Browse Articles

Tumor mutational burden to predict overall survival independent of TP53 status in TCGA bladder cancer cohort.

833 Background: Tumor mutational burden (TMB) is an emerging biomarker in bladder cancer and is linked to response to immune checkpoint inhibitors. However, its association with survival in untreated TCGA populations and its interaction with TP53 mutation status remain under-investigated in nontrial, publicly available cohorts. We evaluated the prognostic value of TMB and TP53 mutations in The Cancer Genome Atlas (TCGA) bladder urothelial carcinoma (BLCA) dataset. Methods: Publicly available TCGA-BLCA PanCanAtlas (2018) data were obtained via cBioPortal. Tumor mutational burden (TMB, mutations/Mb) was derived from sample level nonsynonymous mutation counts. High TMB was defined using the standard clinical threshold (≥10 mut/Mb) and a cohort-specific median cutoff (5.8 mut/Mb). TP53 mutation status was extracted from the mutation annotation file (MAF). Overall survival time and status were obtained from patient level clinical data. Cox proportional hazards models adjusted for age and sex were used, and Kaplan–Meier curves generated for visualization. Variant histology and stage were excluded due to limited availability in this dataset. Results: A total of 408 patients were included after excluding missing survival/predictor data, with 180 deaths observed. High TMB (≥10 mut/Mb) was significantly associated with improved overall survival (HR 0.60, 95% CI 0.41- 0.89; p = 0.011). Using a median-based cutoff, high TMB remained associated with improved survival (HR 0.56, 95% CI 0.41- 0.77; p < 0.001). TP53 mutation was not independently associated with survival (HR 1.0, p > 0.5), and no significant interaction between TP53 and TMB was observed (p > 0.90). Age was an independent risk factor (HR 1.03 per year, p < 0.001), while sex was not significant. Conclusions: In TCGA BLCA, high tumor mutational burden is independently associated with improved overall survival, regardless of TP53 mutation status. TP53 does not modify the prognostic effect of TMB. These findings support TMB as a robust prognostic marker even outside immunotherapy treated populations and warrant validation in clinical cohorts.

Availability of clinical trials investigating prostate cancer (PC) in the United States (US).

43 Background: Availability of clinical trials for advanced cancers in the US varies greatly by geographical region, with just 81.5% of the population living within 30 miles of a PC clinical trial site (Swenson et al., JAMA Oncol. 2024). However, PC trial distribution in US, in relation to local geographic and socioeconomic barriers of access, has not yet been characterized. Methods: Utilizing the ClinicalTrials.gov trial database, we collated all interventional PC trials enrolling adults dated June 1, 2019, to June 1, 2025. We then compiled age-adjusted PC incidence and mortality rates for each US county with Social Vulnerability Index (SVI) derived from the CDC, NCI, and the Agency for Toxic Substances and Disease Registry data. To investigate PC trial availability, we utilized a zero-inflated negative binomial (ZINB) regression model. This model adjusts for the high proportion of counties without clinical trial sites and estimates potential influence of county characteristics on trial presence. Our results are conveyed in incidence rate ratios (IRRs). Trial characteristics were summarized using descriptive statistics. Model generation used the “pscl” package in R v4.4.3. Results: Our analysis yielded 884 eligible trials across 613 US counties (20.1%). 141 trials (16.0%) investigated curative therapeutics and treatments, while 571 trials (64.6%) investigated non-curative treatments and other methods of supportive care. 446 trials (50.5%) investigated metastatic PC. Just 20 trials (2.3%) explicitly investigated or included neuroendocrine PC. 464 trials (52.5%) were sponsored wholly or partially by pharmaceutical companies. Our model yielded no significant relationship between PC incidence or mortality rates and trial presence (IRR 1.00, 95% CI 0.999-1.01, p=0.16; IRR 1.01, 95% CI 0.98-1.03, p=0.65). Compared to counties with high SVI (highest social vulnerability), counties with low SVI had just over twice as many trials per household (IRR 2.05, 95% CI 1.54-2.74, p<0.001). Counties categorized as low-medium and medium-high also had significantly higher trial presence (IRR 1.63, 95% CI 1.22-2.19, p<0.001; IRR 1.61, 95% CI 1.21, 2.14, p<0.001). Conclusions: Trial availability remains a significant challenge in health care access. Our analysis indicated PC trials were significantly more concentrated in counties with low social vulnerability. Expanding trial access to more socially vulnerable counties is a significant and crucial step in promoting equitable access to vital care.

