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Quinone‐Grafted Chitosan Polymers Enhance Microbial Extracellular Electron Transfer for Living Bioelectronic Devices

ABSTRACT Microbial bioelectronics using electroactive bacteria provide robust and sustainable solutions for sensing, power generation, and chemical production. While most rely on a limited group of Gram‐negative bacteria, Gram‐positive species offer devices with additional functionality and broader environmental ranges. However, their thick, nonconductive cell walls hinder efficient extracellular electron transfer (EET). Here, a living bioelectronic device using a redox‐active polymer to encapsulate Gram‐positive bacteria near an electrode while simultaneously enhancing EET is reported. The redox‐active polymer NQ‐Chit contains naphthoquinone redox groups grafted onto a chitosan backbone and can be ionically cross‐linked to produce redox‐ active hydrogels. To fabricate living bioelectronic devices, NQ‐Chit is blended with the Gram‐positive bacterium Lactiplantibacillus plantarum , deposited on an electrode, and ionically cross‐linked in situ. The NQ‐Chit hydrogel enhances EET current compared to both pure Chit‐encapsulated bacteria and planktonic bacteria with NQ‐Chit–coated electrodes, and Michaelis‐Menten kinetics can describe the dependence of EET current on the concentration of quinone units. The devices remain functional after multiple medium exchanges. Additionally, the redox polymer enhances EET across diverse electroactive bacteria and enables a proof‐of‐concept for detecting environmental chemicals. This work demonstrates that encapsulating electroactive bacteria with redox‐active hydrogels enhances EET and can be implemented in practical bioelectronic devices.

A disease-causing isoleucyl-tRNA synthetase variant leads to altered protein complex formation and cellular stress response

Early prostate specific antigen response and overall survival in metastatic hormone sensitive prostate cancer: Real-world data on age, body mass index, and treatment.

109 Background: Prostate-specific antigen (PSA) response is a strong prognostic marker for overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), as shown in prospective trials. A rapid, deep PSA drop (≤0.2 ng/mL within 6 months) is linked to improved survival, but real-world evidence remains limited. This study examines real-world patterns of early PSA response and its prognostic significance in mHSPC, considering age, body mass index (BMI), and treatment. Methods: Retrospective cohort study of 5,048 U.S. Veterans with mHSPC using Veterans Health Administration data between 2017–2024. Early PSA response was defined as PSA ≤0.2 ng/mL at 6–12 months. OS and PSA response heterogeneity were analyzed by age, BMI, and treatment type (androgen deprivation therapy (ADT) alone, ADT+docetaxel, or ADT+androgen receptor pathway inhibitor (ARPI)). Kaplan–Meier and Cox proportional hazards models evaluated OS while chi-squared tests compared clinical characteristics. Results: Of 5,048 veterans with mHSPC, 2,572 received ADT monotherapy, 511 received ADT+docetaxel, and 1,961 received ADT+ARPI. PSA ≤0.2 ng/mL at 6–12 months was achieved in 30% of patients on ADT monotherapy, 36% with docetaxel-based therapy, and 53% on ADT+ARPI (p<0.001). Higher BMI was associated with greater PSA response rates—29% for BMI<25, 42% for BMI 25–29.9, and 47% for BMI≥30 (p = 0.001). No consistent trend was observed between age and PSA response. Kaplan–Meier analysis demonstrated improved OS for patients achieving PSA ≤ 0.2 ng/mL, regardless of age, BMI, or treatment group. Median survival (MS) by early PSA response was as follows: for PSA ≤0.2 ng/mL (n=1,982), MS was not reached due to >50% survival at 60 months; for PSA 0.2–2 ng/mL (n=1,302), MS was 52 months (ADT), 45 months (ADT+docetaxel), and 44.5 months (ARPI); for PSA 2–10 ng/mL (n=808), MS was 30 months (ADT), 32 months (ADT+docetaxel), and 25 months (ARPI); and for PSA >10 ng/mL (n=952), MS was 20 months (ADT), 22 months (ADT+docetaxel), and 16 months (ARPI). Conclusions: PSA decline to ≤0.2 ng/mL at 6–12 months was a strong predictor of OS regardless of treatment. Combination therapy with ADT+ARPI led to a more robust PSA response rates and better survival. These real-world results are consistent with clinical trial evidence, further supporting the prognostic value of early PSA kinetics as a surrogate marker for survival and clinical outcomes. Hazard model. PSA Threshold Categories Median Survival (months) Adjusted HR* 95% CI P-Value ≤0.2 NR* ref -- -- -- >0.2 to 2.0 48 1.95 1.75 2.17 <0.001 2.0 to 10 29 3.24 2.89 3.63 <0.001 10+ 19 5.76 5.17 6.42 <0.001 *NR = not reached; HR = hazard ratio.

