Browse Articles

IDeate-Prostate01: A phase 3, randomized, open-label study of ifinatamab deruxtecan versus docetaxel in participants with previously treated metastatic castration-resistant prostate cancer.

TPS294 Background: Standard treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT) plus systemic androgen receptor pathway inhibitors (ARPIs), taxanes, radiopharmaceuticals, or targeted therapies. Despite these treatment options, disease progression is inevitable. Treatments that improve upon the outcomes shown with currently available options are urgently needed. B7-H3, a type I transmembrane protein, is overexpressed in prostate cancer and associated with poor prognosis and unresponsiveness to certain treatments. Ifinatamab deruxtecan (I-DXd; MK-2400/DS-7300a) is a B7-H3-directed antibody-drug-conjugate, with a plasma-stable tetrapeptide-based cleavable linker and the potent topoisomerase I inhibitor payload DXd. In preclinical models, I-DXd exerted potent antitumor activity in B7-H3-expressing tumors and acceptable pharmacokinetics and safety. Preliminary results from the first-in-human phase 1/2 IDeate-PanTumor01 study of I-DXd demonstrated antitumor activity and manageable safety in multiple solid tumors, including heavily pretreated mCRPC. Methods: IDeate-Prostate01 is a phase 3, randomized, open-label study. Eligible participants must have: histologically or cytologically confirmed mCRPC; documented prostate-specific antigen (PSA) or radiologic disease progression; and have received 1 or 2 previous ARPIs for metastatic or nonmetastatic hormone-sensitive prostate cancer or CRPC. Prior taxane chemotherapy for mCRPC is not allowed. Approximately 1,440 participants will be randomized 1:1 (~720 participants per treatment arm) to I-DXd at 12 mg/kg intravenously (IV), once every 3 weeks (q3w), or docetaxel at 75 mg/m 2 IV, q3w (with prednisone/prednisolone at 10 mg/day orally, or per label). Randomization will be stratified by metastatic site (liver vs. bone only vs. other), geographic region (Region 1 [Australia, European Union, Israel, Japan, South Korea, Switzerland, United Kingdom, and United States of America] vs. rest of the world), B7-H3 expression (high vs. low vs. unevaluable), and prior prostate-specific membrane antigen-targeted radionuclide therapy (yes vs. no). Dual primary end points are overall survival and radiographic progression-free survival. Secondary end points include time to first subsequent therapy, objective response, duration of response, time to pain progression, time to PSA progression, PSA response, time to first symptomatic skeletal-related event, and safety and tolerability. Recruitment is ongoing. Previously presented at 26th Annual Meeting of the Society of Urologic Oncology; December 2–5, 2025; Phoenix, AZ. Clinical trial information: NCT06925737 .

OMAHA-003: Phase 3 trial of CYP11A1 inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants (pts) with metastatic castration-resistant prostate cancer (mCRPC) after ARPI and taxane-based chemotherapy.

TPS298 Background: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on AR-directed therapies. In patients with mCRPC, activation of AR ligand binding domain somatic point mutations (AR-LBDm) is a common mechanism of resistance to AR-directed therapies. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat can suppress the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway, especially in populations with AR-LBDm. In the phase 1/2 CYPIDES trial, opevesostat showed antitumor activity in pts with heavily pretreated mCRPC, and in those with AR-LBDm. The randomized, open-label, phase 3 OMAHA-003 trial (NCT06136624) is evaluating the efficacy and safety of opevesostat versus ARPI switch in pts with mCRPC after ARPI and taxane-based chemotherapy. Methods: Eligible pts have mCRPC that progressed on androgen deprivation therapy ≤6 mo of screening and during or after treatment with 1 ARPI or 1-2 taxane-based chemotherapies. Pts will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg + fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) until radiographic disease progression, unacceptable toxicity, investigator’s decision, or consent withdrawal. Stratification factors are measurable disease (yes vs no), AR-LBDm status (positive vs negative), and prior cabazitaxel treatment (yes vs no). The protocol was amended to use overall survival as the primary end point in pts with AR-LBDm-positive and -negative disease, separately, and radiographic progression-free survival per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) as a secondary end point. Other secondary end points include objective response rate, and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to initiation of first subsequent anticancer therapy or death, time to pain progression, time to PSA progression, time to first symptomatic skeletal-related event, and safety. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Planned enrollment was amended to approximately 1310 pts (460 AR-LBDm-positive and 850 AR-LBDm-negative). 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: NCT06136624 .

Harnessing caregiver support to improve shared decision-making in metastatic prostate cancer treatment: A US-based quantitative survey.