SOLACE: A phase 1 pharmacokinetic, dosimetry, safety, and dose optimization study for a single dose of ¹⁵³ Sm-DOTMP to treat metastatic bone pain.

TPS271 Background: With patients with bone metastases commonly report pain and significant degradations in quality of life, current treatment options have limitations. Patients may not experience effective relief, and treatments often cause myelotoxicity and high costs. Bone pain is one of the most common forms of pain reported by patients with metastatic disease and significantly degrades quality of life. DOTMP is a bone-seeking chelating agent, and when radiolabeled with samarium-153 ( 153 Sm-DOTMP) is a therapeutic radiopharmaceutical that emits both beta particles and gamma photons to bone metastases. Prior Phase I experience (QSAM-101, n=5) demonstrated no DLTs, manageable hematologic toxicity, and early signals of pain relief. The Phase 1 Samarium Optimized for Long-lasting Analgesia in Cancerous End-stage bone pain (SOLACE) study aims to evaluate pharmacokinetics (PK), dosimetry, safety, and efficacy of a single dose of 153 Sm-DOTMP for the treatment of pain associated with metastatic bone cancer. Methods: This open-label, Phase 1 study includes dose escalation (Part A, n=9-15, up to 3 cohorts) and dose selection (Part B, n=18) in patients with painful metastatic bone lesions. In Part A, 3 patients per cohort will be enrolled in parallel into Cohort 1 and 2 and will receive 0.5 mCi/kg or 1.0 mCi/kg of intravenous 153 Sm-DOTMP, respectively. (Cohort 1: 0.5 mCi/kg; Cohort 2: 1.0 mCi/kg; Cohort 3: 1.5 mCi/kg). If no dose-limiting toxicities (DLTs) are seen in Cohort 2, 3 patients will be enrolled in Cohort 3 (1.5 mCi/kg intravenous 153 Sm-DOTMP). Cohorts 2 and 3 will enroll 3 additional participants if only 1/3 patients had DLT at that cohort; if ≥2 DLTs are seen, no further patients will be recruited at that dose level, and it will be declared a non-tolerated dose. The DLT observation period will be 6 weeks after administration, during which safety and tolerability will be closely monitored. Eligible patients will be aged ≥18 years with histologically confirmed malignancy with multiple metastatic bone lesions including ≥1 confirmed painful (pain score of ≥4 on Numeric Rating Scale 11 [NRS-11]) osteoblastic bone tumor that exhibits avid update as shown by 99m Tc-diphosphonate bone scans ≤60 days of 153 Sm-DOTMP administration. Patients will have had disease progression while on anti-cancer treatment or ineligible for such treatments with painful bone lesions not amenable to palliative EBRT. Patients must have been receiving a stable regimen of bisphosphonates and/or hormonal or endocrine therapy for ≥3 months prior to 153 Sm-DOTMP administration. This study is currently enrolling. Clinical trial information: NCT07197645 .

Optimizing docetaxel bladder penetration following gemcitabine pretreatment: An analysis of concentration and timing protocols.

