Browse Articles

Arbitrary Total Angular Momentum Vectorial Holography Using Bi‐Layer Metasurfaces

ABSTRACT Advanced holographic techniques are increasingly demanded for high‐capacity and secure information processing. In this context, orbital angular momentum (OAM) stands out as a powerful resource for optical multiplexing, offering access to an unbounded set of orthogonal modes. To harness this potential, metasurfaces, with their considerable ability to control light, have emerged as key platforms for OAM‐multiplexed holography. Nevertheless, conventional OAM holography suffers from limited polarization engineering capabilities due to the lack of chirality control in single‐layer metasurfaces. Here, we introduce a bi‐layer metasurface architecture that realizes total angular momentum (TAM) vectorial holography, where TAM represents the combination of spin angular momentum (SAM, equivalent to polarization) and OAM of light. In contrast to previous approaches, this scheme enables true polarization–OAM multiplexing, facilitating the independent generation of vectorial holographic images for each orthogonal TAM input state. This concept is validated numerically and experimentally, confirming the feasibility of TAM vectorial holography. The proposed scheme can be easily integrated with other recent holography generation approaches, such as vector beam multiplexing and bidirectional holography, thereby further expanding its multiplexing capability. This work establishes a versatile framework for advanced full‐vectorial holography, showing how metasurfaces can unlock multiplexing strategies for emerging photonic systems.

Correction: Abstract 2280 Time To Be Knowledgeable 1n TTBK1

Efficacy and safety of darolutamide monotherapy in patients with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR): 52-week results from ARAMON.

167 Background: Darolutamide (DARO), an androgen receptor inhibitor (ARI), demonstrates low blood–brain barrier penetration, limited drug–drug interactions, robust efficacy across multiple disease settings, and a favorable safety profile, as reported in the phase 3 ARANOTE (NCT04736199), ARAMIS (NCT02200614), and ARASENS (NCT02799602) trials. The open-label, phase 2 ARAMON trial (NCT05526248) investigated the use of DARO monotherapy in patients (pts) with oligometastatic castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR). Here, we report the final lead-in outcomes at 52 weeks. Methods: Eligible pts had confirmed CSPC, prior radical prostatectomy (RP) or radiotherapy (RT), prostate-specific antigen (PSA) ≥0.2 ng/mL after RP or ≥2 ng/mL after RT only, with a PSA doubling time ≤20 months, <5 asymptomatic metastatic lesions by conventional imaging and PSMA PET, serum testosterone >150 ng/dL, and an ECOG performance status score (PS) 0–1. Prior androgen deprivation therapy of ≤6 months was allowed if >6 months before start of study treatment. Pts received DARO 600 mg twice daily for 52 weeks. The primary endpoint was change in serum testosterone from baseline to week 12 (secondary endpoint: change from baseline to weeks 24 and 52); secondary endpoints were PSA response and safety. Exploratory endpoints included assessment of fat, glucose metabolism, bone turnover, changes in other sex hormones, and quality of life (QoL). Results: Of 23 eligible pts (evaluable set), the median age was 74 years (range 54–84), 61% were white, 91% had ECOG PS 0, and 87% had Gleason score <8. At study entry, median PSA was 6.0 ng/mL (range 2.1–27.4). From the start of DARO treatment, testosterone increased by 53% at week 12, 56% at week 24, and 48% at week 52. Mean serum testosterone concentrations increased through week 4 and then remained stable through week 52. At week 52, deep PSA responses (PSA <0.2 ng/mL) were observed in 70% of pts, and 87% reached a 90% reduction in PSA. DARO had a favorable safety profile with expected side effects for ARI monotherapy. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2, including feminizing TEAEs (gynecomastia, breast pain, hot flush, nipple pain, breast tenderness), which occurred mostly during the first 6 months of DARO. Minimal changes from baseline were observed over 52 weeks in measures of fat, glucose metabolism, bone turnover, and sex hormones (ie, luteinizing hormone, follicle-stimulating hormone, estradiol). QoL (per FACT-P total score) was maintained during the 52-week study. Conclusions: In pts with CSPC after BCR, DARO monotherapy moderately increased testosterone concentrations from baseline to week 12, which remained stable through week 52. Deep PSA responses were observed, and the safety profile of DARO was consistent with known TEAEs of ARI monotherapy. Clinical trial information: NCT05526248 .

Comparative risk of medication-related osteonecrosis of the jaw and survival outcomes with RANKL inhibitors versus bisphosphonates in metastatic prostate cancer.