Phase 2 study of ASP5541 (PRL-02), a long-acting intramuscular depot injection of abiraterone decanoate, in patients with advanced prostate cancer.

TPS300 Background: Globally, prostate cancer (PC) is the second most diagnosed cancer in men and fifth leading cause of cancer death. Patients (pts) with advanced PC have limited treatment options. While abiraterone acetate (AA) improves survival in pts with metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC), it has low oral bioavailability and a risk of hepato- and mineralocorticoid toxicity. ASP5541 is a long-acting intramuscular (IM) depot injection of abiraterone decanoate that delivers abiraterone to target tissues and lymphatics, reducing systemic exposure. This, and its unique pharmacokinetics, may reduce the need for glucocorticoids, lower mineralocorticoid toxicity, and decrease treatment burden. A Phase 1 study of ASP5541 (NCT04729114) in pts with advanced PC established 1260mg every 12 weeks (Q12W) as the recommended Phase 2 dose based on safety, pharmacodynamics (PD), and efficacy data. This Phase 2 study aims to evaluate the efficacy and safety of ASP5541 (± prednisone [pred]) vs AA in pts with advanced PC. Methods: This randomized, Phase 2 study (NCT07005154) plans to enroll ~218 adults with PC across 3 cohorts. Inclusion criteria are histologically/cytologically confirmed metastatic PC with ECOG PS 0/1 (2 if due to bone pain); and baseline serum testosterone <50ng/dL (for mCRPC). Eligible adults will have received androgen-deprivation therapy (ADT), consisting of prior bilateral orchiectomy or concurrent gonadotropin-releasing hormone agonist or antagonist therapy, plus a cohort-specific regimen (Table). In Cohort 2, ASP5541 will be administered without pred. Primary endpoints are shown in the Table. Secondary endpoints for all cohorts are radiographic progression-free survival; PSA50; time to PSA progression, objective response rate, duration of response, best overall response, PSA undetectable rate at ≤0.02ng/mL for all cohorts and at ≤0.2ng /mL for Cohorts 1 and 3 only; PSA90 (Cohorts 2, 3); safety, PD, and time-to-pain progression. Recruitment is planned across the Americas, Europe, and the Asia-Pacific region. Clinical trial information: NCT07005154 . Cohorts Indications Randomization N Treatment Primary endpoints 1 Androgen receptor pathway inhibitor (ARPI)-naïve mCRPC 1:1 50 per group Group A: ASP5541 + pred + ADT; Group B: AA + pred + ADT Proportion of pts with PSA90 2 ARPI-naïve mHSPC 1:1 (for Groups B and C) 10 for Group A; 50 for Group B and 50 for Group C Group A (safety run-in): ASP5541 + ADT (steroid free); Group B: ASP5541 + ADT (steroid free); Group C: AA + pred + ADT Group A: rates of no mineralocorticoid toxicity (grade ≥1 hypokalemia or grade ≥2 hypertension)Group B and C: proportion of pts with PSA ≤0.2 ng/mL at 8 months 3 mCRPC or mHSPC(Japanese pts) N/A 3–8 ASP5541 + pred + ADT Safety ASP5541 1260 mg IM once every 12 weeks (Q12W); AA 1000 mg orally (PO) once daily (QD); pred PO 5 mg twice daily for mCRPC and 5 mg QD for mHSPC.

Hormone therapy use and duration with post-operative radiotherapy for recurrent prostate cancer: An individual patient data meta-analysis.

305 Background: Addition of hormonal therapy (HT) to definitive radiotherapy (RT) in localized prostate cancer improves overall survival (OS). However, the effect of HT on OS when added to post-operative RT (PORT) after radical prostatectomy is less clear. Herein, we report an individual patient data (IPD) meta-analysis of randomized trials to quantify the benefit of adding HT to PORT. Methods: The POSEIDON meta-analysis was an IPD meta-analysis of randomized phase 3 trials of PORT±HT utilizing IPD from the MARCAP consortium. The primary outcome was OS. Meta-analyses evaluated the benefit of HT to PORT, addition of short-term HT (ST-HT, 4-6 months), or addition of long-term HT (LT-HT, 24 months) to PORT. Tests for interaction based on pre-PORT PSA and duration of HT were evaluated and non-linear associations between pre-PORT PSA and OS were modeled with cubic splines. Results: Six phase 3 trials were eligible for inclusion in our analysis and had IPD available (6057 patients, median follow-up of 9.02 years). The addition of HT to RT did not improve OS (HR 0.87, 95%CI 0.76-1.01, p=0.06). There was no significant interaction between duration of HT and this effect (p-interaction 0.25), though there was a significant interaction based on pre-PORT PSA >0.5 ng/mL vs. ≤0.5 ng/mL (p-interaction 0.02). For all pre-PORT PSA values, the upper bounds of the 95% CI of the hazard ratio for OS crossed 1 for patients randomized to ±ST-HT (n=3938). For patients randomized to ±LT-HT (n=1088), the upper bounds of the 95% CI for OS fell below 1.0 at PSA >1.6 ng/mL. Conclusions: Our findings provide the strongest level of evidence to date to suggest there is no meaningful OS benefit to adding HT, either ST- or LT-HT, to PORT for PSA <0.5 ng/mL in biomarker unselected patients, with no apparent difference in efficacy for ST-HT versus LT-HT.