785 Background: Shortage and suboptimal efficacy of BCG has spurred the development of novel treatments for patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). Sequential intravesical gemcitabine and docetaxel (Gem/Doce) has emerged as a promising and widely utilized treatment for NMIBC. Furthermore, there are numerous other sequential combination approaches of gemcitabine with other agents in development. There is a need to better understand tissue penetration profiles of sequential intravesical therapies. Herein, we aimed to understand the impact of gemcitabine concentration and duration on subsequent tissue penetration of docetaxel. Methods: IRB approval was obtained at the University of Iowa. Rabbit bladders were obtained and samples were cut into 38 mm diameter sections. Samples were incubated at 37°C and pre-treated with 20 mg/mL gemcitabine (MedChem Express) in artificial urine (Aldon Corporation) at varied incubation times (1x concentration at 0, 1, or 2 hours) and concentrations (0x, 0.5x, 0.75x, and 1x for 2 hours). Next, 0.75 mg/mL docetaxel (MedChem Express) was applied to the tissue for 2 hours. Tissues were flash frozen in liquid nitrogen and stored at -80°C. Each sample was cryosectioned into 50 μm slices, and 200 μg of tissue was weighed and extracted with five times its mass of ethyl acetate (Macron), and docetaxel concentration was determined. Results: There was a statistically significant increase in docetaxel penetration with gemcitabine pre-treatment. With no gemcitabine pre-treatment, the docetaxel concentration decreased to < 0.1 mg/mL after 2 hours. Gemcitabine concentration did not have a major impact on docetaxel penetration. There was similar docetaxel penetration with 1-3 hour gemcitabine pre-treatment. The tissue that was treated with gemcitabine for 4 hours maintained a 0.2 mg/mL concentration of docetaxel after two hours. Conclusions: Our preclinical study has implications for Gem/Doce optimization as well as for other sequential combination therapies. We found that gemcitabine pre-treatment was necessary for sufficient docetaxel penetration. One and two hour gemcitabine incubation times had similar effects. Additional studies are needed to continue to optimize sequential therapy combinations in NMIBC.

Amorphous/Crystalline Heterojunction Engineered High‐Density Strain in RuSeTe for Efficient Alkaline Hydrogen Evolution Reaction

ABSTRACT The efficiency and durability of electrocatalysts for the alkaline hydrogen evolution reaction (HER) are impeded by high overpotentials and sluggish kinetics, limiting their practical application. Here, we present a novel class of RuSeTe‐based electrocatalysts featuring high‐density tensile strain induced by amorphous/crystalline heterojunctions, where the strain distribution density is precisely regulated via interface length manipulation. Theoretical and experimental analyses reveal that the tensile strain optimizes the d‐band center and water adsorption energy, significantly reducing the energy barrier of the Volmer step. The optimized RuSeTe catalyst achieves an ultralow overpotential of 20 mV at 10 mA cm − 2 and a Tafel slope of 33 mV dec − 1 in alkaline media, outperforming state‐of‐the‐art Ru‐based chalcogenides. Furthermore, the catalyst exhibits sustained durability for 1100 h (>45 days) at a current density of 100 mA cm −2 , maintaining a nearly constant potential throughout the test. This work proposes a universal strategy for inducing high‐density strain through amorphous/crystalline heterointerface engineering, offering new insights into designing efficient and stable HER catalysts.

Fusion Strategy Toward Highly Crystalline Non‐Fullerene Acceptor Enables Simultaneously Enhanced Current and Voltage in Organic Solar Cells

ABSTRACT Organic solar cells (OSCs) offer unique advantages, yet their photovoltaic performance is limited by the challenge of optimizing molecular packing in photoactive materials. While A‐D‐A′‐D‐A‐type acceptors have improved efficiency by forming favorable 3D network packing, strategies to further enhance crystallinity without causing detrimental over‐aggregation are scarce. Herein, we report a distinctive non‐fullerene acceptor (NFA) congener, BrTh‐2Cl, via a molecular fusion strategy. This design ingeniously integrates a highly crystalline brominated‐thiophene unit with a chlorinated phenyl group onto the central core, engineering a highly effective terminal functionality that can effectively modulate molecular packing without over‐aggregation. In addition, the blue‐shifted absorption of BrTh‐2Cl caused by weak electron‐withdrawing of thiophene terminal group without malononitrile achieves complementary advantages with light harvest of L8‐BO. The incorporation of BrTh‐2Cl into a D18‐Cl: L8‐BO host blend enhances film ordering and electron mobility for higher current, while simultaneously suppressing non‐radiative energy loss. Consequently, the adjusted OSC achieves a remarkable power‐conversion efficiency (PCE) of 20.82% (certified 20.34%), a significant increase from the 19.03% of the binary device, accompanied by concurrent improvements in both short‐circuit current density and open‐circuit voltage. This work provides an effective molecular fusion strategy by terminal groups to refine molecular packing and propel the photovoltaic performance of OSCs.

