. This study aimed to evaluate the efficacy and safety of a response-adapted treatment schedule and retreatment beyond 6 cycles of Lu-PSMA in patients with mCRPC. Methods: This single-center retrospective study included patients treated with Lu-PSMA between June 2022 and March 2025 who either (1) paused treatment due to deep response to treatment before completing 6 cycles and underwent retreatment upon progression (group 1) or (2) received retreatment upon progression after response to the initial six cycles of Lu-PSMA (group 2). A deep response was defined by ≥90% decline from baseline in PSA and in tumor burden on post-treatment single-photon emission tomography. The decision to continue treatment was made by the treating oncologist based on PSA progression consistent with PCWG3 criteria. The outcomes of interest, included PSA decline of ≥50% (PSA50) and PSA progression-free survival (PSA-PFS) were assessed from baseline and from retreatment after progression. Overall survival (OS) was calculated from the start of initial Lu-PSMA therapy to the last follow-up or death. According to CTCAE v5.0, hematologic adverse events (AEs) of grade ≥3 and renal AEs of grade ≥2 were reported. Results: Of 250 patients who received Lu-PSMA, 22 (9%) patients with a median age of 73 years (IQR: 67-77) were included. Fourteen patients underwent retreatment after an initial favorable response, receiving a median of 4 cycles (range: 2-5) initially, followed by a median of 3 cycles (range: 1-5) upon retreatment. The remaining 8 patients received retreatment after completing the initial 6 cycles, with a median of 2 cycles (range: 1-7) upon retreatment. After a median follow-up of 27.9 months (IQR 18.7-36.1), 4 patients had died, and median OS was not reached (95% CI 30.5-NR). In group 1, the median PSA-PFS was 12.3 months (95% CI 8.3-NR) at initial treatment, and 9 patients (64%) achieved PSA50 upon retreatment with PSA-PFS of 7.1 months (95% CI 3.2-NR). In group 2, the median PSA-PFS was 12.5 (95% CI 11-NR) at initial treatment, and 3 (38%) patients achieved a PSA50 response upon retreatment, with a PSA-PFS of 4.9 months (95% CI 1.4-NR). Overall, 1 (5%) patient experienced G3 leukopenia during initial treatment, while upon retreatment, 5 (23%) experienced G3 anemia, 2 (9%) experienced G3 thrombocytopenia, 1 (5%) experienced G3 leukopenia, and 4 (18%) experienced G2 renal impairment. Conclusions: Response-adapted and retreatment beyond 6 cycles of Lu-PSMA is feasible in patients with mCRPC with an acceptable hematological safety profile, demonstrating encouraging PSA responses and PSA-PFS. Further studies with larger cohorts are warranted to confirm these findings.
Association between metabolic syndrome and treatment outcomes in metastatic prostate cancer: A retrospective cohort analysis.
95 Background: Metabolic syndrome (MetS) affects 25–27% of metastatic prostate cancer patients (mPCa) receiving androgen deprivation therapy (ADT) and may amplify treatment-related metabolic toxicity. The differential impact of MetS on diabetes versus cardiovascular outcomes remains undefined. We examined these endpoints to inform toxicity management in 17,936 real-world patients. Methods: Using TriNetX (2004–2024), we identified 17,936 metastatic prostate cancer (mPCa) patients receiving ADT monotherapy (n=7,261; MetS 25.4%) or ADT plus novel hormonal therapy (ADT+NHT, n=10,675; MetS 26.7%). MetS was defined as ICD-10 E88.810 or ≥3 components (hypertension, dyslipidemia, diabetes, obesity). After 1:1 propensity matching for age, BMI, and baseline PSA, we analyzed 3,686 ADT and 5,710 ADT+NHT patients. Outcomes: metabolic toxicity (myocardial infarction, stroke, incident or progressive diabetes), isolated diabetes progression, PSA progression (≥0.2 ng/mL), and skeletal-related events (pathologic fractures, spinal compression). Median follow-up: 32 months (ADT), 25 months (ADT+NHT). Results: Metabolic syndrome doubled metabolic toxicity rates in both cohorts: 54.4% vs 27.6% for ADT (HR 2.52, 95% CI 2.26–2.80, p<0.0001) and 53.9% vs 28.4% for ADT+NHT (HR 2.31, 95% CI 2.12–2.52, p<0.0001). Notably, diabetes events comprised 90% of metabolic toxicity in MetS patients versus 78% in controls. Despite a 5-fold higher baseline diabetes prevalence in MetS patients, this effect persisted throughout follow-up. Importantly, cardiovascular events showed no increase despite metabolic burden (ADT: 5.2% vs 6.1%; ADT+NHT: 5.3% vs 6.6%), directly contradicting expected cardiovascular amplification in this high-risk population. Isolated diabetes analysis confirmed even higher risk: 49.3% vs 21.5% for ADT (HR 2.83, p<0.0001) and 48.5% vs 21.8% for ADT+NHT (HR 2.66, p<0.0001). No significant associations were observed with PSA progression (41% vs 42% ADT, p=0.44; 49% vs 51% ADT+NHT, p=0.02) or skeletal events. Conclusions: Metabolic syndrome more than doubled diabetes risk without increasing cardiovascular events in mPCa patients receiving ADT, challenging established toxicity assumptions. With diabetes comprising 90% of metabolic toxicity, our findings demonstrate that MetS-related risk is predominantly glycemic rather than cardiovascular. These findings suggest the need for further research to optimize monitoring and management strategies in this high-risk population.