60 Background: Bone-modifying agents (BMAs) are standard in metastatic prostate cancer, preventing skeletal complications but risking medication-related osteonecrosis of the jaw (MRONJ). Evidence guiding prostate-specific management remains sparse. We investigated real-world MRONJ risk, systemic outcomes, and bone metabolism with RANKL inhibitors (RANKLi) versus bisphosphonates (BP). Methods: Men with metastatic prostate cancer (TriNetX Global, 2000–2024) receiving RANKLi or BP were propensity-matched 1:1 (n = 10,964) for key clinical and treatment factors, including baseline corticosteroid use, osteoporosis, osteopenia, and vitamin D levels. Primary endpoints included MRONJ incidence and hazard; secondary outcomes included antibiotic use (≤2 years), survival, and metabolic bone indices. Results: RANKL inhibition was associated with a significantly higher MRONJ incidence (1.30% vs 0.64%; OR 2.05, 95% CI 1.35–3.13; HR 1.82, 95% CI 1.18–2.79; both p < 0.01). Antibiotic use within 2 years was greater with RANKLi (38.5% vs 34.1%; p < 0.001). Despite these toxicities, RANKLi conferred superior overall survival (37.4 vs 32.5 months; HR 0.89, 95% CI 0.83–0.95; p < 0.0001) and reduced hypercalcemia (0.21% vs 0.46%; p = 0.0278). Conclusions: RANKL inhibition nearly doubled MRONJ risk compared with bisphosphonates but provided clear survival and metabolic advantages. The absolute MRONJ risk remained low yet clinically meaningful, reinforcing the importance of proactive dental surveillance and multidisciplinary care. These findings highlight a critical therapeutic balance of greater skeletal and survival benefit at the cost of increased MRONJ risk while managing metastatic prostate cancer. Outcomes with RANKL inhibitors versus bisphosphonates. Outcome RANKL Inhibitors Bisphosphonates p-value Effect Estimate (95% CI) Medication-related osteonecrosis of the jaw (MRONJ) 1.30% (71/5,460) 0.64% (35/5,460) 0.0008 OR 2.05 (1.35–3.13); HR 1.82 (1.18–2.79) Antibiotic use (≤2 years) 38.5% 34.1% <0.001 — Median overall survival (months) 37.4 32.5 <0.0001 HR 0.89 (0.83–0.95) Hypercalcemia incidence 0.21% 0.46% 0.0278 —

Hemoglobin, albumin, lymphocyte, and platelet (HALP) score as a prognostic indicator in patients with bladder cancer undergoing radical cystectomy.

852 Background: Prognosis in cancer patients is a combination of tumor characteristics and immunobiology. While a variety of hemogram parameters have been examined, HALP scores have demonstrated some of the most significant prognostic value across multiple cancers. In this study, we examine the prognostic value of HALP scores in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). Methods: Using our prospective, IRB-approved cystectomy database, we identified patients who underwent RC between 2007 and 2024. Patients with incomplete CBC and CMP data were excluded. Patients were stratified into four quartiles (Q1-Q4, Q1 as reference). Associations of HALP scores with overall survival (OS) and recurrence-free survival (RFS) were assessed with multivariate Cox regression models. Results: The cohort included 1,098 patients who had CBC and CMP data within 60 days prior to RC, and HALP scores were calculated using the formula Hb×Alb×(#AbsLymph÷Pt) (demographics in Table 1). Of note, patients in HALP Q1 and Q2 had significantly more 30- and 90-day complications (p=0.02, p=0.01) and had more severe 90-day complications (p=0.02) compared to higher HALP quartiles (Clavien-Dindo classification). Patients in HALP Q3 and Q4 had improved OS (HR=0.575, p=0.0004; HR=0.673, p=0.01) as compared to Q1 quartile. Additionally, patients in HALP Q3 had improved RFS (HR=0.648, p=0.01). Conclusions: HALP scores are a significant marker for predicting postoperative complications and OSl in patients undergoing RC for BCa. HALP scores could be used for further risk stratification and for optimizing overall fitness before surgery. Demographic distribution of HALP cohort. Characteristics Q1 (N=274) Q2 (N=274) Q3 (N=275) Q4 (N=275) p-value Age, n (%) ≤65 yrs. >65 yrs. 73 (26.6)201 (73.4) 79 (28.8)95 (71.2) 82 (29.8)193 (70.2) 106 (38.5)169 (61.5) 0.01 Sex, n (%) M F 203 (74.1)71 (25.9) 214 (78.1)60 (21.9) 237 (86.2)38 (13.8) 243 (88.4)32 (11.6) <0.001 Charleson Comorbidity Index, n (%) 0 1 ≥2 48 (17.5)61 (22.3)165 (60.2) 59 (21.5)78 (28.5)137 (50.0) 62 (22.5)86 (31.3)127 (46.2) 60 (21.8)63 (22.9)152 (55.3) 0.03 Neoadjuvant chemotherapy, n (%) Y N 112 (40.9)162 (59.1) 114 (41.6)160 (58.4) 192 (69.8)83 (30.2) 68 (24.7)207 (75.3) <0.001 Pathological staging, n (%) Organ confined (< (y)pT2N0) Extravesical (> (y)pT2N0) Lymph node positive (pN+) 138 (50.4)51 (18.6)85 (31.0) 174 (63.5)40 (14.6)60 (21.9) 172 (62.5)43 (15.6)60 (21.8) 204 (74.2)34 (12.4)37 (13.5) <0.001 Complications, n (%) 30-day Y N 90-day Y N 181 (66.1)93 (33.9)7216 (8.8)58 (21.2) 160 (58.4)114 (41.8)193 (70.4)81 (29.6) 160 (58.2)115 (41.8)191 (69.5)84 (30.5) 146 (53.1)129 (46.9)180 (65.5)95 (34.5) 0.02 0.01 Severity of 90-day complications, n (%) None I-II III-V 67 (24.5)149 (54.4)58 (21.2) 90 (32.8)123 (44.9)61 (22.3) 93 (33.8)140 (50.9)42 (15.3) 99 (36.0)133 (48.4)43 (15.6) 0.02