Clinical characteristics and long-term outcomes of extreme responders to first line treatment of metastatic prostate cancer.

266 Background: Contemporary trials show that the median overall survival of patients with metastatic prostate cancer is approximately four to five years. There is limited data on the clinical course and the long-term outcomes of patients who have lived beyond that (extreme responders). This study aimed to investigate the disease characteristics and treatment patterns of patients with long term survival following metastatic disease diagnosis. Methods: Retrospective, single-site study of 247 patients diagnosed with metastatic prostate cancer prior to Jan 1, 2019, and living as of Dec 31, 2024. We compared patients who did and did not develop castration resistant disease on first line therapy. Among those who did not progress on first line therapy, we examined treatment patterns of therapy cessation. Results: 247 patients were included. The mean age of the cohort was 62 years at diagnosis. The median follow up time for the cohort was 103 months (range 72-279 months). 154 (62%) had localized disease at diagnosis and 93 (38%) had metastatic disease at diagnosis. 140 (56%) had Gleason grade group 4 or 5; 121 (79%) of those with localized disease (n=154) were treated with prostatectomy as their primary therapy. 161 (65%) patients had bone only metastases; 45 (18%) had lymph node only metastases, and 25 (10%) had visceral involvement (alone or in combination with other sites). 101 (41%) of patients continued to have castration sensitive disease through a median follow up of 7.8 years. Among those patients, 26 (25.7%) stopped therapy prior to 12/31/2024, and of those, 21 had evidence of testosterone recovery, and 15 continued to have an undetectable PSA. This represents about 6% of our total cohort of patients who survived beyond 5 years and have no evidence of disease even with cessation of all prostate cancer directed therapies. Conclusions: Metastatic prostate cancer is thought to be incurable, however, there are some patients who have castration sensitive disease for long duration and a subset who can successfully stop therapy. Additional research is needed to further characterize clinical and biological parameters of patients likely to have long-term benefits from ADT to potentially stop treatment earlier, saving resources, and mitigating treatment-related adverse effects.

Uncovering Electrochemical‐Mechanical Interplay of Stable Ultrahigh‐Nickel Cathode via Fine Structure Regulation

ABSTRACT Ni‐rich layered oxides with optimized primary particle structures are crucial for developing lithium‐ion batteries with high energy density. Although conventional high‐valence elements doping effectively refines grains for columnar alignment, the industrial understanding of the processing‐structure‐performance relationship is lacking, and thus limits large‐scale production. Herein, we investigate how molybdenum incorporation routes alter microstructure and performance, revealing a link between early structural evolution and capacity increase trends. Unlike the solid‐phase gradient, the co‐precipitation strategy achieves ultra‐dispersed Mo doping, leading to super‐refined primary particles and a dense structure that reduces microcracking through internal stress dissipation. Notably, it also limits electrolyte penetration, thereby influencing the initial Li + transport kinetics. Moreover, this process induces a Li/TM cation‐ordered structure that permeates the entire bulk phase of LiNi 0.95 Co 0.04 Mo 0.01 O 2 , suppressing Li + /Ni 2+ cation disorder and mitigating intragranular/intergranular strain. These combined effects significantly enhance the structural robustness, resulting in a high discharge capacity of 204.9 mAh g − 1 at 5C. This work offers a straightforward and scalable industrial solution for enhancing the overall electrochemical performance of Ni‐rich cathodes.

Layered Double Hydroxide‐Based Sonosensitizer Triggers “Paraptosis+” Multidimensional Cell Death Network for Augmented Sonodynamic Immunotherapy