Comprehensive plasma metabolomic profiling of metastatic urothelial carcinoma (mUC) pre- and post-immune checkpoint inhibitor (ICI) or platinum-based chemotherapy (PBC).
795 Background: Comprehensive plasma metabolomic profiling of mUC patients may identify mechanisms of resistance and new therapeutic targets. We analyzed metabolomic data from mUC patients prior to and following ICI and PBC. Methods: We retrospectively analyzed 648 metabolites in plasma from mUC patients who received ICI or PBC at Dana-Farber Cancer Institute. Paired plasma samples (0.2 mL) were obtained at baseline and after initiating therapy. Comprehensive metabolomic profiling was performed using 3 complementary liquid chromatography-mass spectrometry (LCMS) platforms at the Broad Institute. The metabolites that increased their mean values at least 1.5-fold in ≥1 platform were considered relevant. The paired sample t-test was used to assess the shifts in paired metabolites for significance (p <0.05). Results: 55 patients with mUC from the Dana-Farber Cancer Institute were evaluable: 48 received ICI and 9 received PBC, including 2 who received both. The ICIs administered were PD1/L1 inhibitor monotherapy (n=47) or PD/L1 + CTLA4 inhibitor therapy (n=1). The median age was 68 years, 45 (82%) patients were male and 32 (58%) were post-platinum. The median time between the pre- and post-therapy samples was 150 days. 5 (9.1%) patients had complete response, 17 (30.9%) had partial response, 13 (23.6%) had stable disease and 12 (21.8%) patients had progressive disease. Four metabolites exhibited >2-fold increase in mean fold change in ≥1 platform when comparing post vs. pre-therapy levels following ICI including taurodeoxycholic acid, taurocholic acid and α-carboxy-ethyl-hydroxy-chromans (CEHC) (Table 1). When examining 14 patients where the post-therapy timepoint was within 4 weeks before or after disease progression, the increase of taurocholic acid levels was further amplified to 9.7-fold. In the PBC cohort, 11 metabolites had a mean increase of >2-fold with the most prominent being N-acetylmethionine, which increased 8.29-fold. Conclusions: Taurocholic acid, a conjugated bile acid, exhibited >2-fold increase after ICI therapy, which was further amplified when measured close to disease progression, suggesting association with resistance and potential therapeutic utility of targeting taurine conjugation of bile acids. A greater number of metabolites demonstrated a >2-fold increase following PBC as opposed to ICI suggesting a broader range of resistance mechanisms, with most pronounced increase in N-acetylmethionine, a quencher that terminates oxidative reactions. Further validation from larger cohorts is required, given potential therapeutic relevance. Metabolite Mean fold change post-ICI Mean fold change in post-ICI progressors Mean fold change post-platinum Taurodeoxycholic acid 6.8 4.7 3.33 Taurocholic acid 4.61 9.74 3.55 alpha_CEHC 4.1 2.55 1.09 N-acetylmethionine 2.16 1.77 8.29
Safeguarding VSMC Contractile Phenotype With In Situ circRNA‐mediated Endothelial Olaratumab Engineering to Prevent Vascular Graft Stenosis
ABSTRACT Small‐diameter vascular grafts (SDVGs) often fail due to restenosis driven by endothelial cell (EC)‐derived PDGF‐BB, which shifts vascular smooth muscle cells (VSMCs) toward a synthetic phenotype. Despite mechanistic insights, durable, localized, and cell‐specific control of this crosstalk remains elusive. Here, we developed a circRNA‐based in situ antibody engineering strategy to functionalize SDVGs, reprogramming ECs into local biofactories that secrete Olaratumab (Ola), a PDGFR‐α‐neutralizing antibody, to precisely modulate EC‐VSMC signaling. In vitro, in situ Ola engineering reversed PDGF‐BB‐induced VSMC phenotypic switching, markedly suppressing migration, invasion, and excessive extracellular matrix deposition by attenuating MAPK and PI3K‐AKT pathways. In the rat model, this approach enabled sustained local antibody secretion for up to 24 days, accelerated endothelialization, and significantly reduced neointimal hyperplasia and graft calcification over 6 months, thereby lowering the risk of SDVG restenosis. CircRNA‐based in situ antibody engineering offers a powerful modality to modulate intercellular crosstalk and sustain the VSMC contractile phenotype.
Atomically Resolved Acoustic Dynamics Coupled with Magnetic Order in a Van der Waals Antiferromagnet
ABSTRACT Magnetoelastic coupling in van der Waals (vdW) magnetic materials enables a unique interplay between the spin and lattice degrees of freedom. Characterizing the elastic responses with atomic and femtosecond resolution across the magnetic transition is essential for guiding the design of magnetically tunable actuators and strain‐mediated spintronic devices. Here, ultrafast X‐ray diffraction employed at a free‐electron laser reveals that the atomic displacements, wave vectors, and dispersion relations of acoustic phonon modes in a vdW antiferromagnet FePS 3 are coupled with the magnetic order, by tracking both in‐plane and out‐of‐plane Bragg peaks upon optical excitation across the Néel temperature ( T N ). One transverse mode shows that a quasi‐out‐of‐plane atomic displacement undergoes a significant directional change across T N . Its quasi‐in‐plane wave vector is derived by comparing the measured sound velocity and the first‐principles calculations. The other transverse mode is an interlayer shear acoustic mode whose amplitude is strongly enhanced in the antiferromagnetic phase, exhibiting eight times stronger amplitude than the longitudinal acoustic mode below T N . The atomically resolved characterization of acoustic phonon dynamics that couple with magnetic ordering opens opportunities for harnessing unique magnetoelastic coupling in vdW magnets on ultrafast timescales.