131 Background: Caregivers play a pivotal role for many patients with prostate cancer (PC), providing emotional and physical support and guiding medical management. A quantitative survey was conducted to assess the unmet needs of caregivers for patients with PC in the USA. Methods: A 30-minute online survey was administered anonymously to capture caregivers’ characteristics, caregiving roles/responsibilities, and emotional experiences. Caregivers for patients with non-metastatic and metastatic PC were recruited via direct outreach and social media in collaboration with a patient advocacy group. All participants provided informed consent. Results were aggregated in accordance with anonymity and confidentiality codes of conduct. Only non-hired caregivers of patients with metastatic PC were included in this analysis. Results: Between June and July 2024, 230 caregivers of patients with metastatic PC completed the survey. Caregivers were mostly White (53%), male (54%), the primary caregiver (77%), and lived with the patient (65%). 51% of caregivers responding to the survey were spouses/significant others (32%) or children (19%). Caregivers reported being significantly involved in the patients’ journey, with 82% attending doctors’ appointments, 77% providing emotional support, 76% participating in treatment decisions, and 73% helping with medication management. The level of involvement in some caregiver-reported roles/responsibilities differed by male and female caregivers. For the 188 caregivers that reported going to doctors’ appointments with patients, 69% raised health concerns the patient would not, 67% would ask questions the patient forgot to ask, and 49% would initiate topics the patient felt uncomfortable to raise. Overall, 23% of caregivers did not feel adequately supported with resources to manage patients’ PC treatments; this varied by race with 31% of Black/African American caregivers, 24% of White caregivers, and 11% of Asian or Pacific Islander caregivers feeling inadequately supported. Overall, 58% of caregivers were concerned that the right resources to help their patient might not exist; this varied by race with American Indian/Alaska Native caregivers feeling most concerned (82%) and White caregivers feeling least concerned (50%). Conclusions: Caregivers are essential partners in the treatment journeys of patients with metastatic PC, offering crucial insights into patients’ well-being and practical support to help ensure adherence to the prescribed treatment plan and ongoing whole-person care. However, caregivers express significant concerns regarding support and resources, with perceived differences varying by race/ethnicity. These research findings underscore the need for improved resource accessibility tailored to diverse caregivers participating in informed decision making with health care providers.

Cu ⁺ ‐Driven Ferroionic Structure and Pressure‐Tunable Magnetism in Layered Thiophosphate CuVP ₂ S ₆

ABSTRACT Two‐dimensional (2D) van der Waals (vdW) magnets offer a versatile platform to explore fundamental physics and low‐dimensional functionalities. Metal thiophosphates (MTPs) with mobile Cu + ions exhibit a ferroionic state, where polarization arises from ionic redistribution among multiple nearly degenerate sites. CuVP 2 S 6 uniquely combines intrinsic ferromagnetism from the V sublattice with Cu + ‐driven ferroionic configurational freedom, enabling direct exploration of how ionic dynamics influence magnetic interactions. Herein, high‐quality CuVP 2 S 6 single crystals are synthesized, and their structural and physical properties are systematically investigated. Temperature‐dependent neutron diffraction elucidates a ferroionic structure with dynamic distributions of copper ions across multiple crystallographic sites. The versatile occupations are driven by local symmetry‐controlled orbital interactions between copper ions and surrounding ligands through a second‐order Jahn–Teller mechanism. Magnetic measurements identify a ferromagnetic (FM) transition below 3.3 K. The pressure‐controlled magnetocrystalline anisotropy and interlayer exchange interactions mediated by Cu + migration are demonstrated, boosting the Curie temperature remarkably by over 60% and inducing a soft‐to‐hard FM transition unparalleled within the MTP family. These results demonstrate that ionic configurational freedom provides an efficient route to control magnetism, opening new possibilities for spintronic applications.

Ligand Engineering of Ultrasmall CsPbI ₃ Quantum Dots via In Situ S _N 2 Substitution Enables Bright Rec. 2020 Pure‐Red Perovskite LEDs with Exceptional Current Efficiency