Chiropto‐Neuromorphic Devices Based on a Photocatalytic Dye/Polymer Semiconductor Bulk Heterojunction for Circularly Polarized Light Detection and Memorization

ABSTRACT Neuromorphic computing, which emulates the energy‐efficient processing of the human brain, has emerged as a key technology for next‐generation artificial intelligence. Integrating sensitivity to circularly polarized light (CPL) provides an additional degree of freedom for optical data encoding, yet practical implementation remains limited by material instability and complex, non‐scalable fabrication. This work introduces a chiropto‐neuromorphic device that addresses these challenges through a polarized light‐induced charge transfer doping mechanism. The system employs a solution‐processed bulk heterojunction (BHJ) composed of a chiral boron dipyrromethene (BODIPY) dye and a polymer semiconductor (PBTTT‐C12) to translate CPL handedness into a stable nonvolatile memory state. Chirality‐dependent charge transfer modulates the polymer's doping level, enabling precise control of synaptic weight. The device emulates key biological synaptic functions, including short‐ and long‐term plasticity, paired‐pulse facilitation, and stimulus‐dependent plasticity governed by light number, duration, and intensity, while maintaining distinct chiroptical selectivity. Notably, its energy consumption remains at the picojoule (pJ) level per synaptic event, comparable to biological synapses. By introducing chirality as a new control dimension for synaptic modulation, this study demonstrates a scalable and powerful platform for polarization‐encoded neuromorphic information processing and establishes a foundation for advanced artificial sensory systems capable of handling complex chiral optical signals.

The cytoplasmic protein YedX is a potent inhibitor of CsgA amyloid assembly in E. coli

Mechanistic insights into bacillus Calmette-Guérin (BCG) sensitivity in non-muscle invasive bladder cancer (NMIBC) with ERCC2 alterations.

813 Background: Alterations in the nucleotide excision repair (NER) gene ERCC2 are common in bladder cancer (BC) and confer increased tumor mutational burden (TMB) and neoantigen load. Clinically, ERCC2- altered NMIBC tumors are associated with a favorable response to BCG. Because BCG can generate DNA-damaging reactive oxygen species (ROS) which are repaired by the NER pathway, we sought to determine whether differential response to ROS can explain the sensitibity of ERCC2 -altered NMIBC to BCG. To this end, we treated ERCC2 -altered and wild-type (WT) BC cell lines with hydrogen peroxide (H2O2) to assess the effect of free radical-induced DNA damage on cell death. Methods: The previously described BC cell line KE183 ( ERCC2 -altered KU-19-19 via CRISPR/Cas9) and parental cells (WT KU-19-19) were treated for 48 hours with graded concentrations of H2O2 using serial dilutions by two with a maximum dose of 500uM. A mono-tetrazolium salt (MTT) cell viability assay was performed following treatment and dose-response curves were generated to calculate half-maximal inhibitory concentrations (IC50) across experimental replicates (n=8). Results: The parental (WT) cell line exhibited an IC50 of 39.6 ± 3.3 uM H2O2 while the ERCC2 -altered KE183 cell line demonstrated an IC50 of 43.5 ± 7.2 uM H2O2, indicating comparable levels of cell death in response to oxidative stress. Despite the established increased sensitivity of ERCC2 -altered tumors to intravesical BCG, these results reveal no measurable difference in cytotoxicity following exposure to ROS. Conclusions: These findings suggest that the enhanced BCG sensitivity observed in ERCC2 -altered NMIBC is independent of free radical-induced DNA damage. Instead, BCG sensitivity associated with ERCC2 alterations likely reflects immunogenic mechanisms, such as increased TMB and neoantigen presentation, rather than differences in ROS-mediated DNA damage. Further investigation into ERCC2 alterations as a biomarker of the immunologic effects, rather than oxidative stress, of BCG treatment sensitivity in NMIBC are warranted.

Risk factors and treatment outcomes in metastatic prostate cancer with brain metastases.

