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Angelica herbal supplement AGN-Cogni.Q acute dose safety and pharmacokinetics (PK) dose-response in prostate cancer patients.

372 Background: There are currently no FDA approved modalities for intercepting prostate cancer biochemical recurrence after surgery and pelvic radiotherapy to delay or prevent the need for subsequent androgen deprivation therapy. Preclinical modeling suggests Angelica gigas Nakai (AGN) root, its signature pyranocoumarins decursin D and decursinol angelate DA. and their hepatic metabolite decursinol DOH are potential novel modalities to address this unmet clinical need. Aside from our prior single dose PK study of AGN supplement Cogni.Q in healthy subjects, the acute dose safety and pyranocoumarin PK dose response patterns in cancer patients have not been studied. Methods: A single ascending dose (SAD) PK trial enrolled 12 prostate cancer patients (NCT05375539). Each subject was to receive 800, 1200, 1600, and 2000 mg of AGN-Cogni.Q at weekly intervals and assessed for safety by NCI CTCAE version 5.0, laboratory evaluations (CBC diff, CMP, 24 h) and EKG (5 h) vs pre-dose baseline. At each visit, pre-dose and PK blood was drawn hourly from 2 to7 h and at 24 h. Plasma D, DA, and DOH were quantified by LC-MS/MS. NK and T cells were immunophenotyped at baseline and 24 h after each dose as potential pharmacodynamic biomarkers. Results: Two subjects discontinued after the 800mg dose of AGN-Cogni.Q: Subject #005 experienced an adverse drug interaction with warfarin leading to exclusion of all warfarin users and Subject #010 due to preexisting neutropenia that worsened due to antidepressant med change. Five subjects received the full 4 doses, including Subject #009 with a non-specific ECG T-wave change 5 h after 2000mg dose and the highest DOH C max . Five subsequent subjects received 3 lower doses. No dose-limiting toxicities were observed. The DOH PK dose response was linear with a regression slope for C max of 1.05 and AUC 1.00. However, NK and T cell subtype frequencies in peripheral blood did not change vs. their respective baselines. Conclusions: The exposure PK metrics for DOH display a linear dose response. The AGN-warfarin adverse interaction and EKG safety signal provide critical exclusion criteria and dosage cap for future trials. Phase I/II study (NCT06600698) is ongoing to evaluate the long-term safety and efficacy in prostate cancer patients. Clinical trial information: NCT05375539 .

Adiposity and response to ADT ± AR pathway inhibitors (ARPI) in men with metastatic hormone-sensitive prostate cancer (mHSPC).

233 Background: Adiposity has a complex influence on prostate cancer outcomes that may be stage- and/or treatment-dependent. While linked to worse outcomes in localized disease, increased adiposity has been associated with an improved response to ARPI in metastatic castration-resistant prostate cancer (mCRPC). However, how pre-treatment (intrinsic) versus on-treatment (acquired) adiposity affects outcomes in men with mHSPC receiving ADT ± ARPI is unknown. We hypothesized that elevated intrinsic and greater acquired adiposity would improve the efficacy of ARPI in mHSPC. Methods: Men with mHSPC from a pooled cohort of three single-center, investigator-initiated trials with baseline L3 vertebra CT imaging prior to initiating ADT ± ARPI were included. An AI segmentation tool, Voronoi DAFS, measured body composition (normalized for height [m²]) on CTs obtained before and after six months of ADT ± ARPI. Response to ARPI was evaluated using 6-month PSA response, defined as PSA <0.4, 0.4–4, or >4 ng/mL, and mCRPC progression-free survival (PFS), defined as time from ADT start to development of CRPC or death. Chi-square tests, the Kaplan-Meier method, and proportional hazards regression were used for analysis. Results: In 152 men with mHSPC, median age was 66.0 years, and median PSA was 15.9 ng/mL. Antihypertensive medication use was prevalent (61.8%), 21.1% had type 2 diabetes mellitus (T2DM), and 14.5% had coronary artery disease (CAD). Intrinsic subcutaneous adiposity (SATi) was associated with 6-month PSA response (p = 0.004), with the middle tertile of intrinsic adiposity showing the most favorable response. In contrast, greater acquired SATi after six months of ADT ± ARPI was associated with an inferior 6-month PSA response (p < 0.001; Table), which persisted in a multivariable model. In a multivariable model controlling for differences across the three trials, intrinsic and acquired adiposity were not associated with PFS. Conclusions: Subcutaneous adiposity had a complex association with 6-month PSA response, but neither intrinsic nor acquired adiposity was associated with time to mCRPC. While these findings support a relationship between adiposity and PSA kinetics, a clear link between body composition and the long-term efficacy of ADT ± ARPI was not established. Association between intrinsic and acquired subcutaneous adiposity (SATi) and 6-month PSA response in men with mHSPC receiving ADT ± ARPI. 6-month PSA Univariable intrinsic SATi N PSA <0.4 PSA 0.4–4 PSA >4 p-value <43.833 37 22 (59.5%) 11 (29.7%) 4 (10.8%) 0.004 43.833 to <86.884 71 60 (84.5%) 11 (15.5%) 0 (0.0%) ≥86.884 38 24 (63.2%) 10 (26.3%) 4 (10.5%) Multivariable acquired SATi Change 0.002 Change < 15.9 79 57 (72.2%) 21 (26.6%) 1 (1.3%) Change ≥ 15.9 24 11 (45.8%) 7 (29.2%) 6 (25.0%)