Andrographolide targets syndecan4 to impair its interaction with syntenin and inhibits the biogenesis of small extracellular vesicles

Association of renal function in non-hydronephrotic patients receiving PD-1 ICIs for bladder cancer with treatment response.

767 Background: Renal insufficiency in bladder cancer (BC) patients is often attributed to hydronephrosis, yet it can also result from paraneoplastic nephropathy. In other malignancies, PD-1 immune checkpoint inhibitor (PD-1 ICIs) therapy has been associated with renal function improvement upon treatment response. Our retrospective study investigates whether a similar correlation exists in BC patients receiving PD-1 ICIs. Methods: Based on the populations from the TRUCE-01 (NCT04730219) and TRUCE-02 (NCT04730232) trials, which evaluated tislelizumab-based immunotherapy in bladder cancer (BC), this retrospective analysis included patients who received ≥3 treatment cycles followed by radical cystectomy (RC) or maximum TURBT (M-TURBT). Patients with hydronephrosis were excluded. Data collected included demographics and serum creatinine (SCr) at baseline and post-treatment; eGFR was calculated using the CKD-EPI formula. The primary endpoint was clinical complete response (cCR; no residual lesions found in the specimen from RC or m-TURBT). Secondary endpoints were overall survival (OS) and the rate of eGFR change (RΔeGFR). Statistical analyses included Wald-Wolfowitz test, Pearson correlation, ART-ANOVA, and propensity score matching (PSM). Results: A total of 90 non-hydronephrosis pts with BC were finally included in our study. The median age was 67 years (IQR 61-72), and 73 (81%) were male. Median SCr in baseline was 76.2 umol/L (IQR 65.5-84.2), while median eGFR was 87.9 (IQR 77.8-96.5) mL/min/1. 73m 2 in all pts. After 3 cycles of treatment, 54 (60%) pts achieved pCR, and the median RΔeGFR is +1.59% (IQR -3.09% to +7.03%). In subgroup analysis, we found that RΔeGFR of pts with renal insufficiency (baseline eGFR < 60) were significantly higher than pts without renal insufficiency (median RΔeGFR,+17.2% vs. +1.27%,p = 0.015). Further, Pearson correlation analysis indicated the statistical correlation between baseline eGFR and RΔeGFR (p = 0.023, Rs = -0.243). Moreover, we conducted ART-ANOVA to explore the association between the treatment response and RΔeGFR, suggesting that a significant difference in RΔeGFR between cCR and non-cCR pts is only present in the population with renal insufficiency (Interaction effect: p = 0.001, F value = 11.36). Interestingly, the cCR rate of pts with renal insufficiency at baseline was higher (72% vs. 58%), even though the difference didn’t reach statistical significance. To further validate our findings, we performed PSM in pts with muscle-invasive bladder cancer in our study, indicating that our initial findings remained robust (cCR rate: 86% vs 59%). Conclusions: In a word, our study suggested that for pts with non-hydronephrosis renal insufficiency, renal function improvement during immunotherapy for BC correlates with a better treatment response.

Skeletal-related event impact on prostate cancer mortality in the older population in the US: A 24-year trend regression analysis.