ABSTRACT Paraptosis, a caspase‐independent programmed cell death pathway characterized by cytoplasmic vacuolization, presents a promising alternative for overcoming apoptosis resistance. However, its clinical translation is hampered by the low reactive oxygen species (ROS) generation efficiency and insufficient anti‐tumor efficacy of existing inducers. To address these limitations, we develop defective nickel‐doped ZnMo‐layered double hydroxide nanosheets (DR‐Ni‐ZnMo‐LDH) as a new inducer for paraptosis‐mediated sono‐immunotherapy. Under ultrasound irradiation, the DR‐Ni‐ZnMo‐LDH exhibits excellent singlet oxygen generation activity, superior to that of all the reported sonosensitizers. Mechanistic investigations reveal that the ROS burst generated by DR‐Ni‐ZnMo‐LDH not only effectively induces paraptosis but also concurrently activates apoptosis and ferroptosis, thereby synergistically eliminating apoptosis‐resistant tumor cells. In vitro and in vivo assays confirm that this multi‐modal cell death strategy elicits robust immunogenic cell death, remodels the immunosuppressive tumor microenvironment, and significantly inhibits the growth of primary and distant tumors, with inhibition rates reaching 98.44% and 88.53%, respectively. This study establishes a new material design paradigm for ROS‐mediated sono‐immunotherapy based on paraptosis, effectively overcoming tumor resistance and immunosuppression through multi‐mechanism synergy.

Nitric oxide mediates ET-1-induced-inhibition of NPPB-sensitive Cl− currents in the early distal convoluted tubule of the mouse kidney

Association of urothelial carcinoma with squamous differentiation with Nectin-4 expression and outcomes with enfortumab vedotin (EV) treatment.

865 Background: The Nectin-4 directed antibody-drug conjugate EV has demonstrated high efficacy in metastatic urothelial carcinoma (mUC), but outcomes in patients with divergent histologies remain poorly characterized. Squamous differentiation represents a clinically challenging subtype with distinct molecular features. We investigated Nectin-4 expression patterns and EV clinical outcomes in patients with urothelial cancer with squamous differentiation versus non-otherwise specified (NOS) histology. Methods: We retrospectively analyzed 127 patients with mUC (squamous differentiation vs NOS urothelial carcinoma) treated with EV as standard-of-care across multiple centers. NECTIN4 gene amplification was assessed by fluorescence in-situ hybridization (FISH), and membranous Nectin-4 protein by immunohistochemistry H-scores. Outcomes including ORR, PFS, and OS were documented by the investigators. Chi-square and log-rank tests were used for statistical comparisons. Results: Among 127 evaluable patients, those with squamous histology (n = 23; 18%) demonstrated significantly lower membranous Nectin-4 expression with a median H-score of 20 (IQR 3.5–85) vs 210 (IQR 97.5–290), p < 0.001. NECTIN4 gene amplification frequency was higher in squamous compared to NOS histology (n = 104): 7.7% vs 34% (p < 0.001). Importantly, patients with squamous histology exhibited inferior clinical outcomes to EV: ORR was lower (20.0% vs 51.6%, p = 0.02), median PFS was 2.8 months vs 6.2 months (HR = 2.52, 95% CI 1.45–4.37, p = 0.001), and median OS was 6.5 months vs 13 months (HR = 2.38, 95% CI 1.26–4.49, p = 0.008). Conclusions: Squamous differentiation in advanced urothelial carcinoma is associated with significantly lower membranous Nectin-4 expression and NECTIN4 amplification frequency, corresponding to markedly inferior responses to EV. These findings highlight the critical need for alternative therapeutic targets and novel treatment strategies in this population.

Whole genome–based ultrasensitive circulating tumor DNA clearance as a biomarker of exceptional outcomes with enfortumab vedotin and pembrolizumab in urothelial carcinoma: Preliminary real-world results.

866 Background: Circulating tumor DNA (ctDNA) is an emerging biomarker for monitoring treatment response and minimal residual disease (MRD) in urothelial carcinoma (UC). Serial ctDNA assessment enables real-time tracking of molecular response to therapy. Enfortumab vedotin plus pembrolizumab (EVP) demonstrates strong activity across advanced and localized UC. Ultrasensitive, tumor-informed, whole-genome ctDNA assays offer a highly sensitive approach to quantify molecular response and assess ctDNA clearance as a potential biomarker of exceptional therapeutic benefit and a tool for treatment de-escalation. Methods: Single-institution, retrospective analysis of patients (pts) with UC, including metastatic, inoperable, or localized cisplatin-ineligible muscle-invasive bladder cancer (MIBC) or upper tract urothelial carcinoma (UTUC), treated with EVP. Plasma ctDNA was analyzed using the Next Personal Dx tumor-informed whole-genome sequencing assay, tracking up to 1,800 patient-specific variants with detection down to ~1 part per million. Clinical response was assessed by imaging and cystoscopy, and longitudinal ctDNA levels were correlated with outcomes. ctDNA clearance was defined as undetectable ctDNA at any post-treatment timepoint. Results: Twenty-seven patients with 118 plasma samples were analyzed. Median age was 71 years (range 34–89); 78% were male and 7% Black. Disease site included 22 (81%) MIBC and 5 (19%) UTUC; 17 (63%) had metastatic disease, 9 (33%) received neoadjuvant EVP, and 1 (4%) received adjuvant therapy. Median number of EV cycles was 6 (range 2–12). At the time of analysis, 11 complete responses (42%), 11 partial responses (42%), 3 stable disease (12%), and 1 progressive disease (4%). Pre-EVP ctDNA was available for 18 (67%); 4 (22%) were ctDNA-negative pre-EVP. Among evaluable patients, 11 (48%) achieved ctDNA clearance after a median of 3 EVP cycles (range 1–11), while 12 (52%) had persistent ctDNA positivity. Median follow-up was 13.8 months (range 5.5–48.3); 19 (70%) remain under surveillance, including 9 with metastatic disease. Conclusions: Tumor-informed whole-genome ctDNA kinetics represents a feasible and highly sensitive biomarker of response to EVP in UC. ctDNA clearance correlated with exceptional clinical and radiographic outcomes, whereas persistent ctDNA positivity identified residual or progressive disease. These findings support the use of ultrasensitive ctDNA dynamics for real-time treatment monitoring and as a potential tool for response-based de-escalation strategies. Prospective studies are warranted to validate ctDNA clearance as a biomarker of durable response in UC.