ABSTRACT Ultrasmall‐sized cesium lead iodide (CsPbI 3 ) quantum dots (QDs) are promising candidates for achieving spectrally stable pure‐red perovskite light‐emitting diodes (PeLEDs) meeting Rec. 2020 standards. However, the corresponding devices hardly achieve satisfactory external quantum efficiency (EQE), current efficiency (CE), and luminance simultaneously because of the use of largely excessive insulating long‐chain ligands and additional difficulties in the defect control of ultrasmall CsPbI 3 QDs. Herein, we develop an alkyl iodide‐assisted ligand modulation strategy for CsPbI 3 QDs toward high‐efficiency and bright pure‐red PeLEDs. We elucidate an in‐situ nucleophilic bimolecular (S N 2) substitution reaction between the oleylamine and additionally incorporated short‐chain 1‐iodooctane (IO) molecules during the materials synthesis. The reaction‐generated hydriodic acid (HI) induces non‐destructive surface etching of QDs, enabling exceptional luminescent properties of the strongly confined products. In addition, the S N 2 reaction‐derived secondary amine strongly adsorbs at the surface of QDs, which stabilizes the products with a reduced ligand density, simultaneously enhancing photoluminescence stability and electrical properties of the assembled emissive layers. The resultant devices emitting at 632 nm demonstrate a peak EQE of 21.56%, an impressive luminance of 13,132 cd m −2 , and an exceptional CE of 20.73 cd A −1 , which outperforms state‐of‐the‐art Rec. 2020 pure‐red PeLEDs utilizing ultrasmall‐sized colloidal CsPbI 3 QDs.

Contribution of organic anion transporting polypeptides to bile acid uptake in the Caco-2 cell monolayer and gastrointestinal tract

[ ¹⁷⁷ Lu]Lu-PSMA-617 ( ¹⁷⁷ Lu-PSMA-617) in combination with an androgen receptor pathway inhibitor (ARPI) versus ¹⁷⁷ Lu-PSMA-617 alone for the treatment of metastatic castration-resistant prostate cancer (mCRPC): A real-world prostate cancer disease observation (PRECISION) data platform analysis.

78 Background: 177 Lu-PSMA-617 is currently under investigation in combination with an ARPI in those with metastatic hormone-sensitive prostate cancer (PSMAddition trial: NCT04720157). This observational study was performed to assess the effectiveness of 177 Lu-PSMA-617 in combination with an ARPI in patients with mCRPC in the real-world setting. Methods: This was a retrospective cohort study of adults with mCRPC in the PRECISION data platform, a comprehensive database of prostate cancer patients compiled from diverse clinical settings in the US. Patients who received 177 Lu-PSMA-617 during March 23, 2022–June 27, 2025 were identified, among whom two cohorts were selected for inclusion: those who had evidence of ARPI use (apalutamide, darolutamide, abiraterone, or enzalutamide) at any time during 177 Lu-PSMA-617 treatment (concomitant ARPI cohort), and those who had no other treatment for mCRPC during 177 Lu-PSMA-617 treatment (no concomitant therapy cohort). The index date was initiation of 177 Lu-PSMA-617. Patient characteristics and prostate-specific antigen (PSA) responses were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was estimated using Kaplan–Meier analysis. Results: A total of 1,880 patients treated with 177 Lu-PSMA-617 were identified, 140 in the concomitant ARPI cohort and 1,740 in the no concomitant therapy cohort. The median age was 74 years. Demographic characteristics were balanced between the groups, except that median baseline PSA was lower in the concomitant ARPI cohort when compared with patients in the no concomitant therapy cohort (18 ng/mL vs. 32 ng/mL). Before 177 Lu-PSMA-617 initiation, 94.3% and 73.6% of patients in the concomitant ARPI and 80.9% and 56.7% in the no concomitant therapy cohort had received ≥1 prior ARPI and ≥1 prior taxane, respectively. PSA response rates were broadly comparable between cohorts. The median (95% confidence interval) PFS was 14.7 (11.7–21.3) months among patients in the concomitant ARPI cohort vs 12.5 (11.5–13.6) months in the no concomitant therapy cohort. Ongoing follow-up aims to evaluate the impact of combining ARPI with 177 Lu-PSMA-617 on long-term clinical outcomes, including overall survival. Conclusions: The results of this study demonstrate that 177 Lu-PSMA-617 delivers clinical benefits inpatients with mCRPC with or without ARPI; however, addition of an ARPI may potentially improve these benefits. Prospective randomized controlled studies are needed to confirm this.

Phase 1 dose escalation and expansion of AB001 in patients with metastatic castration resistant prostate cancer (mCRPC): The ARTISAN trial.

TPS289 Background: Treatment options for patients with mCRPC have been improved by radioligand therapies such as beta-emitting 177 Lu-PSMA-617. However, prostate cancer remains the fifth leading cause of cancer mortality, with the lives of more than 250,000 men shorted by mCRPC each year. New therapies with differentiated mechanisms of action that could extend survival while retaining quality of life are needed. Alpha-particle emitting radioisotopes offer significant advantages compared with beta-emitters. Alpha particles have higher atomic mass (4), charge (2+), and linear energy transfer. Furthermore, the short particle range (<100 µm) is expected to minimize damage to surrounding normal tissue. 212 Pb is attractive for alpha radiotherapeutics due to its short 10.6 hour half-life which fits well with the rapid tumor uptake achievable with PSMA-targeting small molecules. The ARTISAN trial is a Dose Escalation Expansion study of AB001, a 212 Pb-labelled, PSMA-targeted small molecule alpha-radiotherapeutic. Methods: This is a Phase 1, open-label, multicentre study in patients with advanced PSMA-positive mCRPC. Participants must have received previous treatment with at least one androgen receptor pathway inhibitor and at least one prior taxane. The study will evaluate the safety and tolerability of AB001 in two populations: participants with mCRPC who have not received prior treatment with 177 Lu-PSMA radioligand therapy and participants who have been treated with at least one dose 177 Lu-PSMA therapy. Dose Escalation will identify the recommended dose and schedule for each population for Dose Expansion. A Time-to-Event Bayesian Optimal Interval (TITE BOIN) design is employed to allow dosage optimization by both escalation of the 212 Pb radioactive dose (MBq) and assessment of optimal cycle duration. Dose Expansion will further evaluate safety, tolerability, and preliminary activity of AB001 in the two populations. Assessment of AB001 biodistribution and dosimetry estimation by 212 Pb SPECT imaging will be used in addition with radioactive and ligand PK evaluation to enable efficient dosage optimization of AB001 in this Phase 1 trial. Clinical trial information: NCT07214961 / EU CT 2024-516523-14.

Outcomes of radium-223 therapy in combination with enzalutamide for metastatic castration-resistant prostate cancer: A multicenter retrospective analysis in Japan.

66 Background: The PEACE-3 trial demonstrated improved radiographic progression-free survival (rPFS) with radium-223 (Ra-223) plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (mCRPC). This study evaluated real-world outcomes and safety of the combination in a multicenter Japanese cohort. Methods: We retrospectively analyzed patients with metastatic castration-resistant prostate cancer (mCRPC) who received radium-223 (Ra-223) between January 2020 and December 2023 at 84 Japanese institutions. Eligible cases included those treated with Ra-223 plus androgen-deprivation therapy (ADT) with enzalutamide (ADT+ENZ) or Ra-223 with ADT alone (ADT-only). Patients receiving other systemic therapies were excluded. Propensity score matching balanced baseline factors. Primary endpoints were time to progression and overall survival (OS); secondary endpoints were 6-cycle completion, pain non-deterioration rate (PNDR), radiologic response, symptomatic skeletal events (SSE), and safety. Results: A total of 386 patients were analyzed after matching. The median age was 74 years; 82% had ECOG PS 0–1, and 74% had ≤EOD2 disease. Prior ARSI exposure during the CRPC phase was higher in the ADT+ENZ group (111.4% vs. 90.2%; multiple responses allowed), whereas prior chemotherapy was less common (30.2% vs. 51.5%). Over 70% of patients in both groups completed at least 6 cycles. The median time to progression was longer with ADT+ENZ (6 vs. 5 months, p=0.01), and there were fewer PSA progressions (71.1% vs. 81.5%, p=0.03). No significant differences were observed in radiologic response, PNDR, or new pain. Grade ≥3 toxicities were uncommon (anemia 6.1%, neutropenia 5.2%). In the ADT+ENZ group, the absence of bone-modifying agents was linked to a higher risk of SSE (RR 3.09, p=0.0015). OS and cancer-specific survival were similar (32 vs. 36; 35 vs. 37 months). Conclusions: This nationwide retrospective analysis found that Ra-223 combined with enzalutamide improved PFS with comparable safety and no OS difference. These findings support PEACE-3 and underscore the role of bone-modifying agents in reducing SSE risk. Progression-free survival and reasons for progression after Ra-223 initiation. Variable ADT+Enzalutamide (n = 192) ADT monotherapy (n = 194) p-value Progression status at data cut-off  Progressed 149/192 (77.6%) 157/194 (80.9%) χ² p=0.42  Not progressed (censored at cut-off) 43/192 (23.4%) 37/194 (19.1%) Progression-free survival from Ra-223 initiation (months) 6 (5 - 10) 5 (4 - 8) 0.01 Reasons for PD determination after Ra-223 initiation*  Radiographic progression 74/149 (49.7%) 81/157 (51.6%) 0.73  PSA elevation 106/149 (71.1%) 128/157 (81.5%) 0.03  Onset or worsening of clinical symptoms 30/149 (20.1%) 32/157 (20.4%) 0.96  Other 6/149 (4.0%) 10/157 (6.4%) 0.44 *Multiple responses allowed.

CdS/ZnSe Quantum Dot Assembled Clusters vs. Dot‐on‐Rod: Charge Separation and Utilization for Efficient Photocatalytic NO ₃ ⁻ ‐to‐NH ₃ Conversion

ABSTRACT Photocatalytic NO 3 − reduction with semiconductor nanocrystals has promising prospects for ammonia (NH 3 ) synthesis, which typically relies on broad light absorption, efficient charge separation, and high surface reactivity. Represented herein is, however, contrary to the widely accepted facts that long‐lived charge separation favors higher photocatalytic efficiency, i.e. ZnSe@CdS dot‐on‐rods with better charge separation unexpectedly yield NH 3 with much lower efficiency (4.10 mmol h −1 g cat. −1 ) than CdS/ZnSe assembled clusters (53.85 mmol h −1 g cat. −1 ). Mechanistic studies reveal that the intimate binding of ZnSe on CdS in dot‐on‐rods accelerates charge separation by 3 orders of magnitude, while the electron transfer from CdS to NO 3 − and the hole transfer from ZnSe to 1‐phenylethanol proceed at 10 8 s −1 . As a result, the comparable charge transfer rates in the assembled cluster of ZnSe and CdS quantum dots enable effective utilization of separated electrons and holes timely for photocatalytic NO 3 − ‐to‐NH 3 reaction, while the imbalance of fast charge separation and slow utilization of electrons and holes in dot‐on‐rods leads to inferior NH 3 yield. The kinetic balance for photocatalytic NO 3 − ‐to‐NH 3 reaction offers valuable guidance for orchestrating multi‐step photochemical events to realize elegant transformations.

A GluN2B disease-associated variant promotes the degradation of NMDA receptors via autophagy

Bridging global gaps: Expanding GU oncology education through iECHO telementoring.

592 Background: As treatments within genitourinary (GU) oncology become increasingly complex, new educational methods are essential to keep practitioners informed. This report examines the worldwide impact and engagement levels of a dedicated telementoring initiative designed for GU oncology professionals. Methods: Program data were reviewed from November 1, 2024, to August 17, 2025, covering a single GU curriculum delivered over 24 sessions totaling 30 hours. Key metrics assessed included participant demographics, geographic reach, professional roles, and interactions with educational materials. Results: The program enrolled 242 individuals, resulting in 286 session attendances and 90 additional ad-hoc participations. There were 85 unique user logins to the learning platform. The initiative achieved broad international engagement, especially from Latin American countries such as Argentina, Paraguay, Ecuador, and Uruguay. Physicians comprised the largest participant group. Sessions with the highest attendance addressed stem cell transplantation for germ cell tumors and prostate cancer, while urothelial and penile cancers were secondary topics. Analysis showed that reading materials were the most frequently accessed resources. Conclusions: This telementoring approach effectively shared specialized GU oncology expertise with a diverse and international audience. The strong participation and interaction rates underline the model’s scalability and value for ongoing medical education.

Guarding the kidneys in the immunotherapy era: Pooled incidence and severity of immune-related nephritis in renal-cell carcinoma treated with PD-1/PD-L1–based regimens.

489 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have redefined renal-cell carcinoma (RCC) management. However, immune-related nephritis (IRN) remains an uncommon but clinically relevant toxicity that can lead to treatment interruption or irreversible renal injury. The true pooled incidence and severity of IRN across modern phase III RCC trials have not been systematically quantified. Methods: A systematic review and single-arm random-effects meta-analysis was performed according to PRISMA guidelines. Eligible studies included phase III RCC trials evaluating PD-1/PD-L1–based immunotherapy alone or combined with VEGF-targeted therapy. Any-grade and grade ≥3 IRN data were extracted from peer-reviewed publications and supplementary materials ( NEJM , Lancet ). Pooled incidence estimates were calculated using a random-effects model with the Paule–Mandel estimator for between-study variance (τ²) and Hartung–Knapp adjustment for confidence intervals. Statistical heterogeneity was quantified using I². Results: Four trials (KEYNOTE-426, CLEAR, CheckMate-9ER, CheckMate-214) encompassing 1,535 patients in experimental arms were included. Any-grade IRN occurred in 1.1% (95% CI 0.7–1.7; I² = 34%), and grade ≥3 IRN in 0.4% (95% CI 0.2–0.7; I² = 29%). Incidence was highest with ICI + VEGF-TKI combinations (1.5–1.7%) and lowest with dual-ICI therapy (~0.8%). The estimated τ² was 0.00016, indicating modest between-study variance. No dialysis-requiring events were reported, and > 85% of cases resolved with corticosteroids. Conclusions: Immune-related nephritis occurs in approximately 1% of RCC patients receiving PD-1/PD-L1–based therapy and is rarely severe. Most events are grade 1–2, steroid-responsive, and reversible. These data provide the first pooled benchmark for renal immune toxicity in RCC and support routine renal monitoring from treatment initiation. Findings are particularly relevant to older adults, who represent the majority of RCC patients and often have reduced baseline renal reserve.

Prognostic value of baseline serum IgG in metastatic clear cell renal cell carcinoma treated with first-line IO–TKI therapy.

563 Background: Serum immunoglobulins (IgG, IgA, and IgM) may reflect systemic immune status and potentially influence the efficacy of IO–TKI therapy. This study aimed to investigate the prognostic value of baseline serum immunoglobulin levels in patients with metastatic renal cell carcinoma (mRCC) receiving first-line IO–TKI therapy. Methods: A total of 121 mRCC patients treated with first-line IO–TKI therapy between August 2019 and April 2025 were retrospectively analyzed. Baseline serum IgG (8.6–17.4 g/L), IgA (1.0–4.2 g/L), and IgM (0.3–2.2 g/L) levels were categorized as “elevated” or “normal” based on the upper limit of the reference range. Kaplan–Meier analysis was used to assess associations with progression-free survival (PFS) and overall survival (OS). Spearman correlation was applied to evaluate the relationship between IgG and IMDC risk score. Results: The median follow-up was 31.0 months (95% CI, 26.0–41.0). The median PFS was 18.0 months (95% CI, 16.0–39.0), while the median OS was not reached (95% CI, 44.0–NA). Elevated baseline IgG levels were significantly associated with inferior OS (p = 0.037), whereas IgA and IgM showed no significant association with OS or PFS (all p > 0.05). No correlation was observed between IgG levels and IMDC score (ρ= 0.07, p = 0.44). Conclusions: Baseline serum IgG level was independent of IMDC risk classification and showed a significant association with overall survival in patients with metastatic clear cell renal cell carcinoma receiving first-line IO–TKI therapy. Elevated baseline IgG identified a subgroup with unfavorable prognosis and may serve as a readily accessible prognostic biomarker deserving validation in prospective studies.

Proton Provision‐Conversion‐Spillover Cascade Programming on Dual Supported Pt Atoms for Robust Hydrogen Production

ABSTRACT Rational proton engineering offers a powerful strategy for enhancing the hydrogen evolution reaction (HER) performance of single‐atom catalysts (SACs). Notably, achieving concerted proton management across multiple reaction steps presents a highly efficient approach, yet it remains more challenging to implement than single‐step regulation. Here, we propose a domino‐type proton provision‐conversion‐spillover programming for Pt SACs in acidic HER, enabled by ultrathin porous nitrogen‐doped carbon (main 1–2 atomic layers, sub‐1 nm) encapsulated TiN nanowires with tips as dual‐support tip‐platform (Pt‐NC 1 @TiN NWs). Experimental and theoretical results demonstrate that this platform triggers tip‐distance‐spillover domino effects to drive a proton cascade throughout HER. Specifically, NC 1 @TiN nanotips induce tip‐enhanced effect that promotes interfacial proton accessibility. Concurrently, the short‐distance Pt/TiN vertical coupling optimizes electronic modulation of unsaturated Pt‐N 2 sites to enhance their intrinsic activity. Exposed TiN sites function as hydrogen spillover centers to facilitate H 2 desorption. Consequently, Pt‐NC 1 @TiN NWs achieve a superior Pt mass activity of 153.5 A/mg Pt @‐100 mV, surpassing Pt/C by two orders of magnitude. Notably, it reaches 2 A/cm 2 at low cell voltage of 1.75 V and sustains stable operation at 1 A/cm 2 for 1200 h in proton exchange membrane water electrolyzer (PEMWE). This work indicates the potential of harnessing multi‐step domino processes for advanced catalyst design.

Engineering an orthogonal ubiquitin transfer cascade with RING E3 RNF38 by phage display to reveal its regulation of nuclear transport

Four-year outcomes of a genetic-based screening protocol for prostate cancer: Unveiling the Italian paradox.