Phase III, randomized, double-blind, placebo-controlled study of adjuvant saruparib (AZD5305) in patients with BRCAm localized high-risk prostate cancer who are receiving radiotherapy and androgen deprivation therapy (EvoPAR-Prostate02).
TPS412 Background: PARP inhibitors (PARPi) are approved for the treatment of patients with metastatic castration-resistant prostate cancer. Saruparib is a new generation PARPi that selectively inhibits and traps PARP1. In the Phase I/IIa PETRA study (NCT04644068), activity with saruparib monotherapy (PSA 50 , objective response) has been observed in patients with advanced/metastatic prostate cancer. The Phase I/II PETRANHA study (NCT05367440) has demonstrated that saruparib can be safely combined with androgen receptor pathway inhibitors to treat patients with metastatic prostate cancer. The Phase III EvoPAR-Prostate02 study (NCT06952803) is evaluating the efficacy and safety of adjuvant saruparib versus placebo in patients with early-stage, high-risk prostate cancer with BRCA1 / BRCA2 gene mutation (BRCAm) who have received definitive radiotherapy (RT) and are receiving a standard concomitant androgen deprivation therapy (ADT) regimen. Methods: EvoPAR-Prostate02 is a two-cohort, randomized, double-blind, placebo-controlled study. Eligibility criteria include age ≥18 years, diagnosis of high-risk or very high-risk localized/locally advanced prostate adenocarcinoma or high-risk biochemical recurrence following radical prostatectomy, with a confirmed BRCAm by central tumor tissue testing. Patients must have completed primary or salvage RT with curative intent, with no evidence of disease or disease detected only in the pelvis at time of study entry, and must still be receiving ADT. Key exclusion criteria include persistent cytopenias, conditions with predisposition to bleeding, and history of myelodysplastic syndrome/acute myeloid leukemia. In both Cohort A (ADT alone) and Cohort B (ADT plus abiraterone/prednisone), randomization is 1:1 to saruparib or placebo. Treatment with saruparib/placebo continues for 24 months or until unacceptable toxicity, confirmed disease progression by blinded independent central review (BICR), or patient-initiated withdrawal. ADT and abiraterone treatment duration is limited to 24 months, inclusive of pre-study regimen. The primary endpoint is metastasis-free survival (MFS), confirmed by standard clinical imaging (computed tomography/magnetic resonance imaging and bone scan, or prostate-specific membrane antigen-positron emission tomography [PSMA PET]), as assessed by BICR. Overall survival (OS) is a key secondary endpoint. Statistical analyses of MFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 700 patients will be randomized. Recruitment began in July 2025 and is ongoing. Clinical trial information: NCT06952803 .
Short term intensified pembrolizumab and tivozanib for high-risk renal cell carcinoma: STRIKE! (Alliance A032201).
TPS577 Background: Pembrolizumab (pembro) for one year following resection of localized high risk clear cell renal cell carcinoma (ccRCC) in a phase 3 trial resulted in improvement in relapse-free survival and overall survival (Choueiri, NEJM 2024). However, 20% of patients still experienced a relapse within 2 years with no biomarker yet identified to predict who will respond to or needs adjuvant therapy. Addition of a tyrosine kinase inhibitor (TKI) to immunotherapy (IO) is a standard of care in metastatic ccRCC, but to date no studies have addressed the addition of a TKI to IO in the adjuvant setting. Subsequently, phase 3 STRIKE! was developed to explore the benefit of 6 months of tivozanib (tivo) added to pembro vs pembro alone in the adjuvant setting for resected high risk ccRCC. Methods: Eligible patients have an ECOG performance status ≤2 and a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features after complete resection of the primary tumor, with pathology revealing pT2 grade 4 disease or any grade ≥ T3 or TxN1. Patients are also eligible if they developed metastasis within a year after resection and then underwent resection, definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) with no evidence of active disease (M1NED). Patients will be randomized 1:1 to intravenous pembro for 48 weeks with or without the addition of tivo 1.34 mg by mouth daily D1-21 q28D for 6 months stratified by stage (T2T3 vs T4/N1 vs M1NED) . With no limit on dose holds or interruptions of tivo, dose reductions of tivo to 0.89 mg D1-21 q28D or tivo 0.89 mg every other day are allowed. No dose reductions of pembro are permitted. Following baseline imaging to confirm no disease, imaging is performed every 12 weeks for first year, every 16 weeks for second year, every 24 weeks for third year and then annually until 5 years after registration or progression. The primary endpoint will be disease-free survival (DFS) as assessed by investigator, with secondary endpoints being overall survival, safety and tolerability. The study will enroll 1040 patients to detect a minimum detectable hazard ratio of 0.67 (24-month DFS 84% in experimental arm) with 90% power. Quality of life analysis will compare global quality of life and fatigue between the two arms. Imaging and specimens will be banked for future research. The study opened to accrual in April 2025 and at this time 106 patients have enrolled. Clinical trial information: NCT06661720 .