62 Background: Prostate cancer with brain metastases (PCBM) are rare and carry poor prognosis. While prior studies suggest neuroendocrine (NE) histology and prolonged hormone therapy (HT) may contribute to PCBM, risk factors and optimal treatment strategies for PCBM are poorly understood. Methods: The National Cancer Database was queried for patients diagnosed with metastatic prostate cancer (mPCa) from 2010-2021. Demographics and tumor characteristics were compared between patients with and without PCBM. PCBM incidence and risk factors were assessed with temporal analysis and multivariable logistic regression. Overall survival (OS) was analyzed using Kaplan-Meier and Cox proportional hazards model. Subgroup analyses examined combinations of systemic (HT, chemotherapy, and immunotherapy) and local treatments including surgery, whole brain radiation (WBRT), and stereotactic radiosurgery (SRS). Results: Of 231,702 patients with mPCa, 2,562 (1.1%) had PCBM. No significant temporal increase in PCBM incidence was observed. PCBM more often had NE histology, other visceral metastases (particularly liver), and high Gleason grade. NE histology (aOR: 5.77, 95% CI: 4.90-6.79), liver metastases (aOR: 2.26, 95% CI: 2.06-2.49), and other visceral metastases (aOR: 2.47, 95% CI: 1.10-5.54) were independently associated with PCBM. Patients with PCBM had worse OS (15.1 vs 32.6 months, p<0.001). HT was associated with improved OS compared to no systemic therapy (17.2 vs 4.2 months, p<0.001). Immunotherapy and HT were associated with improved OS compared to HT alone (42.6 vs 17.2 months, p=0.002). In multivariable analysis, immunotherapy had a positive OS benefit (aHR: 0.20, 95% CI: 0.05-0.75) while WBRT was associated with worse OS (aHR=3.38, 95% CI: 1.69-6.76). Chemotherapy, surgery, and SRS had no significant OS benefit after controlling for confounding. Conclusions: PCBM is associated with aggressive disease features such as NE histology. However, we observed no significant temporal increase in incidence despite increasing NHA adoption. Liver metastases were associated with PCBM risk, warranting consideration of further brain imaging in these patients. Durable survival appears primarily dependent on systemic disease control, with local therapies potentially offering benefit in select cases. These findings underscore the need for molecular stratification and advocate for the inclusion of PCBM patients in future clinical trials. Multivariable Cox proportional hazards model for overall survival in PCBM. Variable aHR p-value Age (Cont) 1.035 0.002 CCI (Ref = 0) 1 ≥2 1.6871.557 0.0650.229 cT Stage (Ref <cT4) cT4 1.360 0.179 Histo (Ref = Adeno) NE 3.447 0.003 Other Mets (Ref = None) ≥1 Organ 1.696 0.119 HT (Ref=No) Yes 1.071 0.830 Chemo (Ref=No) Yes 0.780 0.327 Immuno (Ref = No) Yes 0.197 0.017 Surgery of Distant Site (Ref=No) Yes 1.588 0.262 SRS (Ref=No) Yes 0.386 0.198 WBRT (Ref = No) Yes 3.380 <0.001

Association of HER2 and NECTIN4 expression with clinical outcomes in patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin +/- pembrolizumab (EVP).

796 Background: NECTIN4 and HER2 immunohistochemistry (IHC) expression are emerging biomarkers and targets of approved therapies in aUC. There are limited data on outcomes with EVP in combination biomarker subsets. Methods: Pts with aUC treated with EVP who had tissue samples available for IHC staining were separated based on expression of NECTIN4 (H-score < 200 vs ≥200) and HER2 (IHC 0/1+ vs 2+/3+). Clinical outcomes were compared in 4 biomarker subsets (NECTIN4 High /HER2 High , NECTIN4 High /HER2 Low , NECTIN4 Low /HER2 High , NECTIN4 Low /HER2 Low ). For IHC staining, Abcam clone EPR15613-68 and Ventana clone 4B5 were used for NECTIN4 and HER2, respectively. Observed response rate (ORR) was evaluated using χ² test; progression-free survival (PFS) and overall survival (OS) were analyzed via Kaplan-Meier and Cox proportional hazards models (NECTIN4 Low / HER2 Low used as reference). Results: Among 69 pts with aUC and available biopsies between 9/2017 – 10/2024, 58 had both NECTIN4 and HER2 IHC data. Breakdown into 4 biomarker subsets and outcomes with EV+/-P are shown in the Table. Baseline pt characteristics including age, sex, primary tumor location, tumor histology, and prior lines of therapy were similar across groups. HER2 and NECTIN4 expression were significantly correlated (p = 0.01). For the overall cohort (n = 58), 28 pts had EVP and 30 had EV treatment. With a median follow up of 19.7 months (mos), ORR was 44%, mPFS 6.4 mos, and mOS 19.7 mos. No statistically significant differences in ORR, PFS, and OS were observed among the 4 subsets. Analyzing NECTIN4 IHC alone, pts with very high expression (H-score > 250, n = 19) had prolonged mPFS relative to the rest (16.9 vs 5.4 mos, p = 0.02), but no mOS difference (45 vs 15.9 mos, p = 0.1). Conclusions: In this single-institution retrospective study of pts with aUC treated with EV-based regimens, there were no significant differences in clinical outcomes between groups separated by combination of NECTIN4 and HER2 tumor expression. Analysis was limited by modest sample size across the 4 biomarker subsets. In an exploratory analysis, superior mPFS was observed in pts with very high NECTIN4 H-score (> 250). These findings should be validated in larger cohorts. NECTIN4 High / HER2 High (n=26) NECTIN4 High / HER2 Low (n=9) NECTIN4 Low / HER2 High (n=9) NECTIN4 Low / HER2 Low (n=14) ORR - % 48% (12/25) 38% (3/8) 57% (4/7) 33% (4/12) ORR Comparison* OR (95% CI), p 1.9 (0.5 - 10), p=0.4 1.2 (0.2 - 8.0), p=0.8 2.6 (0.4 - 20), p=0.3 NA mPFS - months (95% CI) 9.7 (6.4 - NR) 4.6 (1.8 - NR) 37.8 (4.2 - NR) 4.3 (1.9 - NR) mPFS Comparison*HR (95% CI), p 0.5 (0.2 - 1.1), p=0.08 0.8 (0.3 – 2.5), p=0.7 0.4 (0.1–1.3), p=0.1 NA mOS - months (95% CI) 22.4 (10.4 - NR) 9.6 (7.4 - NR) NR (6.5 - NR) 8.6 (4.2 - NR) mOS Comparison*HR (95% CI), p 0.5 (0.2–1.3), p=0.1 1.0 (0.3–2.5), p=0.8 0.4 (0.1–1.3), p=0.1 NA *NECTIN4 Low / HER2 Low group used as reference.