Chemo‐Mechanical Failure and Reinforcement of Solid Electrolyte Films for Practical All‐Solid‐State Li Metal Pouch Cells

ABSTRACT All‐solid‐state Li metal batteries (ASLMBs) are the key to achieving high energy densities; however, studies on practically relevant pouch‐type cells remain scarce. A critical challenge lies in integrating thin solid electrolyte films, particularly under the high pressures required for cell assembly, which has been largely overlooked. Here, we reveal the inherent incompatibility of conventional sulfide solid electrolyte films with Li metal during pouch cell assembly. To address this challenge, we introduce a simple yet effective post‐engineering strategy that modifies the chemical interactions between Li 6 PS 5 Cl and nitrile butadiene rubber binders, significantly enhancing the mechanical robustness and Li metal compatibility, even under 450 MPa isostatic pressing. Complementary experimental analyses and finite element method simulations identify the underlying enhancement mechanism as the improvement of mechanical properties, which increases the interfacial friction. Leveraging these advancements, we successfully assemble LiNi 0.70 Co 0.15 Mn||Li ASLMB pouch cells without any interlayers through single‐step pressurization, achieving remarkable performance at 3 MPa, with 400‐cycle stability at 60°C and reliable operation at 30°C. Finally, we demonstrate a proof‐of‐concept bipolar‐stacked ASLMB pouch cell, showcasing its scalability and practicality. These findings establish a new benchmark for ASLMBs and provide key design principles for advancing practical high‐energy all‐solid‐state technologies.

Supramolecularly Engineered Flexible Zinc‐Iodine Batteries for Wearable Electronics

ABSTRACT Flexible aqueous zinc‐iodine batteries (AZIBs) have emerged as promising candidates for the power source in wearable electronics, owing to their intrinsic safety and cost‐effectiveness. However, electrochemical and mechanical interface instability between zinc anodes and electrolytes under deformation prevent the reliable performance of AZIBs in practical applications. Here, we present a synergistic supramolecular interactions engineering strategy utilizing hydrogen bonding, ion‐dipole, and coordination interactions to enhance interfacial stability by creating a polyacrylamide‐trehalose‐ dimethylglycine (PATT) hydrogel electrolyte with strengthened interfacial adhesion, reduced water activity, and facilitated ion transport. With PATT, Zn||ZnI 2 cell delivers an areal capacity of 4.2 mAh cm − 2 with 85.2% retention after 6000 h, while multilayer pouch cell maintains 1.2 Ah with 92.3% retention over 175 cycles. Excellent mechanical resilience and electrochemical stability of Zn||ZnI 2 cells are further observed under successive loading cycles of bending and stretching. The strain‐sensing capability of PATT hydrogel is also investigated, thereby enabling the energy supply and hand motion capture with monolithic material. A smart glove for virtual reality interaction is demonstrated to highlight the potential of PATT hydrogel in achieving mechanical‐robust wearable electronics.

<i>PARP1</i> and <i>BRCA1/2</i> expression and overall survival in high risk of recurrence localized clear cell-type renal cell carcinoma.

514 Background: Poly(ADP-ribose) polymerase 1 (PARP1) senses single strand DNA damage and catalyzes repair mechanisms. PARP inhibitor (PARPi) suppresses PARP1 activity and promotes cell death in BRCA1 or BRCA2 mutated cancers that are homologous recombination repair deficient (HRD) via a phenomenon known as “synthetic lethality”. Utility of PARPi in HRD-negative (HRDn) cancers remain uncertain, although in a preclinical study overexpression—but not endogenous levels—of BRCA2 in mouse hybridoma cells led to HRD and increased sensitivity to DNA crosslinking agents, suggesting potential sensitization to PARPi. In renal cell carcinoma (RCC), HRD mutations are rare and the role of PARPi remains investigational. In this study, PARP1 and BRCA1/2 expression and overall survival (OS) in high risk of recurrence localized clear cell-type renal carcinoma (hrr-ccRCC) were explored. Methods: Batch-corrected bulk mRNA profile (RNA Seq V2 RSEM) and clinical data of HRDn stages II grade 4-only (n = 4) and III (n = 100) ccRCC from The Cancer Genome Atlas Pan-Cancer project were reviewed. Gene expression was classified “high” if mRNA level is higher than median, otherwise it was classified “low”. Survival analyses were Log-rank Kaplan-Meier. Group comparisons were two-tailed Mann-Whitney test. Results: In HRDn hrr-ccRCC (n = 104), BRCA1 and BRCA2 were upregulated by median fold change (mFC) of 1.6 and 3.7, respectively, whereas PARP1 was downregulated by mFC 0.8 compared to normal control (n = 72, all p &lt; 0.0001). BRCA1 and BRCA2 levels were positively correlated (R 2 = 0.71). Median duration of follow-up for OS was 36.5 months (IQR 20.9-60.0). High BRCA2 (n = 54) was associated with superior OS compared to low BRCA2 (n = 50) with hazard ratio (HR) for death at 0.34 (95% CI 0.19-0.63, p = 0.0008). When high BRCA2 group was further stratified by PARP1 level, those with concomitant low PARP1 (n = 16) trended towards a superior OS compared to those with high PARP1 (n = 38) with HR 0.19 (95% CI 0.06-0.60, p = 0.067). Similarly, high BRCA1 (n = 53) was associated with superior OS compared to low BRCA1 (n = 51) with HR 0.53 (95% CI 0.29-0.96, p = 0.04). However, no differential OS was seen when high BRCA1 group was stratified by PARP1 level. No differential OS was seen when low BRCA1 or low BRCA2 groups were stratified by PARP1 level. Conclusions: In this retrospective analysis of HRDn hrr-ccRCC, high BRCA2 was associated with superior OS which was more pronounced with concomitant low PARP1 . High BRCA1 was also associated with superior OS, but PARP1 levels had no influence. The findings of this study may imply a potential therapeutic value of PARP1 suppression with PARPi by mimicking low PARP1 expression in treating HRDn hrr-ccRCC with BRCA2 overexpression. Further investigation is warranted.