Phase 1/2 OMAHA-U01 substudy 01A: Oral CYP11A1 inhibitor opevesostat alone or in combination with other therapies in participants with metastatic castration-resistant prostate cancer (mCRPC).
TPS585 Background: mCRPC remains an incurable disease and therapeutic agents with novel mechanisms of action are needed for this patient population. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. In the phase 1/2 CYPIDES study, opevesostat showed antitumor activity in participants with heavily pretreated mCRPC. OMAHA-U01 is an adaptive, open-label, rolling-arm, multicenter, phase 1/2 umbrella study designed to evaluate opevesostat-based investigational therapies in participants with prostate cancer. Substudy 01A (NCT06353386) will evaluate the safety and efficacy of opevesostat alone or in combination with other therapies in participants with previously treated mCRPC. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening, and on or after 1-2 androgen receptor pathway inhibitors for metastatic or nonmetastatic hormone-sensitive prostate cancer and nonmetastatic or mCRPC. Prior treatment with ≤1 taxane-based chemotherapy regimen for mCRPC is allowed. A safety lead-in phase for all opevesostat-based experimental combinations (~10 participants in each arm) will establish the recommended phase 2 dose (RP2D), followed by an efficacy phase (opevesostat alone, ≤100 participants; opevesostat-based combinations, ~40 participants each). Participants will be randomly assigned 1:1:1:1 to receive opevesostat 5 mg PO BID, opevesostat 5 mg PO BID plus olaparib (RP2D), opevesostat 5 mg PO BID plus docetaxel (RP2D), or opevesostat 5 mg PO BID plus cabazitaxel (RP2D). Randomization for the efficacy phase will be stratified according to AR-LBD mutation (AR-LBDm) status (positive or negative). The primary end point for the safety lead-in phase is safety and tolerability. Primary end points for the efficacy phase are safety and prostate-specific antigen response rate per Prostate Cancer Clinical Trials Working Group (PCWG) criteria. Secondary end points include objective response rate and radiographic progression-free survival per PCWG-modified RECIST v1.1 by blinded independent central review (BICR), overall survival, duration of response by BICR, time to first subsequent anticancer therapy, and time to pain progression. The predefined eligibility cap for pts with AR-LBDm-negative status has been reached, and the study is currently only enrolling pts with AR-LBDm-positive status. Clinical trial information: NCT06353386 .
Examining the impact of TGF-ß activity on fibroblast infiltration and immune exclusion in MIBC.
851 Background: In urothelial cancer, transforming growth factor β (TGF-β) signaling in fibroblasts has been correlated with poor respose to immunotherapy (IO). We examined TGF- β activity scores in relation to the tumor micro-environment (TME) from muscle invasive bladder cancer (MIBC) patients and whether this correlated to response to neoadjuvant chemoIO utilized in the BLASST-01 trial. Methods: We assessed a prospective commercial cohort (PCC) consisting of the de-identified and anonymized transcriptome-wide expression profiles of N = 604 MIBC patients from the clinical use of the Decipher Bladder TURBT test that were available in the Decipher GRID registry (NCT02609269). Molecular subtypes were categorized by the consensus-MIBC subtyping model. Using GRID signatures, we applied the molecular signatures database hallmark gene set collection to quantify TGF-β hallmark signaling scores. Furthermore, we used TIDE (a computational framework on Tumor Immune Dysfunction and Exclusion) to quantify TME-related scores for cancer associated fibroblasts (CAF), immune exclusion, T regulatory cells and cytotoxic T-lymphocytes. The BLASST-01 trial investigated 4 cycles of neoadjuvant gemciatine, cisplatin, and nivoumab followed by radical cystectomy (RC). Pre-treament tumor specimens were examined for associations between molecular scores and pathological response (≤ypT1N0) at RC. Multivariable logistic regression analyses for pathologic response were adjusted for patient age and sex. Results: Intersection of TGF-β hallmark signaling scores with consensus molecular subtypes in the PCC cohort, we found elevated scores for the stroma-rich molecular subtype (p < 0.001). Furthermore, we found TGF-β scores had a significant positive correlation with CAFs (r = 0.41, p < 0.001), T regulatory cells (r = 0.33, p < 0.001) and immune exclusion (r = 0.47, p < 0.001), whereas we found a significant negative correlation between TGF-β hallmark signaling scores and infiltration of cytotoxic T-lymphocytes (r = -0.31, p < 0.001) and interferon γ (r = -0.35, p < 0.001). Additionally, TGF-β was highly correlated to hallmarks pathways related to epithelial-mesenchymal transition (EMT) (r = 0.36, p < 0.001) and angiogenesis (r > 0.31, p < 0.001) For BLASST-01, transcriptome data were available for 37/43 (86%); median age was 65 (IQR, 58-70), 41% were female, 89% were cT2N0 and 35% had pathological complete response. Higher scores for TGF-β signaling (OR 0.03, p < 0.005), immune exclusion (OR 0.37, p < 0.03) and CAFs (OR 0.41, p < 0.03) were associated with no pathological response, whereas cytotoxic T lymphocytes were significantly associated with pathological complete response (OR 7.04, p < 0.02). Conclusions: The present study demonstrates that molecular TGF-β activity scores are associated with fibroblast infiltration and immune exclusion, suggesting TGF-β attenuates response to neoadjuvant IO for MIBC.