Zn ²⁺ Engineered Low‐Barrier LiNbO ₃ Enables Visible‐Light Programmable Ferroelectric Memristors for Noise‐Immune Neuromorphic Vision

ABSTRACT Lithium niobate (LiNbO 3 ), owing to its unique ferroelectric polarization and excellent optical properties, has shown great potential in high‐performance optoelectronic integrated devices. However, the high polarization switching energy barrier makes it difficult to achieve polarization reversal under low‐power visible light, severely limiting its practical applicability. Here, Zn 2+ ions were doped into the LiNbO 3 lattice to modulate the local lattice structure via valence‐state imbalance, effectively suppressing the formation of Nb Li 4+ antisite defects and reducing electron‐trap density. Meanwhile, the narrowed bandgap enhanced carrier excitation efficiency and improved depolarization‐field screening, lowering the polarization switching energy barrier by approximately 69% and enabling polarization reversal under low‐energy visible light illumination (10 mW cm −2 ). Accordingly, the fabricated Pt/Zn‐LiNbO 3 /Nb:SrTiO 3 optoelectronic bimodal memristor exhibits ultra‐stable switching voltage characteristics, with a voltage coefficient of variation as low as 2.2%–3.2%; a high on/off ratio of approximately 10 3 ; 2 4 clearly distinguishable resistance states; retention exceeding 10 4 s; and excellent endurance up to 10 8 cycles. Under visible light stimulation, the device emulates multiple representative synaptic functions, including short‐term to long‐term memory (STP–LTP) transition, paired‐pulse facilitation (PPF), and associative learning. Moreover, an optical reservoir computing neural network constructed from the device's multilevel optical memory and synaptic features achieves a high recognition accuracy of 98.6% on the noise‐corrupted MNIST dataset, demonstrating robustness and visual recognition capability comparable to biological systems. This study proposes a new materials design paradigm for constructing low‐barrier, high‐performance ferroelectric optoelectronic systems with integrated sensing, storage, and computation functionalities.

A conserved salt bridge network stabilizes the hepatic organic anion transporters OATP1B1 and OATP1B3

Real-world early quality of life (QOL) changes on IO-based regimens in the prospective observational ODYSSEY metastatic renal cell carcinoma (mRCC) study.

476 Background: Lack of standardized reporting and collection of patient-reported outcomes (PROs) limits cross-trial comparisons of first-line IO-based regimens for mRCC. Prospectively collected real world data may fill this important knowledge gap. Pts with stable/improved QoL at 3 mo versus baseline have longer median OS than pts with worse/unobserved HRQoL versus baseline (Cella, 2024). Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology), no prior systemic therapy (ST), and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. Descriptive statistics are used to show PRO score changes from baseline. We evaluate longitudinal change from baseline in PRO scores using least squares mean (LSM). Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Higher score indicates better QOL. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Results: As of 10/1/25, 360 pts were managed with ST, including 266 pts on IO-based combinations: 35 cabozantinib + nivolumab (C+N), 49 lenvatinib + pembrolizumab (L+P), 40 axitinib + pembrolizumab (A+P), and 142 ipilimumab + nivolumab (I+N). Overall median follow-up is 12.1 mos (IQR 6, 24). Age, sex and race were similar across regimens. Prior nephrectomy (50%) was lower than in trials. C+N and L+P pts had less clear cell (56 and 65%) versus A+P and I+N pts (94 and 82%). A+P pts had more favorable IMDC risk (19%) and less poor risk (14%). Baseline QOL was variable across regimens, with L+P generally the lowest. Absolute changes in PROs from enrollment to mo 3 (early change) by regimen are shown in the Table. LSM change from baseline in FKSI-19 and FKSI-DRS favored IO-IO versus IO-TKI at 3 mos but not at 6 mos (not shown). Conclusions: While early change in PROs did not meet the MID threshold between the IO-TKI and I+N cohorts, different patterns of early change are apparent among specific IO-TKI regimens. IO-TKI regimens exhibited higher variation in early PRO change vs I+N. As the data matures, we will associate baseline PROs and early PRO changes with early death and other outcomes. Clinical trial information: NCT04919122 . 3 month change. Instrument C+N (N=35) L+P (N=49) A+P (N=40) All IO-TKI(N=124) I+N(N=142) FKSI-19, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.3 (11) 2.8 (13) -3.2 (12) -0.2 (12) 0.7 (10) Median (IQR) 1.4 (-7, 6) 5.0 (-7, 11) -1.0 (-14, 5) 1.4 (-10, 8) -0.3 (-5, 6) FKSI-DRS, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.8 (5) 1.5 (7) -1.8 (6) -0.3 (6) 0.8 (5) Median (IQR) -0.5 (-5, 3) 2.0 (-5, 5) -1.0 (-5, 3) 0.0 (-5, 4) 0.0 (-2, 4) FACT-G, N (%) 27 (77) 32 (65) 29 (73) 88 (71) 102 (72) Mean (SD) 2.1 (14) 5.2 (16) -3.5 (15) 1.4 (15) 0.3 (13) Median (IQR) 4.0 (-4, 10) 1.2 (-6, 13) -6.4 (-11, 4) 1.6 (-8, 10) 1.6 (-7, 8)