SWOG S1602: A phase III randomized trial to evaluate BCG strain differences and priming with intradermal BCG before intravesical therapy for BCG-naïve high-grade non-muscle invasive bladder cancer (NCT #03091660).

LBA629 Background: Whether BCG strain influences clinical efficacy is unclear. BCG shortages and a reliance on a single strain may impact disease outcomes. Evidence also suggests that priming with intradermal (ID) BCG vaccination prior to intravesical (IVe) BCG enhances anti-tumor immunity and cancer clearance. Co-primary objectives address these issues. Methods: The trial design calls for 924 eligible patients with BCG naïve non-muscle invasive bladder cancer (NMIBC) (HG Ta/T1 +/- CIS or CIS alone) with negative purified protein derivative (PPD) to be randomized in a 1:1:1 ratio, to IVe TICE (Arm 1), IVe Tokyo-172 (Arm 2), or ID + IVe Tokyo-172 (Arm 3) BCG, stratifying on age group and clinical stage. IVe BCG included 6 weekly instillations (induction) and three weekly instillations (maintenance) at 3 and 6 months (mo), then every 6 mo for 3 years. Objective 1 tests whether Tokyo-172 BCG is non-inferior (NI) to TICE BCG, specifying a NI hazard ratio=1.34 (84% power). Objective 2 tests whether priming with ID prior to IVe Tokyo-172 is superior to IVe Tokyo-172 (HR=0.71, 83% power). The primary endpoint is high-grade recurrence-free survival (HG-RFS) censored at last cystoscopy, using a one-sided α=0.021 for each test. A Cox model adjusting for the stratification factors is used. Secondary endpoints include adverse events, 6-mo biopsy-proven complete response (CR) in patients with CIS +/- Ta, T1, duration of CR, PPD conversion and HG-RFS, progression-free survival (PFS) and quality of life. Max follow-up is 5 years. Results: 1000 (984 eligible) patients were enrolled from 2/17-12/20. Median (IQR) follow up is 4.6 (3.6, 5.0) yrs. Median age (range) is 70 yrs (26, 99), 17% are female, 9% are non-white, and 34% had CIS at entry. HG-RFS, CR, duration of CR at 4 yrs, and PFS were similar among arms (Table). PPD conversion occurred in 29% and was not correlated with HG-RFS. Gr 1-2 AE rate was similar (67%, 71%, and 67%) and Gr 3-4 (no Gr 5s) rate was 6%, 11%, and 14% for Arms 1,2, and 3, respectively. Conclusions: Tokyo-172 is non-inferior to TICE BCG in terms of HG RFS and CIS CR and is similar for PFS. Gr 3-4 AE rate is higher with Tokyo-172. Priming with Tokyo-172 BCG does not improve HG RFS. PPD conversion is not prognostic. Clinical trial information: NCT #03091660 . CIS Component N (eligible) 5-yr HG RFS HG RFSHR (95.8% CI) @ 5-yrPFS PFS HR(95% CI) @ CR %(95% CI) 4 yr CR duration Tice Ive 333 (330) 58% 79% 62%; 71/114(53%, 71%) 80% Tokyo Ive 332 (327) 64% *0.82(0.63, 1.08) 79% *0.99(0.70, 1.39) 60%; 66/110(50%, 69%) 83% Tokyo ID + Ive 335 (327) 63% **1.00(0.76, 1.33) 77% **1.07(0.76, 1.51) 63%; 69/109(54%, 72%) 80% 3 mo. PPD + conversionY vs. N 782 evaluable225 (29%)557 (71%) 69%67% ^HR=0.91(0.68, 1.22) * Tokyo-172 vs. Tice, ** Tokyo Priming vs. Tokyo no priming. ^conversion to PPD + vs. – @ adjusted for 2 strat factors (and arms for PPD model). PFS event = MIBC, metastasis, or death.