Strain‐Induced Magnetic Ordering Unlocks Spin‐Conserved Catalysis in Lithium‐Oxygen Batteries
ABSTRACT Designing advanced ferromagnetic catalysts with robust intrinsic magnetism and efficient spin polarization is critical for enabling spin‐selective electron transfer between triplet O 2 and singlet Li 2 O 2 in lithium‐oxygen batteries (LOBs), yet controlling magnetic ordering and spin states at the atomic scale remains a fundamental challenge. Here, we present a lattice tensile strain engineering to construct strained CoS 2 anchored on reduced graphene oxide (s‐CoS 2 /rGO), achieving significantly enhanced ferromagnetic exchange interactions and spin polarization. Experimental and theoretical analyses reveal that a ∼4% tensile strain along the (111) plane induces spontaneous parallel alignment of atomic magnetic moments, generating intrinsic magnetic anisotropy and coherent single‐domain architectures. This lattice distortion enhances d‐p orbital hybridization and establishes spin‐polarized conduction channels at Co─S active sites, enabling parallel‐spin electron transfer to adsorbed O 2 and effectively bypassing the spin‐flip energy barrier associated with O 2 /Li 2 O 2 conversion. As a result, the s‐CoS 2 /rGO catalyst exhibits elevated spin‐polarized current densities, a markedly reduced O 2 dissociation barrier, and superior catalytic kinetics, delivering ultra‐long cycling exceeding 2000 h at 200 mA g −1 . This work offers a general approach for designing high‐performance ferromagnetic catalysts and highlights the critical role of spin‐state engineering in advancing next‐generation LOB technologies.
Saruparib + androgen receptor pathway inhibitor (ARPI) + androgen deprivation therapy (ADT) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): The phase 1/2 PETRANHA trial.
177 Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) + ARPI + ADT have improved clinical outcomes versus ARPI + ADT alone in pts with metastatic castration-resistant prostate cancer (mCRPC), particularly those with BRCA mutations. Interim efficacy results from the Phase 1/2 PETRANHA study (NCT05367440) showed high rates of undetectable prostate specific antigen (uPSA) levels in pts with mHSPC who received saruparib, a PARP1 selective inhibitor, + ARPI + ADT, irrespective of homologous recombination repair mutation (HRRm) status (Azad A, et al. ESMO 2025 [2384MO]). We report updated efficacy and safety results for pts with mHSPC. Methods: Pts received oral saruparib 60 mg once daily + physician’s choice of ARPI (enzalutamide, abiraterone acetate or darolutamide) + ADT. ADT for up to 6 months prior to consent was permitted. Prior chemotherapy for metastatic prostate cancer was not allowed. Treatment continued until disease progression or intolerable toxicity. Results: At data cutoff (June 10, 2025), 93 pts with mHSPC were treated with saruparib + ARPI (enzalutamide [n=3], abiraterone acetate [n=14] or darolutamide [n=76]) + ADT, with a median follow-up of 16.4 months (min–max, 0.0–34.8). Overall, 55.9% (52/93) of pts had high volume disease, 12.9% (12/93) had visceral metastasis, and the baseline median PSA level was 2.5 ng/mL. In response evaluable pts (34/93), the objective response rate (ORR) was 82.4% (28/34; 80% CI, 71.1–90.5), including 5 complete responses (14.7%). The confirmed uPSA rate at any time was 69.9% (65/93; 80% CI, 63.0–76.1) and confirmed 52-week uPSA rate was 76.7% (46/60; 80% CI, 68.2–83.7). For pts with HRRm versus non-HRRm, ORR was 100% (4/4) and 85.7% (12/14); confirmed uPSA rate at any time was 71.4% (10/14) and 70.6% (24/34); and confirmed 52-week uPSA rate was 77.8% (7/9) and 73.9% (17/23), respectively. The combination had a manageable safety profile (Table). Conclusions: In pts with mHSPC, saruparib + ARPI + ADT induced high ORRs and high 52-week uPSA rates. Efficacy was observed regardless of HRRm status. The safety profile of the combination was manageable with no new safety signals. These findings warrant confirmation in the ongoing Phase 3 EvoPAR-Prostate01 trial. Clinical trial information: NCT05367440 . Safety summary (N=93). Median total duration of saruparib / ARPI exposure, months (min–max) 16.3 (0.7–35.6) / 16.5 (0.7–35.6) Safety parameter, n (%) Any AECausally related to saruparib 92 (98.9)83 (89.2) Any Grade ≥3 AECausally related to saruparib 45 (48.4)29 (31.2) Any serious AECausally related to saruparib 24 (25.8)8 (8.6) Saruparib / ARPI discontinuation due to AE* 7 (7.5) / 3 (3.2) Saruparib / ARPI dose reduction due to AE* 24 (25.8) / 3 (3.2) Saruparib / ARPI interruption due to AE* 52 (55.9) / 36 (38.7) *Irrespective of the action taken on other drugs. AE, adverse event.