Hypervigilance: A phase Ib clinical trial to optimize risk-benefit of nezastomig (PSMAxCD28 costimulatory bispecific antibody) plus cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer (mCRPC).

TPS295 Background: Prostate cancer harbors an immunosuppressive tumor microenvironment (TME), with few effector T cells and absent costimulatory signaling required for optimal T cell activation. Nezastomig is a first-in-class bispecific antibody targeting prostate-specific membrane antigen (PSMA) and CD28, the canonical co-stimulatory receptor on T cells. In an ongoing first-in-human phase 1/2 trial in patients with mCRPC (NCT03972657), nezastomig plus cemiplimab (anti-PD-1) induced durable clinical responses closely associated with immune-mediated toxicities. These toxicities were typically observed to be early-onset (within the first six weeks of dosing [unpublished]). We therefore hypothesized that with intensive toxicity monitoring and mitigation strategies and a less frequent dosing interval, the combination of nezastomig plus cemiplimab will have an acceptable risk-benefit profile and lead to durable clinical responses. Methods: This is an open-label, single-center phase Ib clinical trial in patients with mCRPC refractory to standard treatment options or refusing or intolerant to the current standard of care. Prior immunotherapies (including T cell engagers) and prior PSMA-targeted radioligand therapy are permitted. Patients receive three weekly doses of nezastomig as part of a monotherapy lead-in phase and then transition to every three-week dosing with the combination of nezastomig plus cemiplimab. A back-fill Bayesian optimal interval (BF-BOIN design has been implemented to find the recommended phase II doses, with dosing decisions based on safety, efficacy, and favorable immune TME changes (increase in CD8+ T cells and decrease in CD4+FoxP3+ regulatory T cells) identified in paired pre- and on-treatment tumor biopsies obtained after the first dose of combination therapy. Four dose levels of nezastomig will be investigated, ranging from 30 mg to 600 mg; the dose of cemiplimab is fixed at 350 mg IV every three weeks. Strict stopping rules have been implemented for patient safety. A total of up to 60 patients will be enrolled on study. The study is currently open and enrolling and to date, n=6 patients have been enrolled in the initial cohort (NCT06826768). Clinical trial information: NCT06826768 .

Pathologic findings and clinical outcomes after immune checkpoint blockade in renal cell carcinoma patients undergoing deferred consolidative nephrectomy.

525 Background: Consolidative nephrectomy (CN) is undertaken in selected patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint blockade (ICB). However, patient selection and post-operative management (e.g. treatment discontinuation) remains controversial. Standardized pathological response assessment may provide prognostic insight. We evaluated the association between pathological features and clinical outcome in patients undergoing CN after ICB. Methods: A multicenter retrospective study of patients with locally advanced or mRCC who underwent CN following ICB between 2018 – 2025 across five US centers was performed. Clinical and pathological features (tabulated by institutional genitourinary pathologist and oncologist) were collected both at baseline and during follow-up. The primary endpoint was 18-month progression-free survival (PFS) from CN by pT0 status (no residual viable tumor). Secondary endpoints included 18-month PFS according to major pathological response (MPR), defined as ≤ 10% residual viable tumor, residual sarcomatoid component (yes/no), and post-operative residual measurable disease. PFS was estimated from the date of surgery until progression or last follow-up using Kaplan-Meier method and differences in 18-month PFS between subgroups were compared using a two-sample z-test. Results: 137 patients were included; median age 63 years, 78% had stage IV disease; 87% clear cell RCC. Median follow-up was 34 months since start of ICB and 22 months after CN. ICB regimens included anti-PD1 + CTLA4 (42%), anti-PD1 + TKI (50%), and anti-PD1 monotherapy (7%). Median ICB duration prior to CN was 5.6 (IQR 2.8 – 12) months and median time to CN from last treatment was 1.2 months. Overall radiological objective response per investigator-assessed RECIST 1.1 pre-CN included CR 0.7%, PR 44%, SD 46%, PD 3.5% and median primary tumor shrinkage was 17.6%. On pathology, 12% achieved pT0, 22% MPR, 75% had histologic grade ≥3, and 14% had sarcomatoid features. Among pT0 patients, 29% received anti-PD1 + CTLA4 and 59% IO-TKI. At 18-months post-CN, the PFS was 100% for pT0 vs. 55% for non-pT0 (p < 0.01). Patients without sarcomatoid component (68% vs. 27%) showed significantly improved 18-month PFS (p < 0.01) and those with a MPR showed a trend toward longer 18-month PFS (72% vs. 55%, p = 0.14). Among stage IV patients, the absence of postoperative measurable disease (n = 51) was associated with superior 18-month PFS (70% vs. 43%, p < 0.01). Immediately after CN, 49% discontinued ICB and 54% discontinued TKI. Conclusions: Pathologic complete response was associated with longer PFS among patients undergoing deferred CN after ICB. These findings highlight the clinical relevance of standardized pathologic assessment in RCC and suggest that selected patients may achieve durable disease control following surgery.