Results of a prospective, single-center phase-II study on modern androgen deprivation therapy followed by cytoreductive radical prostatectomy in men with de novo metastatic hormone-sensitive prostate cancer (mHSPC).

197 Background: Cytoreductive prostatectomy (CRP) may provide oncologic benefit for specific patients. The goal of this study is to evaluate overall survival (OS) and progression-free survival (RFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who underwent CRP after induction therapy with modern combined androgen deprivation therapy. Methods: Between 2018 and 2025 85 consecutive patients with mHSPC were entered into a prospective data registry. All men were diagnosed by multiparametric MRI and MRI-fusion biopsies of the prostate. Metastatic disease was diagnosed with molecular imaging by 68Ga or 18F - PSMA-PET/CT in all patients. Men were started on combined androgen deprivation with the use of LHRH-analogues/antagonists and androgen receptor pathway inhibitors such as abiraterone acetate/prednisone, apalutamide or enzalutamide for 6 months. At 6 months, therapeutic response was evaluated by PSA nadir, mpMRI and PSMA-PET/CT. All patients were treated with CRP and pelvic lymphadenectomy; combined ADT was continued for 2 years. Androgen receptor mutations in the ligand binding domain as well as HSB3D1 mutations were analyzed and correlated with outcome. As in Stampede Arm H OS, CSS and MFS at 3 years were calculated. Results: All patients underwent cRP and pelvic lymph node dissection. Mean age was 63 (45-76) years. Median follow-up was 54.1 (12-90) months. Median initial PSA and median PSA at time of surgery was 110 (25-465) ng/ml and 1.25 (&lt;0.01-5.6) ng/ml, resp. M1a, M1b and M1c were present in 28 (20.9%), 98 (73.1%) and 8 (6.0%) men. Pathohistology revealed pT0 in 4 (4.7%) pts and pT2a-c, pT3a/b in 13 (15.3%) and 68 (80%), resp. pN+ and R1 was observed in 37 (43.5%) patients and 29 (34.1%) pts, resp. No local recurrences were observed. Clavien-Dindo grade III and IV complications occurred in 13 (15.3%) and 2 patients. No, mild (1-2 pads/day) or severe incontinence was observed in 67.7%, 18.2%, and 14.1%, resp. 3-year OS, MFS and CSS was 94.6%, 93.7% and 96.8%, resp. Overall survival was 88.5%, median OS was 84 months, median clinical progression free survival was 72 months. OS was significantly inferior in M1 high volume (61.9% vs 92.8%, p=0.002). A high frequency of L702H (18, 2.2%), W742C (30, 35.3%), 0xH875Y, 0x878A, 40xF877L (40, 47%) und HSD3B1 (23, 27%) whereas no mutations for H875Y and T878A were identified. Conclusions: Based on our data, cRP results in an oncological outcome which is at least comparable to RT. One major benefit of cRP is the low rate of local symptomatic failures. Pathohistology demonstrates persistent locoregional viable disease in 2/3 of patients which underlines the need for an effective local therapy. The role of AR and HSD3B1 mutations for PFS and OS will be presented.

Estimated net benefit of talazoparib (TALA) + enzalutamide (ENZA) for patients (Pts) with mCRPC using a Q-TWiST analysis.