A pragmatic phase 2 trial of locally ablative therapy in oligo-progressive genitourinary (GU) tumors: LAYOVER

TPS291 Background: Oligoprogressive disease (OPD) may represent an opportunity for locally ablative therapies to provide disease control in patients otherwise responding to systemic therapy. In GU malignancies, retrospective data suggest that ablating resistant clones in OPD sites with metastasis-directed therapies (MDT) such as stereotactic ablative radiotherapy (SABR) while continuing systemic therapy can delay further progression. Limited prospective trials have assessed MDT in oligoprogressive GU malignancies. As pragmatic trials assess the efficacy of interventions in a heterogenous, representative patient population under otherwise routine clinical care, this streamlined design is well-suited to evaluate the role of MDT in patients with oligoprogressive GU cancers. Methods: This pragmatic Phase 2 study enrolls patients with histologically or biochemically confirmed GU cancers into three cohorts: prostate cancer, urothelial carcinoma, and renal cell carcinoma. Eligible patients are ≥ 18 years old, currently receiving systemic therapy and have demonstrated ≥ 3 months of clinical benefit on current treatment, defined as treating provider assessment of stable disease and not requiring change in systemic therapy. Patients must have OPD, defined as radiographic progression in 5 or fewer metastatic lesions. Patients cannot have progressing intracranial lesions or a history of treatment-related toxicities that preclude the use of locally ablative therapies. Eligible participants are assigned to receive SABR or image-guided percutaneous ablation per the discretion of treating physicians, while continuing systemic therapy. Patients will be followed for up to 5 years following ablative local therapy. The primary endpoint of the trial is 3-month disease control rate (DCR), defined as continuation in systemic therapy without changes or permanent discontinuation for 3 months following first day of ablative local therapy. Secondary endpoints include evaluation of high-grade toxicity, overall survival, and time to systemic treatment failure. A lead-in stage of 15 participants are enrolled for each cohort, and based on Simon’s minimax two-stage design, if ≥ 2 patients are responding at 3-months, then additional expansions are planned to reach a total of 50 participants. The prostate cancer cohort has completed accrual of the lead-in phase and met criteria for further expansion, while other lead-in cohorts continue to accrue. Clinical trial information: NCT06101290 .

Decoding High‐voltage LiCoO ₂ : From Degradation to Stabilization Toward Durable Li‐ion Batteries

ABSTRACT Li‐ion batteries (LIBs) employing the commercially established LiCoO 2 (LCO) cathode continue to dominate the market for portable electronic devices. Enhancing their volumetric energy density is crucial for extending the operational duration of advanced smart devices. One direct approach to increasing both specific capacity and energy density involves elevating the cut‐off charging voltage to above 4.6 V (vs Li/Li + ). However, high‐voltage operation induces severe material degradation and battery failure, impeding further development of high‐voltage LCO technologies. This review first emphasizes the growing necessity for high‐voltage cathodes in contemporary LIBs, followed by a detailed exploration of the failure mechanisms of LCO at voltages up to 4.6 V. A systematic evaluation of emerging stabilization strategies is provided, covering foreign‐ion (co‐)doping, surface modifications, structural design, and electrolyte additives, all aimed at enhancing their structural integrity and electrochemical performance. Innovative battery design approaches and modification strategies for LCO‐based full cells are also discussed. Finally, the review concludes by identifying key scientific challenges and proposing targeted research avenues to enable high‐energy and durable LIBs using high‐voltage LCO. This review aims to offer guiding principles with significant implications for the rational design and development of high‐voltage cathode materials for advanced LIBs.

Desymmetrized Metamaterials Enable Perfect Absorption

ABSTRACT Metamaterials enable the reconstruction of physical field properties through controlled local symmetry breaking, thereby challenging conventional paradigms in physics. Nevertheless, realizing such symmetry manipulation often requires intricate composite structures to satisfy specific symmetry conditions, which unavoidably compromises reliability under extreme environmental conditions. Here, inspired by the generalized Kerker effect, we introduce singular points within a desymmetrized all‐ceramic metamaterial to relax these constraints. In this design, inversion symmetry breaking is confined to a single structural element, and the thermal tolerance is determined solely by the intrinsic melting point of the ceramic. Specifically, a variable blind‐hole geometry patterned on ceramic plates is employed to establish D 4v symmetry, enabling precise manipulation of odd and even modes and their mutual interference under the theoretical framework of bound state in the continuum (BIC). This mechanism generates a singular mode that suppresses both forward and backward scattering, yielding near‐lateral electromagnetic wave propagation and externally near‐perfect absorption. Furthermore, the intrinsic self‐supporting nature and near‐field polarization sensitivity of this architecture significantly enhance its application potential. By decoupling generalized Kerker effects from strict symmetry requirements, this flexible strategy expands the design space for functional metamaterials, thereby promoting the development of advanced devices with unique electromagnetic properties.