Bio‐Inspired Hierarchical Nanoreactor With Hetero‐Coordinated Fe–P–Co Bridges for Whole‐Pathway‐Regulated Electrocatalytic Oxygen Reduction

ABSTRACT Efficient oxygen reduction reaction (ORR) requires coordination of oxygen adsorption, transport, and catalysis at active sites. Yet most studies address only one step, overlooking whole‐pathway O 2 regulation and thus limiting performance. Here, we report a bioinspired Co‐doped Fe 2 P on N‐doped carbon featuring a hierarchical eucalyptus‐like nanoarchitecture, engineered to regulate oxygen throughout the electrochemical cycle, where Fe–P–Co hetero‐coordinated bridges anchored to the carbon substrate through Fe─N bonds induce strong electronic coupling and polarization. The hierarchical structure generated local electric fields that enriched OH − and O 2 , while multilevel porosity accelerated oxygen transport. This enabled coordinated optimization of oxygen adsorption, transfer, and active‐site electronic configuration. This nanohybrid achieved a half‐wave potential of 0.938 V vs. RHE, sustained discharge in Al‐air batteries for 373 h, and delivered an energy density of 3487 Wh/kg. Theoretical simulations revealed that Co‐doping shortened Fe─P bonds and tuned the Fe electronic environment, lowering the d‐band center and weakening Fe 3d‐O 2p interactions, which reduced the *OH desorption barrier and accelerated ORR kinetics. In situ Raman spectroscopy revealed that Fe–P–Co bridges served as active centers facilitating *OH release during ORR. These findings indicate that integrating hierarchical architecture, hetero‐coordinated Fe–P–Co bridges, and electronic‐state modulation enables whole‐pathway O 2 management for efficient oxygen electrocatalysis.

A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant

Unveiling the rare: p16 expression and real-world management of penile cancer in Bolivia—Insights from a country with high HPV and penile cancer prevalence.

6 Background: Penile squamous cell carcinoma (PSCC) is rare but a major challenge in regions with high human papillomavirus (HPV) prevalence. Bolivia ranks among South American countries with the highest HPV infection and penile cancer rates, yet no molecular or outcome data have been published. This study presents the first Bolivian real-world cohort evaluating p16 expression, clinicopathologic features, and outcomes. Methods: Cross-sectional, ambispective (retrospective–prospective) observational study of patients with PSCC treated at the Instituto Oncológico del Oriente Boliviano (2018–2025). Fifty-three patients were included. Demographic, clinical, and histologic data (Cubilla prognostic index, p16 IHC) were reviewed, as well as treatments and responses. Results: Median age was 59 years. Phimosis occurred in 18.9%, and 22.7% had premalignant lesions. p16 positivity was found in 43.4%. No HIV-positive patients were identified. The glans was the predominant site (47.2%), followed by glans–prepuce (22.6%). Grades were mainly G2 (66%) and G1 (32.1%). Subtypes included keratinizing (24.5%) and conventional squamous (28.3%). Lymphovascular invasion appeared in 39.6%, perineural in 21%, and lymphocytic infiltrate in 28%. According to Cubilla index, 71.7% were high-risk. Stage IV disease predominated (37.7%). Surgery was performed in 51 patients: 22.6% total penectomy with bilateral lymphadenectomy, 7.5% penectomy alone, and 5.7% with orchiectomy. Complications were rare (infection 3.8%). Neoadjuvant chemotherapy was given only to 9.4%, adjuvant to 28.3%, and radiotherapy to 21%. Conclusions: This first national series shows high HPV-related (p16+) penile cancer prevalence (43.4%), comparable to Brazilian/Paraguayan data (40–50%), slightly higher than Argentinian reports (~35%), and well above North American and European data (20–30%). Most patients presented with locally advanced disease, reflecting diagnostic delay. These data supported the 2024 introduction of male HPV vaccination in Bolivia and the creation of the IOOB Uro-Oncology Tumor Board (2023), which standardized neoadjuvant chemotherapy use. Findings underscore the need to improve genital hygiene education, expand HPV vaccination, and train physicians for early detection of premalignant lesions and malignant tumors in this high-incidence region.