194 Background: In TALAPRO-2, 1L TALA + ENZA showed significantly prolonged OS and rPFS vs placebo (PBO) + ENZA in pts unselected (cohort 1) and selected for homologous recombination repair gene alterations (HRRm cohort 2). Long-term safety and patient-reported outcomes (PRO) were reported previously (data cutoff: Sep 3, 2024). This post hoc analysis evaluated the longitudinal Q-TWiST benefit of TALA + ENZA vs PBO + ENZA in both cohorts by contextualizing the clinical benefit of extended life and delay in disease progression, accounting for impact on QoL due to toxicity and disease progression, and integrating them into a single value using TALAPRO-2 data. Methods: Using restricted mean survival time, mean OS was partitioned into time experiencing toxicity prior to progression (TOX), time without toxicity or symptoms of disease progression (TWiST), and time in state of disease progression assessed by blinded independent central review (REL). Utility value was calculated from individual EQ-5D-5L responses. A threshold analysis was conducted using a hypothetical range of values typically reported in similar analyses and a range of scores estimated from TALAPRO-2 data. Time in each health state was weighted by utilities then summed to estimate Q-TWiST. Mean between-treatment differences for each health state were calculated, and bootstrap methods used to estimate CIs for means and mean differences. Results: In both cohorts, time in TOX was slightly longer with TALA + ENZA vs PBO + ENZA while time spent in TWiST was much longer with TALA + ENZA (Table). In both cohorts, time in REL was shorter with TALA + ENZA (more time spent without progression) vs PBO + ENZA (Table). OS was numerically longer with TALA + ENZA vs PBO + ENZA for both cohorts (Table). Regardless of the range of utility values explored for each health state, Q-TWiST estimates for both cohorts were numerically longer for TALA + ENZA vs PBO + ENZA (mean differences ranged from 3.1 to 11.7 months). Conclusions: In TALAPRO-2, TALA + ENZA showed longer Q-TWiST vs PBO + ENZA, indicating a net benefit in unselected and HRRm mCRPC pts. Those receiving TALA + ENZA had a greater quality-adjusted time (shorter REL) because pts spent more time without progression in TALA + ENZA than PBO + ENZA. The resulting Q-TWiST benefit further supports use of 1L TALA + ENZA in unselected and HRRm selected mCRPC pts. Clinical trial information: NCT03395197 . Cohort 1 (Unselected) Cohort 2 (HRRm only) Mean (95% CI), months TALA + ENZA (n=402) PBO + ENZA (n=403) Mean difference TALA + ENZA (n=200) PBO + ENZA (n=199) Mean difference TOX 2.1 (1.6, 2.6) 1.4 (0.9, 1.9) 0.6 (-0.1, 1.3) 1.8 (1.3, 2.3) 0.6 (0.3, 0.9) 1.2 (0.6, 1.8) TWiST 34.0 (31.4, 36.6) 27.5 (24.8, 30.2) 6.5 (2.8, 10.3) 30.3 (27.2, 33.4) 19.8 (16.8, 22.7) 10.5 (6.2, 14.8) REL 7.0 (3.6, 10.4) 10.5 (7.0, 13.9) -3.4 (-8.3, 1.4) 8.2 (4.2, 12.3) 13.2 (9.3, 17.1) -5.0 (-10.6, 0.6) OS 43.1 (40.8, 45.3) 39.4 (37.1, 41.6) 3.7 (0.6, 6.9) 40.3 (37.7, 43.0) 33.6 (31.0, 36.2) 6.7 (3.0, 10.4)

BR.31 Trial: Adjuvant Durvalumab as the Third Contender in Resected Non–Small Cell Lung Cancer

Harnessing Chain Mobility via Protonation for Tough and Isotropic Hydrogel

ABSTRACT Fabricating hydrogels with isotropically high tensile strength, stretchability, and toughness is crucial for applications in tissue engineering, stretchable bioelectronics and soft robots. However, many toughening strategies, including mechanical training, directional freezing, and solvent exchange, often induce anisotropy or fail to enhance all these metrics simultaneously. Herein, we report a strategy to fabricate ultra‐tough, isotropic poly(vinyl alcohol) (PVA) hydrogels by synergistically modulating polymer chain mobility and physical crosslinking through sequential acidification, freeze‐thawing, and salting‐out. Acidification protonates the hydroxyl groups, suppressing premature interchain hydrogen bonding and promoting network homogenization. Subsequent salting‐out deprotonates the hydroxyl groups to strengthen the interpolymer hydrogen bonds, forming crystalline domains that act as strong, reversible physical crosslinks. The resulting hydrogel achieves a high tensile strength of 29.5 MPa, stretchability of 2683%, and record‐high toughness of 424 MJ m −3 among isotropic hydrogels, even surpassing most anisotropic hydrogels in their reinforced direction. This strategy offers a generalizable platform for engineering tough, isotropic hydrogels with broad potential across bioengineering, additive manufacturing, and soft robotics.

Erratum: Tunable Magnetism and Intrinsic Exchange Bias in Al‐Substituted Terbium Iron Garnet

A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer: The RAD VACCINE MIBC clinical trial.

750 Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are ineligible for cisplatin-based neoadjuvant chemotherapy (CNAC) posing a significant unmet need. Immune checkpoint inhibition (ICI) is an alternative strategy and has been combined with other systemic or local therapies to improve the pathologic complete response (pCR) rate, a surrogate for durable disease control. Stereotactic body radiation therapy (SBRT) at 8 Gy × 3 can induce immune activation and immunogenic cell death, potentially synergizing with ICI as an in situ vaccine generating tumor specific responses. Methods: We conducted a phase II prospective trial in patients with cT2–4aN0M0 MIBC who were ineligible or declined CNAC, evaluating the safety and efficacy of Sasanlimab (PF-06801591; two 300 mg SC doses, 28 days apart) with SBRT to the tumor (8 Gy x 3 fractions at 48-hourly intervals starting on the 2 nd ICI cycle) prior to radical cystectomy (RC). Using Simon’s 2-stage design, 15 patients were enrolled in a safety lead-in, targeting 33 total with the primary endpoint of pCR. Secondary endpoints included adverse events, health-related quality of life (EORTC QLQ C30), and recurrence free survival. Exploratory endpoints assessed germline/somatic sequencing, immunogenic cell death (Serum DAMP/iDAMP ratio), and spatial immune profiling. Results: From March 2022–April 2025, 33 patients were enrolled (predominantly urothelial, 73% ≥ cT3). Four withdrew due to progression after intervention before RC. The trial met its primary endpoint - 44.8% pCR (pT0) rate and 75.9% down-staged to pT0/Ta/T1. Two-year metastasis free survival was 72.2% overall, 92.3% for pCR, and 56.3% for non-pCR patients (p = 0.02). CTCAE grade ≥3 treatment-related AEs occurred in 9.1%: adrenal insufficiency (6.1%) and nephritis (3.0%, resolved with steroids). Grade ≥3 Clavien Dindo 30-day surgical AEs occurred in 13.8% of patients without any mortality. No significant deterioration in EORTC QOL C30 was observed from baseline through ICI therapy, SBRT or RC. Integrated single nuclei RNA sequencing, spatial transcriptomics, and multiplex flow cytometry revealed divergent response mechanisms. One patient subset presented mature tertiary lymphoid structures (TLS) and elevated T follicular helper cell frequency that associated with a germinal center TLS B cell response. Another patient subset exhibited robust dendritic cell expansion associated with an activated CD4+ T cell response. Conclusions: In situ vaccination (SBRT with ICI) achieved a meaningful pCR rate with acceptable toxicity in CNAC ineligible MIBC. These promising clinical and mechanistic findings support this strategy in future trials with other systemic agents to improve pCR with the potential for improved distant control, and organ preservation. Clinical trial information: NCT05241340 .