Heterogeneity and synergistic inhibition of the poly(ADP-ribose) polymerase and androgen receptor signaling pathway in patients with metastatic castration-resistant prostate cancer.
236 Background: Our previous study demonstrated that olaparib combined with abiraterone improves survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, compared with olaparib monotherapy. However, reliable biomarkers are urgently needed to identify patients who are more likely to benefit from olaparib treatment, particularly in the context of combination therapy. Methods: A total of 221 consecutive mCRPC patients were included, including 135 who received olaparib combined with abiraterone and 86 who received olaparib monotherapy. The predictive value of PARP1 mRNA expression and androgen receptor (AR) signaling biomarkers (AR activity [AR-A] and AR pathogenic variants [AR-PV]), was evaluated across single-cell RNA, bulk RNA, and DNA levels in relation to olaparib treatment outcomes. Results: PARP1 and AR-A exhibited marked heterogeneity in mCRPC. In tumor cells, PARP1 expression was significantly positively correlated with AR-A score. Compared with olaparib monotherapy, olaparib combined with abiraterone significantly improved progression-free survival (PFS) and overall survival (OS) in mCRPC patients, particularly among those harboring a PARP1 high /AR-A high signature or a BRCA variants/AR-nPV signature. Conclusions: Biomarkers reflecting DNA damage repair deficiency and AR signaling have potential value in guiding the selection of mCRPC patients for olaparib treatment, particularly in the context of combination therapy. Patients harboring a PARP1 high /AR-A high signature or a BRCA variants/AR-nPV signature are more likely to benefit from olaparib combined with abiraterone or olaparib monotherapy. These findings warrant further validation through prospective clinical trials.
Contemporary survival and treatment outcomes in malignant spermatic-cord tumors: A two-decade population-based analysis.
593 Background: Malignant spermatic-cord tumors (SCTs) are exceedingly rare, and population-level survival data in the modern era are limited. Historically, outcomes were limited by incomplete excision and high local recurrence, leading to recommendations for selective adjuvant radiotherapy. With modern imaging and improved histologic classification, presentation patterns and survival may have evolved. This study defines contemporary survival benchmarks and treatment utilization for malignant SCTs in the United States. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program was queried for microscopically confirmed malignant SCTs (primary site C63.1). Analyses were restricted to first matching primaries and excluded autopsy/death-certificate-only records. Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and summarized at 5 and 10 years. Stratifications included age (<40, 40–59, ≥60 years), and diagnosis era (2000–2005, 2006–2011, 2012–2016, 2017–2022). Treatment variables included RX Summ-Surg Prim Site, Radiation recode, and Chemotherapy recode. Results: A total of 403 patients with malignant SCTs were identified. All underwent definitive surgery. Age-specific CSS demonstrated excellent outcomes in younger patients, with 5- and 10-year CSS of 100% and 92.9% for <40 years, 93.6% and 86.9% for 40–59 years, and 87.9% and 83.3% for ≥60 years, respectively. Beam radiation was uncommon but present, with era-specific row percentages of 5.8% (2000–2005), 3.2% (2006–2011), 2.7% (2012–2016), and 3.6% (2017–2022). Chemotherapy use was observed at about 10–15% across eras. Localized-stage cases increased from approximately 55% to 70% over two decades, while regional and distant stages declined, demonstrating modest stage migration toward earlier detection. Stage-specific survival showed the expected prognostic separation (localized > regional > distant). Conclusions: Malignant SCTs achieve durable, near-curative survival with definitive surgery, even at the population level. Consistently high CSS despite minimal adjuvant use highlights that outcomes are driven by complete surgical resection and early detection rather than therapeutic escalation. The rising share of localized-stage cases reflects stage migration from improved imaging and histologic precision. These findings establish the largest and most contemporary national survival benchmarks for this rare malignancy and reinforce the need to optimize margin-negative surgery, early recognition, and age-tailored follow-up to sustain long-term cure and prevent late recurrences.
Association of SETD2 mutation with prognostic features and susceptibility to acute kidney injury in renal cell carcinoma.