Efficacy and safety of disitamab vedotin combined with intravesical electromotive mitomycin-C in patients with HER2-expressing high-risk non–muscle-invasive bladder cancer: A phase II study.

772 Background: HER2 expression is an independent predictor of poor response to Bacillus Calmette–Guérin (BCG) therapy. Disitamab Vedotin (RC48-ADC), an anti-HER2 antibody–drug conjugate, inhibits HER2-mediated downstream signaling and delivers the cytotoxic payload monomethyl auristatin E (MMAE) to eradicate tumor cells, demonstrating efficacy in advanced bladder cancer. This study aimed to evaluate the safety and efficacy of RC48-ADC combined with intravesical electromotive mitomycin-C (MMC) in patients with HER2-expressing high-risk non–muscle-invasive bladder cancer (HR-NMIBC). Methods: In this single-arm, open-label, multicenter, phase II trial, 40 patients would be enrolled. All patients underwent complete transurethral resection of bladder tumor (TURBT) and were confirmed as HR-NMIBC according to European Association of Urology (EAU) guidelines. HER2 expression was defined as immunohistochemistry (IHC) 1+, 2+, or 3+. Eligible patients received RC48-ADC (2.0 mg/kg every 2 weeks for 4 cycles, followed by 2.0 mg/kg every 4 weeks for 4 cycles) plus intravesical MMC instillation for one year. The primary endpoint was 12-month disease-free survival (DFS). Secondary endpoints included DFS, overall survival (OS), and safety. Results: Between June 2024 and October 2025, 18 patients were enrolled. The cohort comprised 88.9% (16/18) males and 11.1% (2/18) females, with a median age of 63 years (range: 38–81). HER2 IHC expression levels were 1+ in 16.7%, 2+ in 61.1%, and 3+ in 16.7% of patients. High-risk features included pT1 stage (44.4%), grade 3 (G3) disease (38.9%), and multiple, recurrent, and large tumors ( > 3 cm; 11.1%). As of October 2025, no recurrence or progression events were observed. One death occurred due to causes unrelated to study treatment. All treatment-related adverse events (TRAEs) were grade 1-2, including peripheral sensory neuropathy (33.3%), alopecia (22.2%), fatigue (5.6%), and rash (5.6%). No grade ≥3 TRAEs were reported. Conclusions: The combination of RC48 and intravesical MMC demonstrated promising efficacy and favorable tolerability in patients with HER2-expressing HR-NMIBC, providing a viable alternative to BCG therapy and thereby preventing the need for subsequent cystectomy in this population.

Family awareness of genetic risk in affected Caucasian ancestry members with bladder cancer (BC) associated with germline variants in DNA‐repair genes (gDRGs).

868 Background: The aim of this study is to evaluate the awareness of Bladder Cancer (BC) in families with at least one affected Caucasian ancestry member harbouring germline variants in DNA‐repair genes (gDRGs). Methods: Data were collected from a prospective, monocentric cohort study founded by AIRC - Fondazione AIRC per la Ricerca sul Cancro (registered and emended with the number ID-IG-25027-V1.3). The study was conducted from June 2024 to August 2025 in a university tertiary hospital by a multidisciplinary approach to the patient (collaboration of the Departments of Oncology, Urology, Pathology, Radiology, and Medical Genetics Laboratory). We recruited patients with pathological diagnosis of muscle invasive BC (MIBC) who underwent radical cystectomy (RC). All the patients were offered to be tested for pathogenic variants (PVs), likely pathogenic variants (LPVs) and variants of unknown significance (VUS) in gDRGs. We includes Germline Homologous Recombination Repair (gHRR) plus Mismatch Repair (gMMR) variants. All of them who were positive for at least one variant were contacted to offer a family genetic counselling and testing for un-affected first-degree members. Un-affected gDRG positive members were offered a structured screening for early diagnosis of BC. The primary endpoint was to evaluate the willingness of un-affected subjects to be tested. The secondary endpoint was the acceptance to participate and attend, if resulted positive, to the screening programme. Results: Among 75 eligible patients, 72 underwent successful germline sequencing and 23 patients (30.6%) harboured at least one gDRG variant (mainly in ATM, ATR, BARD1, BRCA1-2, CHEK2, PALP2 and PMS2). Over those 23 patients, 22 (95.6%) accepted to share the genetic outcome with their un-affected family members. We identified 55 un-affected subjects aged between 35 and 75 years old (probands). Only 3 (5.4%) probands refused to be tested for gDRG variants. One (1.8%), with a family history of BRCA2, declared to have been previously tested as positive, and 51 (92.8%) were interested to be tested. All of them, if resulted positive, were agreed to participate in the subsequent screening programs by annual urine cytology, urine molecular test (Epicheck/Xpert Bladder Detection test), abdominal ultrasounds assessment and cystoscopy when indicated. Conclusions: These preliminary findings seem supporting a high awareness of genetic risk of affected Caucasian ancestry patients with BC when associated to gDRGs. We strongly support the urgent need to implement and expand awareness and BC screening programs in genetic high-risk populations.