Targeting the splicing factor CWC22 induces mitotic slippage through repression of BubR1 expression and CDK1 activity in cancer cells

Trastuzumab deruxtecan (T-DXd) in pretreated patients (pts) with HER2-expressing bladder cancer: Final results from the bladder cancer cohort in Part 1 of DESTINY-PanTumor02 (DP-02).

734 Background: In the DP-02 Part 1 primary analysis, T-DXd showed clinically meaningful antitumor activity in HER2-expressing tumors, with an investigator-assessed (INV) objective response rate (ORR) of 37.1%. In the bladder cancer cohort, ORR was 39.0% (56.3% and 35.0% in HER2 IHC 3+ and IHC 2+ tumors, respectively). Findings from the final analysis, including an overall ORR of 37.5%, were consistent with the primary results. Here, we report subgroup analyses in the bladder cancer cohort (urothelial carcinoma, including transitional cell carcinoma of the renal pelvis, ureter, urinary bladder, or urethra). Methods: DP-02 is a two-part, open-label, Phase 2 study (NCT04482309). Part 1 evaluated T-DXd (5.4 mg/kg Q3W) in HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced/metastatic solid tumors after ≥1 systemic treatment (Tx), or without Tx options. The primary endpoint was INV confirmed ORR. Secondary endpoints included INV duration of response (DOR) and progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included subgroup analyses of efficacy outcomes. Results: At data cutoff (Oct 2024), 41 pts with bladder cancer received T-DXd (median follow up: 12.65 [range 0.4–42.9] months [mo]; median Tx exposure: 6.2 [range 0.4–40.8] mo; median Tx cycles: 8.0 [range 1.0–56.0]). INV ORR was 41.5% (17/41; 95% CI 26.3, 57.9). Of the 17 pts with an objective response (OR), 7 had received > 2 prior Tx regimens, 14 had received prior anti-PD-L1 Tx, and 7 had a prior cystectomy. The Table shows efficacy outcomes in all pts and by IHC 3+/2+ expression by central testing; results were generally consistent by the local or central HER2 IHC test result used for enrollment. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4 (9.8%) pts (n = 1 Grade 1; n = 3 Grade 2). Conclusions: T-DXd continued to show durable and clinically meaningful activity in HER2-expressing bladder cancer; responses were seen in pts with varied Tx backgrounds. Safety was consistent with the known profile, with no new signals. Data further support T-DXd as a Tx option for pts with pretreated HER2-expressing advanced bladder cancer. Clinical trial information: NCT04482309 . All pts IHC 3+ IHC 2+ n* 41 16 20 Pts with an OR, n (%) [95%CI] 17 (41.5) [26.3, 57.9] 9 (56.3) [29.9, 80.2] 8 (40.0) [19.1, 63.9] Complete response 1 (2.4) 1 (6.3) 0 Partial response 16 (39.0) 8 (50.0) 8 (40.0) Stable disease ≥5 weeks 17 (41.5) 5 (31.3) 8 (40.0) Progressive disease † 7 (17.1) 2 (12.5) 4 (20.0) Median DOR, mo (95% CI) 9.5 (4.3, 11.8) 8.7 (2.8, 10.6) 10.3 (4.3, 17.8) Median PFS, mo (95% CI) 7.0 (4.2, 9.7) 7.4 (3.0, 11.9) 7.8 (2.6, 11.6) Median OS, mo (95% CI) 12.8 (11.2, 15.1) 13.4 (6.7, 19.8) 13.1 (11.0, 19.9) *5 pts were enrolled, per protocol, as IHC 3+/2+ by local testing with IHC 1+/0/unknown tumors by central testing; † includes RECIST-defined disease progression and death.

Germline platelet polygenic risk score to predict renal cell carcinoma survival via sustained thrombocytosis.