58 Background: Skeletal-related events (SREs) are a common cause of morbidity and mortality in metastatic castration-resistant prostate cancer (mCRPC). These complications are managed using bone-modifying agents (BMAs), radiation therapy, and surgery, and lead to diminished quality of life irrespective of their castration status. We sought to evaluate the mortality trends for patients with PC and SREs in patients of >65 years from 1999 to 2023 using the CDC WONDER (Wide-ranging Online Data for Epidemiologic Research) database. Methods: The database was searched from January 1, 1999, to December 31, 2023. Mortality trends were assessed by identifying prostate cancer international classification of diseases-10th revision code (ICD-10 code C61) as the underlying cause of death in individuals aged >65 years, and (SREs) as contributing causes using the following ICD-10 codes: S02, S12, S22, S32, S42, S52, S62, S82, S92, T02, T08, T10, T12, T14.2, Y93.2, E55, M80, M81, M84.4. Joinpoint 5.0 software was used to analyze mortality trends. Results: From 1999 to 2023, a total of 3,231 deaths were reported. Trend analysis revealed a decline in overall mortality from 1999 to 2014, with an annual percentage change (APC) of -1.60 (CI: -2.6, -0.5; p = 0.005), followed by a significant increase in mortality from 2015 to 2023, with an APC of 5.30 (p = 0.0001). When stratified by age, individuals aged 65-69 showed an insignificant decline in mortality over the entire study period. For those aged 70-74, mortality significantly decreased from 1999 to 2014 (APC: -3.02, CI: -5.0, -0.9; p = 0.008), but experienced an exponential increase from 2014 to 2023 (APC: 14.07, CI: 8.7, 19.6; p = 0.00005). In the 75-79 age group, mortality significantly decreased from 1999 to 2011 (APC: -5.6, CI: -9.5, -1.6; p = 0.0091), followed by a robust increase from 2011 to 2023 (APC: 7.06, CI: 2.7, 11.5; p = 0.002). For individuals aged >80 years, the trend showed an insignificant decline in mortality from 1999 to 2023 (APC: -0.260, CI: -0.8, 0.3; p = 0.380). Conclusions: Our study revealed significant trends in prostate cancer mortality attributable to SREs, contributing to a sharp increase from 2015 to 2023. Age-stratified analysis revealed that substantial mortality is reported in patients aged 70-79, with the most pronounced rise occurring after 2014. These findings emphasize the growing burden of SREs in older prostate cancer patients, underscoring the need for targeted interventions along with a focus on patient-reported outcomes to improve survival and quality of life.

CONSOLIDATE: A phase I/II study of radiotherapy combined with enfortumab vedotin (EV) for locally advanced bladder cancer with paired translational ctDNA and utDNA.

TPS912 Background: Locally advanced muscle invasive bladder cancer (LA-MIBC) is currently treated with sequential lines of systemic therapy, with local therapies rarely pursued. Trimodal therapy (TMT) with concurrent chemotherapy and radiotherapy (RT) is a curative local therapy; however, poorly tolerated with suboptimal outcomes in this patient population. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has demonstrated promising activity in LA-MIBC, and pre-clinical models have shown synergy between ADCs and RT. This phase I/II study is being conducted to determine the safety and efficacy of the combination of EV with RT and to analyze translational biomarkers, including circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA), with treatment response and outcomes. Methods: CONSOLIDATE is enrolling T4N0 or T1-4N2-3 LA-MIBC patients. Key exclusion criteria include prior pelvic RT and metastases beyond regional lymph nodes. Prior to study enrollment, patients must receive at least 2 cycles of EV with pembrolizumab. Patients must have no evidence of progression from EV with pembrolizumab prior to study enrollment. The phase I component of the study was conducted to determine the safe EV dose to be combined with RT with the starting dose of 1 mg/kg day 1 and 8 every 28 days during days of RT. RT schedule is 55 Gy in 20 fractions delivered over 4-5 weeks. Post study maintenance EV is optional per medical oncologist discretion. Primary endpoint of the phase I lead-in is safety of this combination therapy, with progression free survival as the primary endpoint of the phase II component. Key translational endpoints include ctDNA and utDNA collected prior to EV+RT and at 3 month follow up using an ultra-sensitive, tumor- informed minimal residual disease (MRD) assay. The planned enrollment is 41 patients, with 6 patients in the Phase I component. Patient characteristics from Phase I are summarized in Table 1. All patients receive intensity modulated RT with pelvic lymph nodes and selective lymph node boosting included. We will continue to enroll patients in the Phase II component with paired, bespoke ctDNA and utDNA assays for post-hoc minimal residual disease detection and prognostication. Clinical trial information: NCT06434350 .

Circulating angiogenic–myeloid cytokine axis to predict benefit from first-line immune-checkpoint inhibitor combinations in metastatic clear cell renal cell carcinoma.