Correlation without causality between BAP1 loss and the metastasis-associated <i>miR-183/96/182</i> cluster expression in renal cell carcinoma.

531 Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and is characterized by high genetic heterogeneity. Mutations in BRCA-associated protein 1 (BAP1) are associated with more aggressive tumor biology and poorer survival outcomes. MicroRNAs (miRNAs) play a central role in gene regulation and have been investigated as potential biomarkers in various cancer types. Approximately one-third of ccRCC patients present with metastatic disease at diagnosis, while another third develop metastases during disease progression. Due to the lack of valid predictive biomarkers, we analyzed the expression profiles of various miRNA clusters in ccRCC. Methods: miRNA expression profiles were analyzed from 120 ccRCC tumor samples obtained from the University of Texas Southwestern Medical Center as well as from the KIRC-TCGA database. miRNA expression levels were validated using quantitative RT-PCR (qRT-PCR) and correlated with clinicopathological parameters. Additionally, functional analyses were conducted in cell culture and mouse models to investigate the BAP1-mediated regulation of the miR-183/96/182 cluster. Results: A significant upregulation of the miR-183/96/182 cluster was observed in BAP1 -mutated ccRCC tumors compared to PBRM1 -mutated or wild-type tumors. Increased miRNA expression correlated with significantly poorer overall survival and shorter metastasis-free survival. Furthermore, high expression was associated with more aggressive histopathological characteristics, including advanced tumor stage and rhabdoid differentiation. In mouse models, overexpression of miR-182 significantly promoted metastasis. Luciferase reporter assays suggested that BAP1 may influence miRNA cluster expression at the promoter level. However, no direct regulatory mechanism involving BAP1 was identified. Conclusions: Our findings demonstrate that increased expression of the miR-183/96/182 cluster is a poor prognostic marker in ccRCC, associated with reduced overall survival and shorter metastasis-free survival, similarly to the effects of BAP1 loss. Despite the observed correlation, a causal relationship between BAP1 loss and miR-183/96/182 dysregulation could not be established at the molecular level. Nevertheless, the expression of this miRNA cluster may serve as a potential biomarker for risk stratification and therapeutic decision-making in ccRCC patients.

Toripalimab in patients with previously treated advanced upper tract urothelial carcinoma: A subgroup analysis of the phase II POLARIS-03 trial.

817 Background: Toripalimab, a PD-1 inhibitor, is approved in China as second-line therapy for metastatic urothelial carcinoma (mUC). This subgroup analysis evaluated its efficacy and safety in previously treated patients with metastatic upper tract urothelial carcinoma (mUTUC). Methods: In the phase II POLARIS-03 trial, patients with mUTUC received toripalimab (3 mg/kg Q2W) until progression or unacceptable toxicity. Tumor response was assessed by an independent review committee (IRC) per RECIST v1.1. PD-L1 expression and tumor mutational burden (TMB) were assessed by immunohistochemistry and whole-exome sequencing, respectively. Results: Between June 2017 and September 2019, 71 patients were enrolled. As of June 16, 2025, with a median follow-up of 70.5 months, the IRC-assessed objective response rate (ORR) was 26.8% (95% CI, 16.9–38.6), and the disease control rate 46.5%. Median duration of response was 45.0 months; median progression-free survival (PFS) 1.9 months (95% CI, 1.8–4.4) and median overall survival (OS) 11.2 months (95% CI, 7.7–31.2). PD-L1–positive tumors (n = 23) showed higher ORR (34.8% vs 20.5%), longer PFS (2.3 vs 1.8 mo; HR 0.71, 95% CI 0.40–1.28) and similar OS (11.1 vs 11.2 mo; HR 0.99, 95% CI 0.55–1.78). Among 63 patients with WES data, TMB-high tumors (≥10 mut/Mb; n = 14) achieved ORR 42.9% vs 22.4% in TMB-low, median PFS 5.3 vs 1.8 mo (HR 0.51, 95% CI 0.24–1.08; P = 0.079) and median OS 55.3 vs 11.1 mo (HR 0.49, 95% CI 0.22–1.09; P = 0.079). Frequent alterations included TP53 , KMT2D , TERT , CDKN2A/B , and FGFR3 ; responses were notable in SMARCA4 -mutated (75%) and NECTIN4 -amplified (50%) tumors. Treatment-related adverse events occurred in 95.8% of patients, grade ≥3 in 36.6%, with no treatment-related deaths. Conclusions: Toripalimab demonstrated durable efficacy and manageable safety in previously treated mUTUC. TMB-high status and limited metastatic burden were associated with better outcomes, supporting the potential of biomarker-guided immunotherapy in this rare population. Efficacy outcomes by PD-L1 and TMB subgroups in patients with mUTUC. Subgroup ORR (%) mPFS (mo) mOS (mo) Overall (n=71) 26.8 1.9 11.2 PD-L1–positive (n=23) 34.8 2.3 11.1 PD-L1–negative (n=44) 20.5 1.8 11.2 TMB-high (≥10 mut/Mb, n=14) 42.9 5.3 (HR 0.51; P = 0.079) 55.3 (HR 0.49; P = 0.079) TMB-low (&lt;10 mut/Mb, n=49) 22.4 1.8 11.1 PD-L1, programmed death-ligand 1; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; TMB, tumor mutational burden; HR, hazard ratio. Data cutoff: June 16, 2025.