543 Background: Polygenic risk scores (PGS) reflect inherited germline variants fixed from conception and is measured early in life. While renal cell carcinoma (RCC) PGS has been developed for incident risk, its relevance to prognosis and treatment outcomes falls short. Moreover, several routine hematologic measures, partly under germline control, are prognostic in RCC, yet the extent to which their PGS influences survival remains unexplored. Methods: We assembled 495 RCC patients who underwent tumor sequencing and analyzed OS using left-truncated Cox proportional hazards regression with hematologic PGS and technical covariates. We performed survival analyses with different time origins: (1) from diagnosis (left-truncated at sequencing), (2) from sequencing, and (3) from ICI initiation. 321 PGS of hematological measures were drawn from the PGS Catalog. Results: Across 321 CBC-related scores, two PGS met false discovery rate (FDR) significance for OS in RCC: a PRS for higher platelet counts (PGS002660) associated with worse survival (Hazard Ratio [HR] 1.37, Confidence Interval [CI]: 1.17 - 1.62 , q=0.027), whereas a PRS for higher RDW (PGS004826) was protective (HR 0.74, CI: 0.63 - 0.87, q=0.027). PLT PGS showed clear fidelity capturing its intended biological trait (R² = 0.06, p = 0.001 in RCC; 0.03, p = 3x10 -51 pan-cancer). The PRS survival association was attenuated by 51% after adjusting for time-varying platelet counts measured longitudinally, while PLT remained strongly adverse (HR 1.40, CI: 1.29 - 1.58, p = 1.1x10 -11 ), suggesting effect operates through PLT levels. Tumor mutational burden did not modify PGS effects, consistent with prior observations of limited prognostic utility in RCC. Pan-cancer analyses demonstrated that PLT PGS effects during immune checkpoint inhibitor therapy were significant exclusively in RCC among 17 cancer types. Conclusions: Germline determinants of PLT are associated with RCC survival and operate predominantly through sustained elevation of circulating PLT rather than independent molecular pathways. These findings substantiate thrombocytosis’s adverse prognosis in RCC and establish PLT PGS as a heritable instrument that mechanistically links constitutional biology to longitudinal hematologic parameters and clinical outcomes. The integration of PLT PGS with serial CBC measurements offers potential to refine risk stratification and patient selection. Association of polygenic risk scores with overall survival in RCC. Variables 1 HR 95% CI P-value / q-value PLT (PGS002660) 1.37 1.17 - 1.62 p = 1.3 x 10 -4 q = 0.027 RDW (PGS004826) 0.74 0.63 - 0.87 p = 2.7 x 10 -4 q = 0.027 RDW (PGS001908) 0.76 0.65 - 0.89 p = 5.8 x 10 -4 q = 0.044 PLT (time-dependent) 1.43 1.29 - 1.58 p = 1.1x10 -11 PLT (PGS002660) adjusted for PLT 1.12 0.95 - 1.32 p = 0.20 PLT (PGS002660) adjusted for TMB 1.25 1.06 - 1.46 p = 6.9x10 -3 Interaction PLT (PGS002660) * PLT 0.88 0.80 - 0.97 p = 8.0x10 -3

Prognostic utility of lactate dehydrogenase in patients with metastatic seminoma.

604 Background: Serum tumor markers play an important role in risk classification, prognostication, staging, and monitoring of treatment in germ-cell tumors (GCTs). While alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) are validated prognostic markers, recent investigations have suggested a correlation with lactate dehydrogenase (LDH) and treatment response and survival. Here, we evaluated LDH levels and survival in patients with advanced seminoma. Methods: The prospectively maintained Indiana University (IU) testicular cancer database was queried for patients with metastatic seminoma treated with first-line therapy. Pts were assigned to having a LDH <2.5 upper limit of normal (ULN) or ≥2.5 ULN based on pre-treatment LDH levels. Baseline characteristics were summarized. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Results: 113 pts were included in the study. Median age at diagnosis was 39.21 (22.80-68.72). Primary site was testis in 104 (92%), retroperitoneum in 6 (5.3%), and mediastinum in 3 (2.7%). Metastasis sites were retroperitoneal lymph nodes in 85%, pelvic lymph nodes in 12.4%, lung in 7.1%. IGCCCG risk was good in 92% and intermediate in 8%. 68.6% of pts were treated with BEPX3, 19.8% with EPX4, 1.2% with VIPX4, and 9.3% with other regimen. Median hCG was 3.50 (0.5-11,600). Median LDH was 349 (34-6550). Median follow-up was 2.30 years (0.02-19.11). 61 pts had LDH <2.5 ULN, 52 pts had LDH ≥2.5 ULN. For those with LDH <2.5 ULN, 3yr PFS was 91.5% (78.7-96.8) vs. 62.8% (45.2-76.1) for those with LDH ≥2.5 ULN, p= 0.0050. However, 3yr OS for those with LDH <2.5 ULN was 100% (100-100) vs. 95.2% (82.0-98.8), p= 0.6218. Conclusions: Patients with metastatic seminoma and LDH ≥2.5 ULN had inferior 3-yr PFS compared with normal LDH, but there was no difference in OS.

Metastasis-directed therapy with or without pembrolizumab for oligometastatic clear cell renal cell carcinoma: Pooled analysis of two prospective single-arm phase II trials.

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .