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A Water‐Soluble PVA Macrothiol Enables Two‐Photon Microfabrication of Cell‐Interactive Hydrogel Structures at 400 mm s <sup>−1</sup>
ABSTRACT Two‐photon polymerization (2PP) has garnered increasing attention for engineering hydrogels with tailored architectures and controlled cellular responses. However, current 2PP strategies typically rely on (meth)acrylated proteins and inefficient chain‐growth crosslinking mechanisms. Although thiol‐ene photo‐click reactions can enhance 2PP efficiency, commercial water‐soluble thiol crosslinkers (e.g., DTT—dithiothreitol) tend to form intramolecular loops and introduce structural defects due to their short molecular length. As a result, high polymer concentrations (often up to 20%–50%) are required to achieve satisfactory print fidelity. Here, we develop a series of water‐soluble, polyvinyl alcohol macromolecular thiol (PVASH, bearing 10–35 thiol groups) for fast high‐fidelity hydrogel microfabrication via 2PP. A two‐step synthesis yields PVASH with tunable degrees of substitution and excellent water‐solubility. Compared to DTT and polyethylene glycol di‐thiol, PVASH‐based hydrogels exhibit reduced swelling, enhanced mechanical properties, and significantly improved printing fidelity. Notably, several complex hydrogel structures are fabricated at laser power as low as 20 mW and high scanning speeds of up to 400 mm s −1 , achieving sub‐micron feature size at 3% polymer concentration. After biofunctionalization with RGD motifs, the micro‐scaffolds support cell infiltration, adhesion, proliferation, and osteogenic differentiation. Altogether, this work reports a new strategy for 2PP microfabrication of cell‐interactive hydrogel structures with unprecedented printing efficiency and precision.
Integrating pharmacists into uro-oncology care: Evaluation of patient satisfaction and well-being.
714 Background: Uro-oncology patients are particularly vulnerable due to age-related comorbidity and polymedication while receiving complex cancer treatment regimens. As a result, therapy safety, efficacy and patient-reported outcomes may be at risk. Pharmacists are rarely part of standard care teams, representing a gap in supportive management. This trial assessed the impact of integrating a pharmacist into uro-oncology care on patient satisfaction (PS) and health-related quality of life (HRQoL). Methods: The prospective, investigator-initiated, single-center pre-post trial included adult outpatients with urothelial (UC), prostate (PC), or renal cell cancer (RCC) either starting or modifying systemic therapy. Following a 6-months observational phase (OPh), a pharmacist was added to the multidisciplinary care team in a 12-months intervention phase (IPh). In IPh, medication reconciliation, symptom burden assessment and individualized drug information was carried out by the pharmacist during a 12-week follow up for each patient. The primary endpoint was PS, assessed by the PS-CaTE questionnaire (Patient Satisfaction with Cancer Treatment Education). HRQoL served as a secondary endpoint, measured using the EORTC QLQ-C30 questionnaire and evaluated according to the Thresholds for Clinical Importance (TCI; Giesinger et al.). Results: Each phase included 79 patients (87% male; median age 71 years [IQR 65.5-79] in OPh vs. 69 years [IQR 62-77] in IPh). The majority suffered either from UC (49% vs. 42%) or PC (43% vs. 53%), whereas RCC prevalence was low (8% vs. 5%). The PS improved markedly with pharmaceutical support after 4 weeks (mean 3.9 vs. 4.5 on a Likert-scale 1-5, mean difference +0.6, p < 0.001) and continued to rise after 12 weeks (3.9 vs. 4.7, +0.8, p < 0.001). Further differentiating by treatment status, PS improved in treatment-naive patients after 4 weeks (4.0 vs. 4.6, +0.6, p < 0.001), whereas pretreated patients showed significant improvement after 12 weeks (3.8 vs. 4.7, +0.9, p < 0.001). HRQoL overall was stable between phases after 12 weeks (mean 56 [SD = 25] vs. 60 [SD = 20] on a 100-point scale, p = 0.212). On the functional scales, the proportion of patients reaching the TCI showed a trend in favor of IPh for physical, role, social and cognitive functioning. Moreover, clinically relevant burden in emotional functioning was significantly lower in IPh (45 vs. 27 patients, p = 0.005). Conclusions: Integrating a pharmacist into the uro-oncology care team significantly improved patient satisfaction and emotional well-being without compromising overall HRQoL. The greatest benefit was observed in treatment-naive patients, while pretreated patients required longer follow-up to achieve similar gains. These findings underscore the clinical value of pharmaceutical support in multidisciplinary uro-oncology care and advocate for its broader implementation in routine practice. Clinical trial information: DRKS00033062.
KEYMAKER-U03 substudy 03B: Novel investigative regimens for previously treated advanced clear cell renal cell carcinoma (ccRCC).
505 Background: The addition of novel mechanisms of action to established treatment strategies may further improve outcomes for patients with previously treated advanced ccRCC. We present updated results from substudy 03B (NCT04626518) of KEYMAKER-U03, a phase I/II study evaluating novel regimens in ccRCC. Methods: Adults with confirmed ccRCC and disease progression on or after PD-(L)1 inhibitor and VEGF-TKI were randomly assigned to open arms: pembrolizumab (pembro)/quavonlimab (qmab; anti–CTLA-4), pembro/favezelimab (fave; anti-LAG3), pembro + MK-4830 (anti-ILT4), pembro + belzutifan (bel; HIF-2α inhibitor), bel + lenvatinib (lenva; VEGF-TKI), and pembro + lenva. Primary end points were safety and confirmed ORR per RECIST v1.1 by BICR. Secondary end points included clinical benefit rate (CBR; CR + PR + SD ≥6 mo), duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, and overall survival (OS). No formal comparisons were made across arms. Enrollment was planned for 50 participants (pts) in each arm, although enrollment would be stopped if the 6-mo PFS rate was ≤40% among the first 20 enrolled pts per protocol design. Results: Overall, 263 pts were enrolled (Table). Median study follow-up was ≥22.9 mo in all arms. Efficacy is reported in the table. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 25%, 11%, 9%, 45%, 63%, and 52% of treated pts in the pembro/qmab, pembro/fave, pembro + MK-4830, pembro + bel, bel + lenva, and pembro + lenva arms, respectively. TRAEs led to death in 2 pts in the bel + lenva arm (cerebral hemorrhage and intracranial hemorrhage) and 1 pt in the pembro + lenva arm (esophageal perforation). Conclusions: Bel + lenva continued to demonstrate the highest antitumor activity followed by pembro + lenva. Pembro + bel activity was similar to historical bel monotherapy. In the small pembro/qmab cohort, median OS was not reached. No responses were observed in the anti-LAG3 or anti-ILT4 combo arms. The safety profile of each treatment was manageable. The HIF/VEGF axis continues to represent a key therapeutic target in previously treated ccRCC. These data support further evaluation of bel + lenva or other VEGF-TKIs. Clinical trial information: NCT04626518 . Pembro + Qmabn = 20 Pembro + Fave n = 20 Pembro + MK-4830 n = 24 Pembro + beln = 62 Bel + lenva n = 64 Pembro + lenvan = 73 ORR (95% CI), % 30 (12-54) 0 (0-17) 0 (0-14) 23 (13-35) 50 (37-63) 44 (32-56) CR, n (%) 0 0 0 2 (3) 3 (5) 1 (1) PR, n (%) 6 (30) 0 0 12 (19) 29 (45) 31 (42) CBR (95% CI), % 35 (15-59) 5 (0-25) 0 (0-14) 35 (24-49) 61 (48-73) 60 (48-72) DOR, median (range), mo NR(2.7-24.4+) – – 23.6 (2.8- 38.6+) NR (2.9-38.4+) 16.6 (2.5+-25.6+) PFS, median (95% CI), mo 5.4 (1.5-17.8) 1.6 (1.4-2.8) 1.5 (1.3-1.6) 5.5 (2.8-8.4) 15.0 (5.9-26.3) 9.7 (7.0-15.2) 12-mo PFS rate, % 34 7 NR 31 53 41 OS, median (95% CI), mo NR (7.8-NR) 22.1 (9.4-NR) 11.0 (6.5-18.0) 22.9 (14.2-NR) 36.4 (25.8-NR) 35.9 (21.9-NR) 12-mo OS rate, % 75 61 44 69 78 80
Immunotherapy in intermediate-risk biochemically recurrent prostate cancer (BCR): The National Cancer Institute experience.
170 Background: Androgen receptor (AR) targeting strategies have demonstrated clinical impact in high-risk BCR (e.g., PSA DT<6 months (mos)) but are associated with significant toxicities. Given the median age of BCR ≥70 years (yrs) and a low risk of death from prostate cancer, patients (pts) with intermediate risk BCR (e.g. PSA DT 6-15 mos) may not require intervention with AR-based treatment and may avoid associated toxicities. The NCI has conducted 2 BCR studies that highlight the potential of immunotherapy in intermediate-risk BCR. Methods: NCT02649439 evaluated PROSTVAC, a pox virus-based immunotherapy, targeting PSA in men with BCR. NCT03315871 evaluated PROSTVAC and CV-301 (a pox virus-based immunotherapy strategy targeting CEA and MUC-1). Both trials had the same eligibility criteria of PSA >0.8 ng/mL post-RP or >2.0 ng/mL after RT, PSADT 5-15 mos; testosterone >100 ng/dL, and negative CT and bone scan. Serial PSA levels were measured, and responses were defined as confirmed declines from an intra-study peak (ISAP) PSA (Madan RA, et al, ASCO GU, 2018). NCT03315871 also employed pre- and post-treatment prostate specific membrane antigen (PSMA) imaging that assessed for PSMA tumor volume (PSMA-TV). Given the similar study designs, treatments and eligibility, these data from these 2 studies are combined in this analysis. Results: A total of 96 BCR pts were treated with immunotherapy in both studies and evaluable for responses. Median baselines included: age 67.5 yrs (range 53.5-83.5), PSA 3.5 ng/dL (0.83-32.9), and Gleason score 7 (4-10). Adverse events were minimal and self-limiting, including injection-site reactions, flu-like symptoms, myalgias, and arthralgias. Among evaluable pts, ISAP PSA declines occurred in 28/96 (29%) pts with a median decline of 19% (11-99%). PSA declines occurred at a median of 77 days (range 0-553) after immunotherapy and lasted a median of 140 days (range 56-1500+). In NCT03315871, 21 pts had pre- and post-treatment PSMA imaging. Decreases in PSMA-TV after treatment were seen in 9/21 (43%) pts after PROSTVAC and CV-301, and all 9 pts had PSA declines or stabilization after immunotherapy. Conclusions: Both NCT02649439 and NCT03315871 evaluated antigen-directed immunotherapy in intermediate-risk BCR without ADT. These data suggest there is potential for immunotherapy (beyond immune checkpoint inhibitors) to delay PSA kinetics in BCR. PSMA-TV response data in NCT03315871 suggest immunotherapy-associated PSA responses impact tumor volume. Immunotherapy may have the ability to impact BCR with minimal toxicity while slowing disease trajectory in intermediate-risk BCR and substantially delaying or diminishing the need for other therapies and associated toxicities in this patient population. Further immunotherapy trials in BCR without ADT are ongoing at the NCI. Clinical trial information: NCT03315871 , NCT02649439 .
Real-world effectiveness and safety of enfortumab vedotin plus pembrolizumab versus gemcitabine-platinum chemotherapy in first-line treatment of advanced urothelial carcinoma: A propensity-matched analysis from the TriNetX global network.
706 Background: Enfortumab vedotin plus pembrolizumab (EV+P) has demonstrated superior OS compared to platinum-based chemotherapy (gemcitabine-cisplatin or gemcitabine-carboplatin, collectively gemcitabine-platinum [GP]) in the EV-302 trial, establishing a new standard for first-line treatment of advanced urothelial carcinoma (aUC). However, real-world data (RWD) directly comparing these regimens remains limited. This study evaluates the RWD and safety of EV+P versus GP using a global electronic health record database. Methods: We conducted a retrospective cohort study using the TriNetX Global Health Research Network, comprising EMR data from 154 healthcare organizations. Patients with advanced or metastatic urothelial carcinoma receiving first-line EV+P or GP were identified. Propensity score matching (1:1) was performed based on age, sex, race, ECOG performance status, comorbidities, and baseline labs, yielding 836 patients per cohort. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization and grade ≥3 adverse events (anemia, thrombocytopenia, neutropenia). Kaplan-Meier analysis and Cox proportional hazards models were used to assess 2-year overall survival (OS). Results: After matching, 836 patients per cohort were analyzed. Median follow-up was 203 days for EV+P and 460 days for GP. EV+P was associated with significantly lower all-cause mortality at 2 years (26.8% vs 47.7%; risk ratio [RR] 0.561, 95% CI 0.492–0.641; p < 0.0001), and higher 2-year survival probability (52.6% vs 44.0%; log-rank p = 0.0339). Hospitalization occurred in 44.5% (EV+P) vs 49.2% (GP; RR 0.905, p = 0.056). Grade ≥3 anemia (20.9% vs 50.7%), thrombocytopenia (2.2% vs 30.0%), and neutropenia (6.1% vs 27.8%) were all significantly less frequent in the EV+P group (p < 0.0001 for all). However, EV+P had higher rates of rash (26% vs 9%), pruritis (18% vs 5%), and peripheral neuropathy (16% vs 7%). In a histologic subtype analysis, EV+P consistently demonstrated longer median survival (626–719 days) and higher survival probabilities (47.6–48.4%) across clear cell, signet ring, squamous, and sarcomatoid urothelial carcinoma compared to GP (median survival 539–568 days; survival probabilities 40.8–44.3%), highlighting superior efficacy of EV+P in these aggressive variants. Conclusions: In this global, real-world cohort with 2-year follow-up, EV+P demonstrated significantly improved survival and reduced hematologic toxicity compared to GP chemotherapy in the first-line treatment of aUC. While EV+P was associated with more skin and neurologic adverse events, these results support the use of EV+P as a preferred frontline option in eligible patients.
High‐Density Topological Defect Array by Two‐Step Interference Photoalignment
ABSTRACT With nematic liquid crystal (LC) topological defects can be created that are important for the generation of laser beams with orbital angular momentum. Arrays of defects have been realized through photoalignment, by projecting images of a spatial light modulator or digital mirror device. However, such pixel‐based approaches seriously limit the achievable density of defects. Here, we propose a scalable method based on two‐step interference illumination to achieve a much higher density. In the first step, a rotating director pattern is generated by the interference of two circularly polarized beams. In the second step, amplitude modulation by two‐beam interference is used to rewrite the pattern and introduce the defects. By adjusting the illumination doses and angles of incidence in both steps, 2D defect patterns are obtained, with spacing down to 1.25 micrometer. The resulting disclination lines are analyzed, and the proposed structure is supported by numerical simulations. For the first time, a high defect density defect grid is obtained through a scalable two‐step photoalignment procedure. This approach enables optical components with large‐angle diffraction and bridges the gap between LC topological optics and metasurfaces.
Multistate Polar Chiral Bobbers in Oxide Ferroelectrics
ABSTRACT Polar topologies in ferroelectric oxides have potential applications in future electronic devices, such as high‐density non‐volatile memory and logic devices. However, their application in multistate storage remains largely unexplored, because the number of accessible topological states is limited. Here, we report a family of polar chiral bobbers in ultrathin (111)‐oriented ferroelectric PbTiO 3 films by combining phase‐field simulations with aberration‐corrected transmission electron microscopy. We find that a chiral bobber can exhibit eight distinct states, which can be applied to multistate storage exceeding the traditional binary (0/1) encoding. The polar chiral bobber can be easily manipulated with low energy to enable transitions between different states. These results suggest that polar chiral bobbers represent one of the promising candidates for applications in next‐generation topological electronics, advanced memory, and quantum computing.
Scalable Solar Evaporator Based on Bandgap Engineered CuMnCrO <sub>4</sub> Spinel Oxide with Salt‐Resistant Property for Contaminated Seawater
Abstract Freshwater scarcity demands innovative solutions that combine efficiency, durability, and scalability. Here, CuMnCrO 4 (CMCO), is presented as a ternary spinel oxide photothermal absorber introduced for the first time in solar desalination, synthesized via co‐substitution of Mn 3 O 4 with Cu and Cr. This multi‐cation design narrows the bandgap from 2.3 to 1.49 eV, markedly enhancing solar absorption across the visible and near‐infrared spectrum and enabling efficient light‐to‐heat conversion. Unlike conventional carbon or single‐oxide‐based systems, CMCO demonstrates record‐high evaporation performance of 4.1 kg m −2 h −1 under 1‐sun, positioning it among the most efficient oxide‐based ISSG materials reported to date. Equally novel is the integration of CMCO with a cotton fabric substrate and hydrophobic polyester strips in an inverted U‐shaped configuration, which ensures continuous water wicking, localized salt separation, and mechanical robustness. This architecture delivers stable operation over three weeks without salt accumulation, overcoming a long‐standing challenge in ISSG. Furthermore, the system retains high efficiency under strongly acidic/alkaline conditions and in oil‐ or dye‐contaminated water, demonstrating unique resilience rarely reported in solar desalination systems. Finally, the modular design enables straightforward scalability from laboratory‐scale strips to large‐area panels. Together, these advances establish CMCO‐based systems as a new materials platform for practical, durable, and scalable solar desalination, offering a sustainable pathway toward addressing global water scarcity.
Bridging trial and practice: Real-world data of adjuvant nivolumab in high-risk muscle-invasive urothelial carcinoma.
710 Background: Adjuvant immune checkpoint inhibition with nivolumab has demonstrated efficacy in randomized clinical trials for patients with high-risk muscle-invasive urothelial carcinoma (MIUC). However, its effectiveness in real-world clinical practice remains unclear. We aimed to evaluate the prognostic impact of adjuvant nivolumab compared with conventional adjuvant chemotherapy or observation in a multicenter Japanese cohort. Methods: We retrospectively analyzed 366 patients with high-risk IMUC (bladder or upper tract urothelial carcinoma: UTUC) who underwent radical surgery between 2016 and 2025 across 22 institutions in the AGEHA database. Among them, 126 received adjuvant nivolumab, 59 received adjuvant chemotherapy, and 181 had no adjuvant therapy. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Kaplan–Meier curves, Cox proportional hazards models, and propensity score matching were applied to adjust for baseline imbalances. Subgroup analyses were performed in patients with prior neoadjuvant chemotherapy (NAC). Results: Adjuvant nivolumab was associated with improved DFS (HR 0.63, 95% CI 0.43–0.94) and OS (HR 0.54, 95% CI 0.28–1.03) compared with chemotherapy or no adjuvant therapy. After propensity score matching, both DFS (HR 0.48, 95% CI 0.31–0.74; p < 0.005) and OS (HR 0.42, 95% CI 0.22–0.80; p = 0.010) remained significantly better in the adjuvant nivolumab group. Subgroup analysis showed consistent benefits in patients with prior NAC. Limitations include the retrospective design and potential residual confounding despite adjustment. Conclusions: This multicenter real-world analysis demonstrated that adjuvant nivolumab after radical surgery significantly prolongs DFS and OS in patients with high-risk urothelial carcinoma. These findings bridge the gap between trial and practice, supporting adjuvant nivolumab as a standard option in real-world settings.
Machine learning-based phenotyping and trial emulation to identify checkpoint inhibitor responders in advanced urothelial cancer.
698 Background: Randomized trials of first-line single-agent checkpoint inhibitors (CPIs) in advanced urothelial cancer (aUC) have shown no overall survival benefit compared to chemotherapy. However, a subset of patients may derive long-term benefit from CPIs. Identifying these patients is challenging due to their delayed treatment effects. We investigated whether machine learning (ML)-based phenotyping within a trial emulation framework could identify patients with improved survival from pembrolizumab vs gemcitabine/carboplatin (GCa) in a patient population similar to KEYNOTE-361. Methods: We used the Flatiron Health nationwide, de-identified EHR-derived database. Patients receiving first-line pembrolizumab or GCa were included. A supervised gradient-boosted survival model using pre-treatment variables (demographics, cancer features, biomarkers, labs, ICD codes) was developed to predict early mortality. Patients in the highest-risk tertile were excluded from the emulated trial, as they were unlikely to benefit from CPIs’ delayed treatment effect. Survival was compared using restricted mean survival time (RMST) and survival probabilities at 3 and 4 years from inverse probability–weighted Kaplan–Meier curves. Results: Among 3706 patients (pembrolizumab, n = 1484; GCa, n = 2222), early mortality was higher with pembrolizumab, but 3-year survival was modestly improved (25.2% vs 19.1%; Δ6.1 [95% CI 2.4-9.8]). RMST was similar at 3 years (15.9 vs 15.9 months; Δ0.0 [95% CI -1.0-1.1]) and 4 years (18.6 vs 17.9 months; Δ0.6 [95% CI -0.7-2.0]). The ML model had strong discriminatory performance (AUCs of 0.78 at 90 days and 0.72 at 1 year). After excluding the highest-risk tertile, pembrolizumab showed superior 3-year survival (33.1% vs 24.7%; Δ8.5 [95% CI 3.7-13.5]) and lower early mortality. RMST differences showed a trend toward improvement at 3 years (19.1 vs 18.1 months; Δ1.0 [95% CI -0.3-2.3]) and favored pembrolizumab at 4 years (22.6 vs 20.8 months; Δ1.8 [95% CI 0.1-3.6]). PD-L1 testing was infrequent (< 10%) and not predictive of survival outcomes. Conclusions: ML-based phenotyping within a trial emulation framework identified a subgroup of aUC patients with improved long-term survival with pembrolizumab monotherapy. While absolute gains were modest, this data-driven approach may help refine patient selection for CPIs with heterogeneous treatment effects.
A phase II trial of nivolumab, ipilimumab and cabozantinib in patients with brain metastases from renal cell carcinoma.
492 Background: The incidence of brain metastases(mets) in patients (pts) with advanced renal cell carcinoma (aRCC) is approximately 12%. Brain mets carry a poor prognosis, with treatment largely limited to surgery and radiation. Although systemic therapies including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICIs) have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is FDA-approved for aRCC with intracranial activity. The phase III COSMIC-313 trial demonstrated cabozantinib in combination with nivolumab and ipilimumab significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. However, the role of this combination in aRCC pts with brain mets remains undefined. We evaluated the safety and efficacy of cabozantinib in combination with nivolumab and ipilimumab in RCC pts with untreated brain mets in a phase II trial. Methods: This phase II trial enrolls pts with asymptomatic and untreated brain mets from RCC. Planned accrual is 20 pts. Prior systemic therapy for aRCC permitted without prior anti–CTLA-4, cabozantinib, or MET inhibitor treatment. Pts will receive nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily followed by nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until disease progression(PD), unacceptable toxicity, or withdrawal of consent. Salvage CNS radiation and surgery are indicated for intracranial PD. The primary objective is intracranial progression free survival (iPFS). Secondary objectives include intracranial safety, Intracranial objective response rate(iORR) by modified RECIST v1.1, extracranial objective response rate(eORR) by RECIST v1.1, extracranial PFS (ePFS) and overall survival(OS). Clinical trial information: NCT05048212. Results: Between February 2023 and December of 2024, 11 pts were enrolled onto this trial. Median age was 61 years (range 38-75), 8 pts had clear cell histology. Only 1 pt received prior therapy with lenvatinib and pembrolizumab. median follow up was 19.5 months. Median iPFS was 12 months (95% CI: 6.5, NA), iORR was 54.5% with 4 complete response(CR), 2 partial response(PR), 4 stable disease(SD) and 1 non CR/non PD. eORR is 36% with 4 PR and 7 SD. ePFS was 8.5 months (95% CI: 6.5, NA). median OS is 13 months (95% CI: 11.3, NA). There was one case of grade 3 encephalitis, with no other CNS adverse events(AEs) reported. 195 AEs of any grade were deemed related to treatment. 26(13.3%) were grade 3 or 4 AEs. There was 1 grade 4 AE (hypophysitis). Conclusions: The combination of nivolumab and ipilimumab with cabozantinib showed encouraging intracranial activity in pts with untreated brain mets from RCC , with acceptable central nervous system toxicities observed. This trial indicates that the combination of ICIs and a TKI is a promising strategy for controlling intracranial disease in RCC pts. Clinical trial information: NCT05048212 .
Obrixtamig (BI 764532) in patients (pts) with relapsed/refractory delta-like ligand 3 (DLL3)-high expressing extrapulmonary neuroendocrine carcinoma (epNEC): Dose expansion part of the phase II DAREON-5 trial.
TPS2 Background: Pts with relapsed/refractory epNEC have poor outcomes with currently available therapies. DLL3 is expressed on the surface of many epNEC cells, offering a promising therapeutic target. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in immune-mediated tumor cell lysis. In an ongoing first-in-human Phase I trial (NCT04429087), obrixtamig monotherapy had promising efficacy in pts with DLL3+ SCLC, epNEC or large-cell NEC of the lung (LCNEC-L) and a manageable toxicity profile, justifying further clinical investigation. The Phase II DAREON-5 trial (NCT05882058) is a dose selection and expansion trial of obrixtamig monotherapy in pts with histologically confirmed relapsed/refractory SCLC, epNEC or LCNEC-L after prior standard of care. The completed dose selection part evaluated the safety and efficacy of two obrixtamig doses. We describe the design of the expansion part of the study that is currently enrolling. Methods: The expansion part of DAREON-5 is assessing obrixtamig antitumor activity at the selected dose for expansion in pts with centrally assessed DLL3-high expressing epNEC; defined as ≥50% of evaluable tumor cells with moderate to strong membrane and/or cytoplasmic DLL3 staining using the VENTANA DLL3 (SP347) assay. Eligible pts have relapsed/refractory, advanced/metastatic, histologically confirmed epNEC after prior platinum-based chemotherapy (≥1 lines of therapy). Pts will receive IV obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per RECIST v1.1, assessed by blinded independent central review. Secondary endpoints include duration of objective response, PFS, disease control, overall survival, treatment-emergent AEs, and patient-reported outcomes. The planned enrollment for the expansion cohort is ~50 pts recruited from the following countries: Belgium, China, Germany, Japan, Portugal, South Korea, Spain, UK and USA. Previously presented at ESMO, FPN (Final publication Number): 1731TiP, Pavel et al. Reused with permission. Clinical trial information: NCT05882058 .
Proximity Induced Magnetic Anisotropy and Trefoil Fermiology in Monolayer FeCl <sub>2</sub> /Bi(111)
ABSTRACT Interfaces between magnetic and non‐magnetic materials play a crucial role in various magnetic heterostructures. The emergence of 2D van der Waals (vdW) magnets has introduced new opportunities for exploring proximity effects in vdW heterostructures. While the influence of magnetic layers on nearby non‐magnetic materials has been widely studied, it remains unclear whether non‐magnetic substrates can similarly modulate the intrinsic magnetic properties of 2D magnets, particularly their magnetic anisotropy. In this work, by analyzing X‐ray magnetic circular dichroism spectra of an epitaxially grown FeCl 2 monolayer on a Bi(111) surface, a reorientation of magnetic anisotropy is observed – from its natural out‐of‐plane to a predominantly in‐plane alignment. This effect vanishes in bilayer FeCl 2 /Bi(111), where the magnetic anisotropy reverts to its intrinsic out‐of‐plane orientation, consistent with the layered antiferromagnetic order of bulk FeCl 2 . Angle‐resolved photoelectron spectroscopy reveals the presence of metallic interface states derived from the Bi surface states, accompanied by charge transfer and emergence of a moiré potential that gives rise to a distinctive trefoil‐shaped Fermi surface. These results demonstrate that non‐magnetic substrates can exert strong proximity influence on the magnetic and electronic behavior of 2D vdW magnets, offering new strategies for engineering magnetic anisotropy and electronic structure in spintronic heterostructures.
In Situ Reformatsky Reaction‐Induced Surface Polymerization Toward an Oriented Monomeric Structure for Superior Zinc Anode Stability
ABSTRACT Addressing the intrinsic heterogeneity of zinc anodes, which triggers dendritic growth and parasitic reactions, is paramount for realizing safe and durable zinc‐ion batteries. The homogenization of in situ active sites and deposition serves as a critical approach to suppress dendrite growth. Herein, this work adopts an in situ Reformatsky reaction capable of eliminating active sites on the Zn surface while simultaneously generating a zincophilic metal‐organic polymer framework. This mechanism not only provides uniform ion channels but also promotes uniform zinc deposition by increasing the density of nucleation sites, ultimately inducing the preferential growth of thermodynamically stable (002) oriented zinc grains. As a result of this meticulously controlled interface, the protected zinc anode exhibits exceptional stability. The symmetrical battery can operate stably for 3,800 h at 1 mA cm −2 and even for more than 600 h at an ultra‐high current density of 10 mA cm −2 . More significantly, the resulting full cell achieves an ultra‐long lifespan exceeding 10,000 cycles at a current density of 5 A g −1 . This work demonstrates a highly effective strategy for practical zinc anodes while establishing a new design paradigm: controlling deposition kinetics through activation energy modulation for stable metal batteries.
The overlooked culprit: Tumor size in muscle-invasive bladder cancer.
836 Background: Bladder cancer staging has historically focused solely on the depth of invasion, and the impact of tumor size remains unclear. This study aimed to assess the role of tumor size on postoperative complications, recurrence-free survival (RFS), and overall survival (OS) in muscle-invasive bladder cancer. Methods: We reviewed our IRB-approved radical cystectomy database for patients who underwent radical cystectomy between 2004 and 2024. Patients with non-muscle invasive disease or (y)pT0 were excluded. Tumors were categorized into four quartiles based final pathological size. Multivariate cox regression analyses were used to assess predictors of OS and RFS. Results: 1,168 patients were included in the analysis. Median tumor sizes were 1.2 cm, 2.5 cm, 3.8 cm, and 6.0 cm in quartiles 1 (smallest) to 4 (largest), respectively. Patients with larger tumors were more likely to have extravesical or lymph node positive disease, variant histology, and lymphovascular invasion (Table 1). The overall 30-day complication rates (Q1: 57.3%, Q2: 53.7%, Q3: 58.4%, Q4: 61.1%) and 90-day complication rates (Q1: 69.8%, Q2: 68.2%, Q3: 68.8%, and Q4: 71.9%) were comparable (p = 0.479, 0.785, respectively). All 90-day complication subtypes and 30- and 90-day readmission rates were comparable between quartiles. Multivariate analysis showed that after adjusting for confounders including age, baseline comorbidities, pathological staging, and adverse pathological features, Q3 had higher risks of recurrence (HR: 1.5, 95% CI: 1.1 – 2.0, p = 0.005) and death (HR: 1.4, 95% CI: 1.1 - 1.8, p = 0.011) compared to Q1, while Q4 showed even greater risks of recurrence (HR: 2.1, 95% CI: 1.5 – 2.7, p<0.001), and death (HR: 2.2, 95% CI: 1.7 - 2.8, p<0.001). Conclusions: Larger tumor size at radical cystectomy is independently associated with worse RFS and OS after adjusting for tumor stage. Although tumor size has long been overlooked in the staging of muscle-invasive bladder cancer, our findings reflect that it may be a neglected yet meaningful prognostic factor deserving renewed attention. Demographics and perioperative characteristics stratified by tumor size quartiles. Patient characteristics Q1 (N=295) Q2 (N=327) Q3 (N=279) Q4 (N=267) P value Age (yrs.) 70.1 ± 10.5 70.4 ± 10.5 71.5 ± 10.1 71.1 ± 11.1 0.318 Gender (Male) 228 (77.3%) 258 (78.9%) 209 (74.9%) 194 (72.7%) 0.308 Neoadjuvant chemotherapy 107 (36.3%) 71 (21.7%) 60 (21.5%) 73 (27.3%) < 0.001 Pathological Staging < 0.001 Organ-confined (≤ (y)pT2N0) 137 (46.4%) 93 (28.4%) 67 (24.0%) 45 (16.9%) Extravesical (> (y)pT2N0) 77 (26.1%) 113 (34.6%) 85 (30.5%) 102 (38.2%) Lymph node positive (pN+) 81 (27.5%) 121 (37.0%) 127 (45.5%) 120 (44.9%) Histologic subtype (variant histology) 67 (22.7%) 99 (30.3%) 84 (30.1%) 116 (43.5%) < 0.001 Positive lymphovascular invasion 105 (35.6%) 164 (50.2%) 165 (59.1%) 154 (57.7%) < 0.001 Adjuvant Chemotherapy 39 (13.2%) 72 (22.0%) 58 (20.8%) 45 (16.9%) 0.021
Three Versus 6 Months of Adjuvant Oxaliplatin-Fluoropyrimidine Chemotherapy for Colorectal Cancer: Final Results of SCOT—An International, Randomized, Phase III, Noninferiority Trial
Adjuvant chemotherapy for colorectal cancer (CRC) with oxaliplatin and fluoropyrimidine was traditionally given for 6 months but is associated with cumulative peripheral neuropathy. The SCOT study (ISRCTN59757862) was an international, randomized, phase III, noninferiority trial investigating treatment reduction from 6 to 3 months. It originally reported noninferior disease-free survival with reduced toxicity and improved quality of life for 3 months of treatment in 6,088 patients. Here, we report overall survival (OS) with 38 months of additional follow-up. Patients with high-risk stage II and stage III CRC were assigned (1:1) to receive 3 or 6 months of either capecitabine and oxaliplatin (CAPOX) or infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX; bolus and infused fluorouracil with oxaliplatin) that were selected before random assignment. With a median of 113 months follow-up and 1,255 OS events, 5-year OS for 3 versus 6 months of treatment was 82.4% in both groups (hazard ratio, 0.96; 95% CI, 0.8 to 1.07), proving noninferiority of 3 months of treatment. Noninferiority of 3 months of treatment for OS was also shown in 1,087 patients with rectal cancer. The duration effect is regimen-dependent with noninferiority shown for CAPOX but not for FOLFOX. In summary, SCOT has shown noninferiority for OS with 3 months of adjuvant chemotherapy treatment, which should be recommended for most patients.
Long-term outcomes with radium-223 in metastatic castration resistant prostate cancer: US patient subset of the 10-year REASSURE global study.
85 Background: Radium-223 (Ra-223) is approved for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases based on its demonstrated overall survival (OS) benefit and favorable safety profile. REASSURE (NCT02141438) was a 10-year, global, prospective, single-arm, observational study of Ra-223 use in pts with bone predominant mCRPC within routine clinical settings. Here we report patient characteristics and outcomes for the US pts who received Ra-223 in the REASSURE global study. Methods: Pts were recruited from August 2014 through December 2017. The observation period for each patient was the start of therapy with Ra-223 to death, withdrawal of consent, lost to follow-up, or end of this study (maximum of 7 years after last administration). In this descriptive final analysis (data cutoff 10-24-2024), we evaluated baseline characteristics, primary endpoints: hematological toxicities, second primary malignancies (SPMs), and secondary endpoints: OS, bone fractures, and pain response (to be reported in full presentation). Results: A total of 498 pts (median age 74 years, 83% White, 12% Black or African American, 2% Asian) with mCRPC comprise the US subset. The proportion of pts with an Eastern Cooperative Oncology Group score of 0 or 1 at study entry was 79%. Prior treatments included systemic anti-cancer therapy in 491 pts (99%), radiotherapy in 312 pts (63%), and blood transfusions in 38 pts (8%). A total of 312 pts (63%) completed 6 injections of Ra-223. The median duration of observation from the start of Ra-223 treatment was 19.0 months (range, 0.4-95.3 months). Any-grade drug-related hematological treatment-emergent adverse events (TEAEs) occurred in 50 pts (10%) (Table). Grade ≥3 drug-related hematological TEAEs occurred in 31 pts (6%). Ten SPMs were reported for 10 pts (2%). The most common sites of SPMs were lung, skin, and pancreas (2 pts each). Median OS was 17.4 months (95% CI, 15.3-19.3 months). A total of 271 pts (54%) received a prior bone protective agent (BPA). Bone fractures were reported in 35 pts (7%) overall, including in 15 pts who had received a prior BPA (6%) and in 20 pts who had not received a prior BPA (9%). Conclusions: In this descriptive analysis of 10-year real-world data from the US, Ra-223 demonstrated a favorable long-term hematological safety profile in pts with mCRPC. Importantly, incidence of SPMs was low across the observation period and relative to national mCRPC data. OS was consistent with other contemporary studies. Despite underutilization of BPAs, the incidence of bone fractures remained low with Ra-223, a bone directed therapy. n=498 Any grade drug-related hematological TEAEs, n (%) Anemia 40 (8.0) Leukopenia 6 (1.2) Myelosuppression 1 (0.2) Neutropenia 6 (1.2) Pancytopenia 3 (0.6) Thrombocytopenia 7 (1.4) Bone fractures, n (%) 35 (7.0) Number of SPMs, n (%) 10 in 10 pts (2.0)
ADC target signatures in urothelial carcinoma: A transcriptomic framework for precision therapy.
821 Background: Nectin-4 targeting antibody drug conjugate (ADC) enfortumab vedotin (EV), in combination with pembrolizumab, is the first-line treatment for patients with metastatic or locally advanced urothelial cancer (UC). However, optimal treatment strategies for non-responders remain an unmet clinical need. We analyzed tumor transcriptomes to identify ADC target expression profiles which may inform treatment selection for these patients. Methods: We conducted a literature search to identify ADC targets approved or under investigation for UC. Molecular targets of interest included Nectin-4 ( NECTIN4 ), Her2 ( ERBB2 ), Trop-2 ( TACSTD2 ), DLL3, B7-H3 ( CD276 ), FGFR3, and PDL1 ( CD274 ). We interrogated The Cancer Genome Atlas (TCGA) dataset, comprising tumors from 434 patients with UC and 19 normal bladder tissue samples. Hierarchical clustering was used to identify recurrent ADC target expression profiles. To validate our findings, we repeated the analysis on an independent cohort of 478 patients with UC from the Oncology Research Information Exchange Network (ORIEN) using R version 4.5.1. Results: Two mutually exclusive patterns of ADC target expression were identified in the TCGA dataset. Cluster 1 (70.2%, n = 318) was characterized by overexpression of ERBB2 , FGFR3 , NECTIN4 and TACSTD2 . Cluster 2 (29.8%, n = 135) was characterized by overexpression of DLL3 , CD276 , and CD274 . The two clusters of ADC targets demonstrated a significant negative correlation (Spearman rho = -0.40, p < 0.0001). Normal bladder tissue did not cluster according to ADC gene expression profiles. In the ORIEN dataset, a similar pattern was observed: where the seven target genes were separated into two clusters. One cluster showed overexpression of FGFR3 , NECTIN4 , and TACSTD2 , while the other showed overexpression of DLL3 , CD276 , CD274 and ERBB2 . The enrichment scores of the two clusters were also negatively correlated (Spearman rho = -0.79, p < 0.0001) in the ORIEN dataset. Notably, ERBB2 clustered with the second group in ORIEN, suggesting biological variability. Conclusions: Through interrogation of TCGA data and validation in an independent ORIEN cohort, we identified two mutually exclusive ADC target expression profiles in UC. Tumors lacking overexpression of NECTIN4 , TACSTD2 , or FGFR3 were enriched for DLL3 , CD276 and CD274 expression, suggesting alternative ADC targets for non-responders to current therapies. The differential ERBB2 clustering highlights potential biological variability of this target. These findings warrant prospective proteomic validation and may inform rational treatment selection beyond EV.
Bio‐Inspired Design of Quasi‐Ordered Structural Color via Stress‐Driven Reconfiguration Enables Ultra‐Secure and Scalable Unclonable Application
ABSTRACT Physically unclonable functions (PUFs) offer intrinsic security for next‐generation authentication systems, yet current optical PUFs face a trilemma—simultaneously achieving high coding capacity, rapid recognition, and scalable manufacturing in one stable system. Inspired by quasi‐ordered photonic structures in Thecla opisena wing scales, we report a stress‐driven microstructural reconfiguration strategy that reversely emulates the natural evolution of photonic domains under mechanical constraints. By controlled imprinting of heterogeneous polymer networks comprising poly(butyl acrylate) microspheres, one can attain spatially random, structurally colored PUF patterns featuring microscopic periodicity and macroscopic disorder. Theoretical simulation reveals that manipulating stress fields in crosslinked elastomers induces stochastic microsphere rearrangements, establishing the physical origin of entropy and unclonability. The resulting mechanically‐induced structural color PUF labels (MSCPLs) exhibit ultrahigh encoding capacity of 2 480×480 (derived from the physical correlation length within 1800 × 1800 µm), sub‐2 s recognition with 99% accuracy via a deep learning assisted strategy of hierarchical classification and dynamic database expansion, and outstanding durability (>85% pattern retention after 1000 bending cycles). Unlike conventional optical PUFs, our strategy enables large‐area fabrication (10 × 10 cm) with superior environmental resilience. This bio‐inspired methodology establishes a robust/scalable platform for secure identification and Internet of Things applications, bridging structural color aesthetics with advanced physical cryptography.
Ionic Liquid‐Assisted Crystallization Strategy Enables Simultaneous Regulation of Microstructure and Trap States for High‐Efficiency Sb <sub>2</sub> (S,Se) <sub>3</sub> Solar Cells
ABSTRACT Developing a feasible and effective crystallization approach to simultaneously amend microstructure and trap states in antimony sulfoselenide (Sb 2 (S,Se) 3 ) absorber is extremely crucial and challenging for high‐efficient solar cells. Herein, a regulation strategy is proposed to control crystallization process of Sb 2 (S,Se) 3 using ionic liquids (ILs) consisted of halide (X) anions (Cl − , Br − , and I − ) and [BMIM] + cations. In particular, the [BMIM]Br creates a liquid microenviroment on Sb 2 (S,Se) 3 surface before decomposition, accelerating the mass transfer, which induces micron‐size grains. Moreover, the [BMIM]Br can promote the [211]‐oriented growth via stronger adsorption on (211) facets of Sb 2 (S,Se) 3 . Additionally, the inhibited S and Se loss results in a near stoichiometric composition of Sb 2 (S,Se) 3 film, which greatly raises the hole concentration and optimizes the band alignment. Very important transformation from severe antisite defect Sb S to slight vacancy defect V Se2 remarkably suppresses the non‐radiative recombination. As a result, with more effective carrier transport and collection, the [BMIM]Br‐modulated device achieves a 10.89% efficiency and a 72.74% fill factor, which are separately one of the highest values for Sb 2 (S,Se) 3 solar cells so far. This work shines a new light on breaking the bottleneck in the development of Sb 2 (S,Se) 3 solar cells.