323 Background: A positive family history is a well-established risk factor for prostate cancer (PCa), making the identification of individuals with inherited susceptibility particularly relevant. The detection of germline pathogenic variants (PVs) in DNA-repair genes (DRGs) further supports the implementation of targeted screening strategies. The present study aimed to investigate the performance and adherence of a personalized screening protocol designed for this high-risk population, integrating both the Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI). Methods: This ongoing prospective study, supported by AIRC-(ID-IG-25027-V1.3), is based on the concept of a dedicated PCa screening protocol. It was conducted at a tertiary referral center in collaboration with multiple departments. The study enrolled men aged 35–69 years carrying documented PVs in DRGs who provided informed consent to participate in the screening program. Probands were classified into two groups: (1) male relatives of women harboring DRG PVs associated with breast or ovarian cancer, and (2) male relatives of men with DRG PVs diagnosed with high-grade PCa (ISUP grade group >2). Participants underwent annual assessments including PSA testing, PHI measurement, DRE, and mpMRI, according to individual risk stratification (PHI <20, 20–40, >40). Results: Between 2021 and 2025, a total of 129 patients were enrolled, with a median age of 52 years (IQR 47–64). Among them, 118 belonged to the group 1 and 11 to the group 2. The most prevalent PVs was BRCA2 (56.0%), followed by BRCA1 (21.6%), ATM (3.4%), PMS2 (2.6%), MSH2 (2.6%), MLH1 (2.6%), PALB2 (2.6%), and MSH6 (1.7%). Screening compliance was high: 95% of participants completed the T1 visit, 86% completed T2, 90% completed T3, and 100% completed T4. Among patients with PHI values between 20 and 40, 85% underwent mpMRI. Three of these showed a positive mpMRI and proceeded to biopsy, which was negative two cases and positive in one. An additional 3 patients underwent biopsy due to clinical suspicion, all yielding negative results. Among those with PHI >40, 75.5% underwent mpMRI followed by biopsy according to protocol, all of which were negative for prostate cancer. At the fourth year of follow-up, the screening program detected its first case of PCa: a BRCA2 carrier with a PVs, whose biopsy confirmed ISUP 4 PCa. The patient has been scheduled for surgery. Conclusions: The screening program detected the first case of PCa in a 57-year-old man. Despite this finding, the overall incidence of PCa in our cohort remains notably lower than reported in international studies, including the IMPACT trial. This unexpected result may suggest the presence of a population-specific protective factor, a phenomenon we refer to as the “Italian paradox.” Nevertheless, given the limited sample size and short follow-up, this observation should be interpreted cautiously.

Genomic risk classifier performance in PET-guided post-prostatectomy patients: Secondary analysis of a randomized trial.

386 Background: Genomic risk assessment with genomic classifiers (GC) have enhanced risk stratification in post-prostatectomy patients, however, validation studies have relied on conventional imaging workup to guide secondary radiation treatment (SRT). Our hypothesis is that GC will remain prognostic in a population receiving PET-guided SRT. Methods: We performed a protocol-specified whole-transcriptome assay (Decipher GC, Veracyte) on prostatectomy specimens from patients enrolled on a randomized trial studying event-free survival [EFS: biochemical/clinical/radiologic progression or systemic therapy initiation] of 18F-fluciclovine or 68Ga-PSMA-11 guided SRT with incorporated PET-guided dose escalation. Treatment volumes and prescription doses were rigidly defined on protocol: no uptake/prostate bed (PB) only - PB XRT (64.8-70.2Gy at 1.8Gy/fx); pelvic nodal (PLN) +/- PB uptake – PLN (45-50.4Gy @ 1.8Gy/fx) + PB XRT; extrapelvic – no XRT. Sites of PET uptake received simultaneous integrated boosts (SIB) of 74-76Gy at 2Gy/fx in PB and 54-56Gy at 2Gy/fx in PLN. GCs were categorized as low (0-0.44), intermediate (0.45-0.6) and high (>0.6) as reported for commercial testing. An optimal cutoff maximizing separation above (AOC) vs below (BOC) was identified using a bias-adjusted log-rank test. Z-test was performed at specified time points to assess EFS between cohorts per study protocol. Results: Of 140 patients enrolled on trial, 69 (49.3%) had prostatectomy specimens available for GC analysis with 44 (63.8%) high, 11 (15.9%) intermediate and 14 (20.3%) low scores. Androgen deprivation therapy (ADT) was given in 4/14 (28.6%) low, 8/11 (72.7%) intermediate, and 36/44 (81.8%) high GC patients based on clinical characteristics. Minimum follow-up was 2.00 years (median 2.9 yrs, range: 2.0-5.0 yrs). High GC was associated with worse 4-year EFS compared to low GC (56.5% vs 84.6%, p<0.01). Optimal GC cutoff was 0.84 with 28 AOC (23/28 with ADT) and 41 BOC (25/41 with ADT). Score AOC was associated with worse 3-year (69.6% vs 89.3%, p<0.01) and 4-year (46.4% vs 70.2% p=0.01) EFS compared to BOC. Use of SIB was associated with improved EFS in score BOC at 2 and 3-years post treatment (81.8% vs 92.3% at both time points, p=0.03); however, SIB was not associated with improved EFS in score AOC at 2 years or beyond. Conclusions: GC remained prognostic for EFS in post-prostatectomy patients treated with PET-guided radiation when assessed at commercial and optimal cutoff values. Dose escalation to sites of PET uptake was associated with improved EFS at 2+ years in BOC (<0.84) patients. Creation of an integrated radiogenomic model based on PET findings and GC is forthcoming.