Trends in advanced-stage prostate cancer over the last decade: Analysis from the National Cancer Database (NCDB).

48 Background: The incidence of stage IV prostate cancer in the United States has risen over the past decade, possibly reflecting changes in PSA screening guidelines. Recent studies have also shown increasing implementation of active surveillance in the initial management of intermediate-risk prostate cancer. However, the impact of these practice changes on trends in advanced disease remains unclear. We evaluated temporal trends in diagnosis, treatment, and survival among men with advanced-stage prostate cancer using the NCDB. Methods: The NCDB (2010–2021) was queried for demographics, comorbidities, PSA, Gleason score, stage, and treatment. Multivariable logistic regression assessed associations with stage IV diagnosis over time. Propensity score modeling balanced treatment (Tx) versus no treatment/active surveillance (nTx/AS) groups based on age, race, region, facility type, insurance, income, education, and PSA. Results: The overall NCDB cohort (n= 1424835), which included patients across all stages, comprised 79.8% White, 15.4% Black, and 4.9% Hispanic men. The median age at diagnosis was 66 years, with a median PSA of 4.4 ng/ml. After inverse probability weighting (IPW), overall survival (OS) was modestly improved in the nTx group compared to the Tx group (HR 0.96; 95% CI 0.93–0.99). However, among patients with stage III–IV disease, the nTx group had markedly worse OS compared with those who underwent Tx (HR, 2.45; 95% CI, 2.33–2.58). For men diagnosed with stage IV prostate cancer, multivariable logistic regression showed that the likelihood of presenting with metastatic disease increased significantly over time. The odds of a stage IV diagnosis rose from 2011 (OR 1.03; 95% CI 1.00–1.07) to 2021 (OR 2.48; 95% CI 2.41–2.56; p &lt; 0.001). Subgroup analysis of men with stage IV prostate cancer found that 77.4% were White, 17.4% Black, and 6.5% Hispanic, with a median age of 69 years and PSA 42.8 ng/mL. Those managed with nTx/AS were older (78 vs 69 years), had higher PSAs (95.7 vs 41.2 ng/mL), were less often treated at research and academic centers (26% vs 40%), and more frequently insured by Medicare (71% vs 56%). Conclusions: The proportion of stage IV prostate cancer diagnoses has significantly increased over the past decade. Among men with advanced-stage (III–IV) disease, OS was significantly improved in those who received active treatment, underscoring the importance of assessing factors that influence withholding treatment. Untreated patients were older, had higher PSA, and were less often managed at academic or research hospitals.

Recent Advances in Wireless Smart Contact Lenses for Ophthalmic Health Management and Eye‐Function Enhancement

ABSTRACT Realizing the full potential of ophthalmic health management and eye–machine interaction via continuous physical, chemical, and physiological signal monitoring and eye movement encoding, eye‐wearable devices necessitate more comfort, wireless, and integration. Wireless smart contact lenses (WSCLs), as a non‐invasive wireless multifunctional eye‐wearable platform that fully satisfies the requirements of monitoring ocular information and treating eye diseases, have garnered significant attention. This comprehensive review summarizes the recent progress in the design, fabrication, and application of WSCLs. First, we introduce the design methodology through a systematic analysis of the substrates, multifunctional coils, and capacitive components, with particular emphasis on the interrelationships among material selection, structural optimization, and performance parameters. Subsequently, the circuit configurations of WSCLs are delineated, focusing on the functional contributions of individual components within the circuitry. Following the fabrication processes employed in WSCLs production are analyzed, with specific attention to the processing techniques tailored for diverse material types. Finally, the application prospects of WSCLs in health monitoring, disease treatment, and human–machine interaction are comprehensively summarized, accompanied by a forward‐looking perspective on future developmental trajectories.

Enhancing post-HIFU surveillance: Diagnostic performance of 18F-PSMA PET/CT and mpMRI for local prostate cancer recurrence.