550 Background: Metastatic clear cell renal cell carcinoma (ccRCC) first-line treatment relies on immune checkpoint inhibitor (ICI)–based regimens, including either dual ICI or ICI plus tyrosine kinase inhibitor (TKI) combinations. Despite clinical advances, selecting the optimal regimen remains challenging. Circulating biomarkers may provide a broader and more accessible overview of the tumor immune status compared with tissue-based biomarkers. Methods: Patients with metastatic ccRCC treated with first-line ICI combinations were included (NCT04932525). A 96-soluble factors panel reflecting immune activation, checkpoint regulation, and angiogenesis was quantified at baseline using the Olink Immuno-Oncology platform. In parallel, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) to identify major circulating immune subsets. Main endpoints included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: The study prospectively included 27 patients: 15 received ICI–TKI and 12 dual ICI. Unsupervised correlation analysis of baseline cytokines identified an angiogenesis/hypoxia cluster composed of PGF, HGF and VEGFA, which were strongly intercorrelated (mean ρ = 0.65, p < 0.001). An angiogenic score, defined as the mean level of these three cytokines, was calculated. Higher scores were associated with shorter PFS and OS in the overall cohort (log-rank p = 0.048 and p = 0.009, respectively). Stratified by treatment, this score retained its negative impact on OS in the dual ICI arm (log-rank p = 0.016) but not in the ICI–TKI group, where conversely higher scores were observed in responders (Wilcoxon p = 0.04), suggesting a differential predictive value. The angiogenic cluster correlated positively with myeloid-related cytokines such as IL6 and CCL23, as well as with a circulating transcriptomic myeloid signature (ρ = 0.60, p = 0.009). Consistently, single-cell RNA analysis revealed enrichment of myeloid cells among non-responders in the dual ICI arm (χ² test, OR = 0.71, p < 0.001), but not in the ICI–TKI group, confirming the link between angiogenic-myeloid activation and resistance to dual immunotherapy. Conclusions: Circulating immune factors provide an accessible window into the systemic immune state of metastatic ccRCC. Angiogenesis- and myeloid-related cytokines formed a functional cluster associated with an immunosuppressive, myeloid-skewed profile predicting lack of benefit from dual ICI but greater response to ICI–TKI combinations. These exploratory findings suggest that circulating angiogenic and myeloid signatures may serve as non-invasive biomarkers to guide first-line treatment selection in metastatic ccRCC. Clinical trial information: NCT04932525 .

Modular Supramolecular Polycations Enable Efficient Delivery of Diverse RNA Therapeutics and Vaccines

ABSTRACT We describe a modular, diverse, and customizable supramolecular‐materials platform that can deliver nucleic acids in vitro and in vivo. The chemistries deployed enable the generation of multiple supramolecular polycations, which can associate with RNA to form polyelectrolyte complexes, but which have the unique feature of reversible cross‐links, via host–guest interactions of monomers that display aromatic amino acid termini with cucurbit[8]uril (CB[8]). Families of supramolecular polymers can be prepared by simple variation in monomer structure, enabling the tuning of properties. We demonstrate that these supramolecular polyelectrolyte complexes with RNA can be prepared easily via automatable procedures to generate nanoparticles that meet Critical Quality Attributes for manufactured RNA vaccines and therapeutics. We show that these materials can deliver RNA to a range of cell types, displaying reporter‐protein expression at levels equivalent to, or greater than, commercial transfection reagents, with no acute adverse phenotypic effects. Finally, we demonstrate the success of our materials platform across a range of nucleic acid types, with expression of mRNA within tumors of an orthotopic Triple‐Negative Breast Cancer mouse model, knockdown of a kinase implicated in cancer progression via siRNA, and effective protection against H1N1 influenza virus challenge in mice following injections of self‐amplifying RNA.