Implementing comprehensive population-wide genomic testing in metastatic prostate cancer (mPCa): A real-world Canadian cohort study.

90 Background: Germline and somatic alterations in genes associated with DNA repair are common in patients with mPCa and have treatment implications. International guidelines uniformly recommend genomic testing for patients with mPCa however a variety of barriers influence uptake. In the Canadian province of British Columbia (population 5.7 million), publicly funded tumor and germline centralized genomic testing became available for all patients with mPCa in May 2022. We reviewed the program to understand uptake, utilization, clinical impact and identify areas for improvement. Methods: This multicenter, retrospective observational study included all patients in British Columbia with mPCa who underwent molecular tumor testing at the Cancer Genetics and Genomics Laboratory (CGL) of BC Cancer from initiation of the program on 24 May 2022 to 24 May 2024. Tumor tissue testing was prioritized with blood based circulating tumor DNA (ctDNA) serving as an alternative where tumor tissue testing failed or was not possible. Data were extracted from the CGL database and electronic medical records, and analysed using descriptive statistics. Results: Over the two-year period, 2119 individual patients underwent a total of 2253 tests; 2018 tissue tests and 235 ctDNA tests. Most tests (83.0%) were requested by medical oncologists. Median turnaround times from receipt of tissue by the laboratory to result date were 31 days, 44 days, and 66 days for ctDNA, tissue and germline tests, respectively. 235 (11.6%) tissue tests failed, and 153 (65.1%) ctDNA tests had undetectable ctDNA. An estimated 113 (73.9%) of the ctDNA tests with undetectable ctDNA could potentially have been avoided by limiting testing to patients with: 1) metastatic hormone-sensitive prostate cancer on androgen deprivation ≤14 days (46 avoidable tests), and 2) progressive metastatic castration-resistant prostate cancer with a predicted ctDNA fraction of ≥2% using the ctDNA.org tool (67 avoidable tests). Of 96 (4.5%) patients with a BRCA1/2 alteration detected, 47.9% received targeted PARP inhibitor treatment by February 2025, with a further 34.3% remaining eligible while responding to their current treatment. Conclusions: Population-wide tumor testing was rapidly adopted in British Columbia, resulting in identification of actionable alterations and facilitating access to targeted therapies in keeping with international guidelines. Education on optimal timing for cfDNA collection is needed to reduce unnecessary testing and improve test yield.

Elemental Selenium Phase‐Change Material for Scalable Ultra‐Low‐Loss Programmable Photonics

ABSTRACT Chalcogenide phase‐change photonics has revolutionized reconfigurable optics by enabling nonvolatile light‐matter control. While low‐loss phase‐change materials (PCMs) with near‐zero extinction coefficients ( k ≈ 0) unlock ideal phase‐only modulation, their growing compositional complexity hinders uniform fabrication and switching stability. Here, we introduce an elemental solution: wafer‐scale (8‐inch) selenium (Se) thin films achieving unprecedented uniformity, full near‐infrared transparency, and ultralow losses across the visible range, meanwhile sustaining one million (10 6 ) reversible cycles without degradation. First‐principles calculations reveal that the giant refractive index switching (Δ n ≈ 0.6) stems from the unique fracture‐reconfiguration dynamics of Se helical chains. Furthermore, we demonstrate a manufacturable, etch‐free platform with laser‐reconfigurable patterns for dynamic image generation and Gaussian‐vortex beam conversion. By harmonizing atomic simplicity with device‐grade scalability, this elemental PCM establishes a new paradigm for high‐performance programmable photonics.