313 Background: Focal therapy (FT), including high-intensity focused ultrasound (HIFU), has emerged as a minimally invasive alternative to radical prostatectomy or radiotherapy for localized prostate cancer. However, post-treatment surveillance remains challenging, as prostate-specific antigen (PSA) kinetics and multiparametric MRI (mpMRI) interpretation are often confounded by residual tissue and post-ablation changes. Although imaging performance following HIFU remains poorly characterized, prostate-specific membrane antigen (PSMA) PET/CT has demonstrated high sensitivity for detecting prostate cancer recurrence. This study aims to perform a head-to-head comparison of PSMA PET/CT and mpMRI in detecting locally recurrent prostate cancer after HIFU. Methods: This single-institution retrospective study included 30 men with biopsy-proven prostate cancer who underwent HIFU followed by both mpMRI and ^18F-piflufolasat PSMA PET/CT prior to confirmatory prostate biopsy. A board-certified abdominal radiologist reviewed imaging blinded to pathology results. Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using biopsy as the reference standard. Proportions were compared using McNemar’s test, and Spearman rank correlation was applied to assess associations between SUVmax, PSA, and ISUP grade groups. Results: Local recurrence was pathologically confirmed in 24 of 30 patients (80%). PSMA PET/CT and mpMRI each detected 18 of 24 biopsy-proven recurrences, corresponding to equivalent sensitivities of 76% (95% CI, 0.60–0.91). Specificity was higher for PSMA PET/CT (83%; 95% CI, 0.44 -- 0.97) than for mpMRI (67%; 95% CI, 0.30 – 0.90). When both modalities were combined, sensitivity increased to 96% (95% CI, 0.80 – 0.99), specificity to 100% (95% CI, 0.61–1.00), and overall accuracy to 96.7% (95% CI, 0.79 –0.98), significantly outperforming either modality alone (p &lt; 0.05). SUVmax demonstrated weak correlation with PSA (ρ = 0.27, p = 0.18) and ISUP grade (ρ = 0.34, p = 0.093). Conclusions: Despite PSMA PET/CT exhibiting higher specificity than mpMRI, both exhibited comparable sensitivity for detecting recurrent prostate cancer following HIFU. Combined imaging significantly improved diagnostic performance, which ultimately minimized false positives and negatives. Dual-modality evaluation may enhance post-treatment surveillance accuracy and guide biopsy decision-making, warranting further validation in larger, prospective cohorts.

Ethnic disparities and variations in testicular germ cell tumours: A retrospective real-world analysis in a single tertiary cancer centre.

595 Background: Testicular germ cell tumours (TGCTs) are the most common malignancy in young men. Ethnic disparities and variations are increasingly recognised as influencing the continuum of clinical care, with a growing emphasis to address the needs of patients from under-represented ethnic backgrounds 1 . Deeper insight into this could validate population trends, identify inequities in presentation and inform strategies to achieve equitable care. However, there remains a paucity of real-world data examining ethnic impact in TGCT, warranting further elucidation. Methods: We retrospectively analysed demographics (age, ethnicity), time to presentation, clinico-pathological characteristics, adverse events on treatment and compliance with follow-up. Inclusion criteria were pts with TGCT diagnosed between January 2021 to December 2023 and managed at Mount Vernon Cancer Centre. Results: We identified 397 pts of which 69.5% (n=276) were White British, 19.1% (n=76) Asian and 11.3% (n=45) Eastern European. Across all ethnicities, incidence peaked in ages 25-45. In Eastern Europeans, 71% were in the 25-45 age range. Asian pts had the youngest age distribution with 21% aged 18-24, while White British pts showed a broader distribution with 29% aged over 45. The histological subtypes across ethnicities showed that Seminoma was the most common, affecting 42.2% of Eastern European, 23.7% of Asian and 56.5% of White British pts. Non-seminomatous germ cell tumours (NSGCT) accounted for 24.4%, 35.5% and 38% of cases respectively. Delayed presentation (&gt;3 months) occurred in 33% of Asian, 26% of Eastern European and 20% of White British pts. The most common reason for delay cited was the belief that symptoms would resolve spontaneously reported by 14% (n=56). Treatment-related adverse events, including thrombocytopaenia and neutropaenia, were analysed for ethnic variation. Retroperitoneal lymph node dissection was performed in 23 patients (6%) whilst stem cell transplantation was undertaken in 19 patients (4.8%) with no significant variation between ethnic groups. Compliance with follow-up was lowest among Asian (48%) and Eastern European (68%) pts, compared with 89% the White British cohort. Conclusions: Ethnic disparities were observed among pts with TGCT, reflected in delayed presentation and poorer compliance with follow-up among Asian and Eastern European groups. In tandem, ethnic variation was evident in disease characteristics - Asian pts presented at a younger age with a higher relative proportion of NSGCT. These findings align with emerging evidence of biological and epidemiological differences, with a rising incidence of NSGCT among Asian pts. This highlights the need for targeted interventions within under-represented populations. Further research is needed to identify factors contributing to the rising incidence of NSGCT observed in Asian pts.

CARPET trial: A phase II trial evaluating trastuzumab deruxtecan in metastatic castration-resistant prostate cancer.

TPS303 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge, as standard therapies, including androgen receptor pathway inhibitors, such as abiraterone and enzalutamide, yield limited responses. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 60–70% of mCRPC cases but is often under diagnosed because it occurs without gene amplification or mutation and is not detected by next-generation sequencing. Immunohistochemistry (IHC) is more appropriate for identifying HER2 expressing tumors. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, has shown efficacy in other HER2-positive (IHC 3+) solid tumors and has received tumor-agnostic approval from the FDA; however, its role in mCRPC is unclear. Previous clinical trials, including DESTINY-PanTumor02, have excluded prostate cancer, though recent case reports show promising responses in HER2+ mCRPC (PMID: 39496182, 40638235). Methods: CaRPET (NCT06610825) is a Phase II, open-label, single-arm, multi-center clinical trial evaluating the efficacy and safety of T-DXd in patients with HER2-positive (IHC 1+, 2+, or 3+) mCRPC who progressed on androgen deprivation therapy (ADT), novel hormonal agents, and taxane-based chemotherapy or were ineligible for taxanes. Eligible patients must have pathologically confirmed prostate adenocarcinoma, mCRPC with serum testosterone &lt;50 ng/dL, documented progression after novel anti-androgens and taxanes (or taxane ineligibility), ongoing ADT, ECOG performance status 0–1, left ventricle ejection fraction ≥50%, and adequate organ function. HER2 status is determined using a prostate-cancer-specific IHC scoring system developed in our center accounting for intra- and intertumoral heterogeneity of HER2 expression. Exclusion criteria include prior HER2-targeted therapy, significant coronary vascular disease, and history of interstitial lung disease or pneumonitis requiring steroids. Patients will receive 5.4 mg/kg T-DXd intravenously every 3 weeks for up to 2 years. The primary endpoint is objective response rate to T-DXd, with secondary endpoints including safety, progression-free survival, overall survival, and quality of life. Exploratory objectives include assessment of HER3 expression and development of liquid biopsy-based assays. Five of the planned 60 patients have been enrolled. Clinical trial information: NCT06610825 .