554 Background: Renal cell carcinoma (RCC) ranks 8 most lethal cancers and is responsible for about 140,000 deaths worldwide each year. Acute kidney injury (AKI) is a frequent complication in this population, SETD2, a histone methyltransferase that mediates H3K36 trimethylation, plays a crucial role in maintaining chromatin stability and DNA repair. Loss-of-function mutations, seen in approximately 15% of clear-cell RCC, are associated with poorer outcomes, and impaired tubular recovery, increasing susceptibility to AKI. With next-generation sequencing now routinely used in RCC, SETD2 status is increasingly available and may help identify patients at greater risk for treatment-related kidney injury, supporting more personalized nephroprotective care. Methods: Five non-overlapping datasets totaling 781 RCC cases (TCGA, DFCI, UTokyo, and MSK cohorts) were analyzed alongside a systematic literature review (PubMed, EMBASE, genomic databases, cutoff August 2025) to assess renal, molecular, and therapeutic outcomes by SETD2 mutation status, including AKI definitions, treatment type, and survival endpoints. Results: Analysis of TCGA-KIRC data on cBioPortal showed that SETD2 alterations were present in about 13% of patients (101 of 780). The SETD2-altered group had a shorter median overall survival of 64.6 months compared with 116.8 months in the unaltered group (p=0.121). Disease-free survival was significantly worse in SETD2-mutated tumors (p=0.0073, q=0.029), while progression-free survival showed a similar trend (p=0.056). Disease-specific survival did not differ significantly (p=0.45). in preclinical models,Suppression of SETD2 enhances renal recovery following injury, supporting its role as a modulator of kidney protection (Wang Y et al., Cell Death Dis. 2023). AKI occurs in 30–55% of RCC patients after nephrectomy and 5–18% during systemic therapy (Kukreja 2020; Seethapathy 2019; Coca 2012). While no human dataset links SETD2 directly to AKI, experimental models show that SETD2 loss impairs tubular repair and mitochondrial stability, promotes oxidative stress, and that its suppression reduces ferroptosis and improves renal recovery (Wang Y et al., Cell Death Dis. 2023). These data suggest SETD2 deficiency may heighten renal vulnerability and worsen outcomes in RCC. Conclusions: SETD2 mutations occur in a significant subset of RCC and are associated with poorer disease-free survival and molecular features of chromatin instability. Although clinical data directly linking SETD2 loss to AKI are lacking, preclinical evidence demonstrates that SETD2 deficiency impairs tubular repair, promotes oxidative stress, and increases susceptibility to renal injury. These findings suggest that SETD2 status may serve as a dual biomarker of tumor aggressiveness and renal vulnerability, warranting prospective evaluation in precision onco-nephrology studies.
Manipulating Room Temperature Phosphorescence Stability of Photoactivated Materials for Multiplex Optical Applications
ABSTRACT Photoactivated organic phosphorescent materials have emerged as promising candidates for optoelectronic applications due to their unique combination of remote controllability and dynamic response characteristics. Despite being a critical parameter governing their practical applicability, the photostability of these phosphorescent materials, particularly under prolonged illumination conditions, has not been systematically investigated to date. Here, we present a series of organic phosphorescent materials exhibiting dynamically tunable room‐temperature phosphorescence (RTP) stability under continuous irradiation. These materials show RTP activation upon initial excitation, followed by significant emission attenuation during sustained exposure. Mechanistic studies reveal that the RTP attenuation is attributed to singlet oxygen‐mediated oxidative damage to the phosphorescent chromophores. Through strategic incorporation of antioxidant stabilizers, we achieve remarkable photostability, maintaining 96% of maximum phosphorescence intensity after continuous irradiation for 1500 s. These findings not only elucidate fundamental photo‐stabilization mechanisms of dynamic RTP but also provide a feasible approach for developing stable phosphorescent materials for advanced optoelectronic applications.
Potentiating Chemo‐Immunotherapy via a Programmable Nanocapsule‐Hydrogel Platform for Sequential Tumor Microenvironment Remodeling
ABSTRACT Durable responses to cancer immunotherapy require both robust antitumor immunity and sustained immune pressure within the immunosuppressive tumor microenvironment (TME). Chemotherapeutics can induce transient immune priming and modulate TME features but are limited by unpredictable immune response durations and systemic toxicity when combined with immunotherapy. To overcome these challenges, we develop a programmable delivery platform integrating chemotherapeutics and immune checkpoint blockade within a silk fibroin hydrogel containing pH‐responsive nanocapsules for controlled temporal release at tumor sites. Leveraging molecular weight differences, the small chemotherapeutic oxaliplatin rapidly diffuses to initiate tumor‐intrinsic immunogenic stress, while the larger anti‐PD‐L1 nanocapsules undergo gradual degradation in the TME, enabling sustained checkpoint engagement. This strategy converts non‐immunogenic tumor cells into a heightened immunogenic state, modulates key immune features of the TME, and supports durable antitumor responses and long‐term central memory T cell persistence in a murine breast tumor model. Our findings demonstrate that this multifunctional platform, combining chemotherapy‐induced immunogenic stress with controlled checkpoint blockade, offers a generalizable approach for designing next‐generation chemo‐immunotherapy combinations in cancer treatment.
The diversity and clinical relevance of germline DNA damage repair gene variants in 3005 patients with metastatic prostate cancer.