A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations.

161 Background: Progression to mCRPC is driven by numerous mechanisms including emergence of AR LBD mutations that reactivate the AR pathway and blunt response to hormone therapies including novel hormonal agents (NHA). MRT-2359, an orally bioavailable MGD that selectively degrades the translation termination factor GSPT1, reduces cellular abundance of many oncogenic proteins including AR, MYC and Cyclin D1. This reduction is associated with robust anti-tumor activity across multiple preclinical models of mCRPC both as a monotherapy or in combination with enzalutamide. Methods: MRT-2359 has been tested in an open-label study to evaluate safety, dose-limiting toxicities (DLTs), pharmacokinetic and pharmacodynamic, and early signals of clinical efficacy (RECIST 1.1, PCWG3). In the monotherapy dose escalation portion of the study, 59 patients with selected tumor types (NSCLC, SCLC, NE tumors) received MRT-2359 orally once daily at doses from 0.5 mg to 2 mg per day in a 5 days on/9 days off (5/9) or a 21 days on/7 days off (21/7) schedule. Once the recommended phase 2 dose of 0.5 mg 21/7 was established, evaluation of MRT-2359 in combination with oral enzalutamide at 160 mg daily was initiated in heavily pretreated mCRPC with RECIST 1.1 measurable disease. Results: As of 22 SEP 25, 18 heavily pretreated patients have been treated with MRT-2359 and enzalutamide including three patients with AR LBD mutations. One (6%) patient had a DLT (grade 3 stomatitis associated with pain). Most frequent adverse events were manageable, grade 1 or 2, and included fatigue (6, 33%), diarrhea (5, 28%) and nausea (5, 28%). Preliminary signals of anticancer activity have been observed, including in all 3 patients with AR LBD mutations, who demonstrated 2 (67%) partial responses (PRs; -62% tumor reduction maintained for 10 cycles in a patient with AR H875Y post NHA, docetaxel and lutetium-177 PSMA; -61% ongoing for 3+ cycles in a patient with AR H875Y post NHA including enzalutamide, docetaxel and lutetium-177 PSMA ) and 1 durable stable disease (SD; -20% ongoing for 8+ cycles in a patient with AR L702H post NHA including enzalutamide, docetaxel and PSMA T-cell engager). Also, all 3 (100%) patients had ≥ PSA50 response (PSA90 in 2 patients with PRs and PSA50 in the patient with SD). Remaining 15 patients without AR LBD mutations had 5 SDs (maintained for 2, 5, 6, 6+, and 8+ cycles, respectively, and no PSA50 responses). The study continues to enroll up to 29 patients with a focus on enrichment for patients with AR LBD mutations, and updated data will be presented at the meeting. Conclusions: MRT-2359, an orally bioavailable, highly selective GSPT1 MGD was safe with encouraging preliminary activity (PR rate 67%, ≥ PSA50 rate 100%) in mCRPC with AR LBD mutations. Clinical trial information: NCT05546268 .

Two‐Dimensional Crystalline Alkyne‐Rich Conjugated Carbonaceous Framework for Extremely Fast‐Charging Lithium‐Ion Batteries

ABSTRACT The development of high‐quality conjugated carbonaceous materials with fast mass transport kinetics is important for fast‐charging lithium (Li)‐ion batteries (LIBs). Here, we report a “molecular locking‐weaving” strategy to synthesize 2D alkyne‐rich Li carboxylate (LC) conjugated carbonaceous framework (LC‐ACF). Large‐area ultrathin LC‐ACF possesses high crystallinity, ordered stacking, and intrinsic mesoporous structure, creating well‐aligned and LC‐bridged fast Li‐ion diffusion channels. The incorporation of LC groups significantly changes the electronic structure of the conjugated framework to improve surface charge and electronic conductivity, endowing LC‐ACF with promoted electrokinetic effects to boost Li‐ion transport kinetics. Consequently, LC‐ACF shows exceptional fast‐charging capability, achieving high capacity (360.2 mA h g −1 , corresponding to 89.6% of the capacity at 0.2 A g −1 delivered in 1 min) and negligible capacity decay (30 000 cycles) at a high current density of 20 A g −1 . LC‐ACF||LiNi 0.8 Co 0.1 Mn 0.1 O 2 (NCM811) full cells deliver an attractive capacity of 118.4 mA h g −1 (achieving 62.3% state‐of‐charge within 1.5 min) and a capacity retention of 90.3% after 3000 cycles at an extremely high rate of 20 C (1 C = 210 mA g −1 ). LC‐ACF||NCM811 pouch cells with outstanding fast‐charging performance were also achieved.