227 Background: Inherited genetic variants in genes linked to DNA damage repair (DDR) can increase the risk of developing aggressive prostate cancer but the full spectrum of relevant genes and deleterious variants is unknown. We sought to determine the landscape of inherited DDR genetic variants and their clinical implications in 3005 patients with metastatic prostate cancer (mPCa). Methods: We performed targeted sequencing on peripheral blood leukocyte DNA from a meta-cohort of 3005 patients with mPCa enrolled for genetic testing between 2014 to 2025, and searched for small variants and large structural variants (SVs) across 32 DDR-associated genes. Only variants annotated as (likely) pathogenic in ClinVar or those predicted to truncate the protein were included. Clinical data for correlative analysis was available for 81%. Additional targeted sequencing on tumor DNA was selectively performed to determine somatic DDR gene status. Results: Germline DDR gene variants were detected in 269/3005 (9%) patients, six had >1 variant, half had evaluable tumor testing available. Germline variants were most common observed in BRCA2 (2.8%), ATM (1.2%), and CHEK2 (1.1%), for which second somatic allele inactivation was detected in 93%, 100%, and 20%, respectively. Rare germline variants were observed in ERCC2 (0.5%), PALB2 (0.4%), BRCA1 (0.4%), and MSH2/6 (0.3%), PMS2 (0.3%), FANCD2 (0.3%), FANCA (0.2%), RAD51B (0.2%) and CDK12 (0.1%), for which second allele inactivation was not observed for ERCC2 , PMS2 and RAD51B (n=13 with evaluable tumor testing). Somatic allele inactivation mechanisms differed per gene; some predominantly inactivated by (partial) loss of heterozygosity ( BRCA2 , CHEK2 , FANCA ) and others by secondary mutations ( ATM , PALB2 ). Novel gene-truncating germline SVs (size 38bp-29.4kb) were identified in 11 patients, making up 3/10 (30%) MSH6 / MSH2 and 2/85 (2%) BRCA2 germline variants. Patients with germline BRCA2 variants had a higher proportion of ≥4 ISUP Grade Group pathology at diagnosis (85% vs 70%, p=0.04) and more progressed to castration-resistance within 1 year (56% vs 40%, p=0.03) compared to patients without germline DDR variants, but synchronous metastatic disease was observed at similar frequencies (59% vs 58%, p=1). Germline BRCA2 variants were associated with a shorter overall survival from initial diagnosis (median 5.0 vs 10.2 years for wildtype BRCA2 , p<0.01), including in a multivariable analysis with age, synchronous metastatic disease and pathology grade group (HR 2.79, 95%CI 1.93-4.04, p<0.01). Conclusions: This large mPCa cohort enabled frequency assessment of common and rare germline variants in DDR genes. BRCA2 was prominently linked to biallelic gene loss in the tumor and disease aggression. Clinical grade tests should account for large germline SVs and consider the different mechanisms of somatic gene inactivation.
Rucaparib vs docetaxel (DTX) or second-generation androgen receptor pathway inhibitor (ARPI) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with <i>BRCA</i> mutations based on Eastern Cooperative Oncology Group performance status (ECOG PS) in TRITON3.
46 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS) vs physician’s choice of DTX or an ARPI. ECOG PS is used as a predictor of prostate cancer survival. In this post hoc analysis, we report results from the BRCA1/2 subgroup of pts stratified by ECOG PS. Methods: Pts with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX or ARPI (abiraterone acetate or enzalutamide). Primary endpoint was rPFS by independent radiology review (IRR). Objective response rate (ORR) for pts with measurable disease and overall survival (OS) were key secondary endpoints. Crossover from physician’s choice to rucaparib was allowed after radiographic progression was confirmed by IRR. Data cutoff was August 25, 2022. Results: Of 302 pts in the BRCA1/2 population, 147 had an ECOG status of 0 (97 rucaparib; 50 physician’s choice) and 155 had ECOG 1 (104 rucaparib; 51 physician’s choice). Baseline characteristics and demographics were generally similar between arms for pts in the ECOG 0 and ECOG 1 groups. Median rPFS favored rucaparib vs physician’s choice for pts with ECOG 0 (11.4 vs 8.2 months; HR, 0.48 [95% CI, 0.30-0.76]) and ECOG 1 (10.9 vs 6.1 months; HR, 0.48 [95% CI, 0.31-0.74]) (Table). Additionally, rPFS favored rucaparib for ECOG 0 and ECOG 1 including those whose prespecified physician’s choice was ARPI or docetaxel (Table). The confirmed ORR (95% CI) of rucaparib vs physician’s choice for ECOG 0 was 54% (37%–69%) vs 16% (3%–40%); the ORR for ECOG 1 was 37% (22%–53%) vs 18% (5%–40%), respectively. Median OS was similar between arms for rucaparib or physician’s choice; median OS was 23.7 vs 21.7 months (HR, 0.91 [95% CI, 0.61–1.37]) for ECOG 0 and 21.8 vs 20.4 months (HR, 0.85 [95% CI, 0.58–1.24]) for ECOG 1. Conclusions: Rucaparib improved rPFS and ORR in pts with BRCA-mutated prostate cancer with an ECOG PS of 0 or 1. OS was similar for these groups in both arms. These data support rucaparib as a treatment option for pts with BRCA-mutated mCRPC, whether ECOG 0 or 1. Clinical trial information: NCT02975934 . Median rPFS in patients in the ECOG 0 and ECOG 1 groups. Rucaparib, n Physician’s choice, n rPFS Rucaparib, median months rPFS Physician’s choice, median months HR (95% CI) rPFS, ECOG 0 97 50 11.4 8.2 0.48 (0.30–0.76) rPFS, ECOG 1 104 51 10.9 6.1 0.48 (0.31–0.74) rPFS, physician’s choice ARPI, ECOG 0 51 24 11.2 5.6 0.42 (0.22–0.78) rPFS, physician’s choice docetaxel, ECOG 0 46 26 11.5 8.8 0.49 (0.24–0.98) rPFS, physician’s choice ARPI, ECOG 1 52 17 11.2 4.5 0.33 (0.16–0.68) rPFS, physician’s choice docetaxel, ECOG 1 52 34 10.7 7.1 0.59 (0.34–1.01)