Additive Manufacturing of Molecular Architecture Encoded Stretchable Polyethylene Glycol Hydrogels and Elastomers

Abstract Polyethylene glycol (PEG) networks are widely used in biomedical applications and are emerging as solid‐state polymer electrolytes for next‐generation lithium batteries. Leveraging additive manufacturing technologies, such as digital light processing (DLP), PEG networks can be transformed into micro‐architected metals and functional biomimetic vascular networks. However, developing stretchable PEG networks, let alone making them 3D printable, remains a fundamental challenge. Here, DLP printable, highly stretchable foldable bottlebrush PEG networks are reported. These networks are formed by rapid photopolymerization of low‐cost commercial chemicals in ambient air. The bottlebrush architecture enables high molecular weight PEG network strands that do not crystallize and remain elastic without solvents at room temperature. Upon large deformation, the folded bottlebrush backbone unfolds to release stored length to enable extreme stretchability. The resulting hydrogels and elastomers exhibit tissue‐like moduli ranging from ≈1 to ≈100 kPa and tensile breaking strains up to 1500%. The applications of bottlebrush PEG networks are demonstrated as matrices for highly stretchable and conductive solvent‐free polymer electrolytes at room temperature (≈900% strain and 1.2 mS cm −1 ), as well as resins for DLP printing of complex architectures, cytocompatible organ‐like geometries, functional devices, and multi‐material structures with seamless interface integration. The developed photocurable bottlebrush PEG networks promise immediate applications in advanced (bio)manufacturing and beyond.

CircAMOTL1 promotes adipose lipolysis and browning in cancer cachexia through miR-211-5p-mediated TET2 activation

Neoadjuvant sacituzumab govitecan (SG) plus pembrolizumab (Pembro), followed by response-adapted bladder sparing and adjuvant pembro, in patients with muscle-invasive bladder cancer (MIBC): SURE-02 primary analysis and biomarker results.

769 Background: Standard-of-care treatment for MIBC is radical cystectomy (RC) with neoadjuvant chemotherapy (CT), but ~50% of patients (pts) are ineligible for/refuse CT and survival for RC alone is poor. Neoadjuvant Pembro and SG monotherapies showed activity in MIBC within PURE-01 and SURE-01 studies. SURE-02 (NCT05535218) is a phase 2 study of neoadjuvant SG+Pembro and adjuvant Pembro, including a bladder-sparing approach depending on clinical response. We report results of primary analysis and final biomarker analyses. Methods: Pts age ≥18 y, ECOG PS 0-1, with histologically confirmed cT2-T4N0M0 MIBC, ineligible/refusing CT, and scheduled for RC received 4 cycles of Pembro 200 mg on D1 and SG 7.5 mg/Kg on D1 and D8, Q3W, followed by postsurgical Pembro x 13 cycles, Q3W. A reTURBT was allowed instead of RC, followed by Pembro x 13 cycles, for pts achieving a clinical complete response (cCR), stringently defined as a negative magnetic resonance imaging (MRI) and no residual viable tumor at reTURBT (ypT0). Primary outcome measure was cCR rate with 19 cCR required to meet the endpoint in a 2-stage design. Transcriptome-wide analyses (Decipher Bladder, Veracyte, Inc) and comprehensive genomic profiling (CGP, Foundation Medicine, Inc) assays were performed on baseline tumor samples. Results: From 10/23 to 02/25, 49 pts were treated and efficacy evaluable. 33 (67.3%) had a cT2 stage, 19 (38.8%) had a centrally confirmed variant histology. The cCR-rate was 38.8% (N = 19; 95%CI: 25.2-53.8); all these pts underwent a reTURBT; ypT≤1N0-x rate was 51% (N = 25). 12m Event-free survival (EFS: defined as any high-grade relapse, progression, further therapy to the bladder or death) was 71% (95%CI: 56.7-88.8); 12m-EFS in cCR was 90.9% vs 59.6% in non-cCR. All cCR pts were metastases-free after a median follow-up of 14 months; 2 pts developed an intravesical relapse. Grade ≥3 treatment-related adverse-events (TRAE) occurred in 8 pts (16.3%). No Grade 5 TRAE occurred. CGP revealed ERBB2 mutations/amplifications in 42.1% of cCR vs 13.7% non-cCR pts. Median TMB was 12.1 in cCR vs 7.9 in non-cCR pts. Variance by subtype showed that Luminal tumors had higher TROP2 and ERBB2 expression, as well as higher KEGG mismatch repair deficiency (MMR) signature. Molecular subtyping revealed higher cCR rates for Luminal subtypes (62% vs 31% in non-Luminal). Higher MMR KEGG signature was significantly associated with longer EFS (100% at 12 months). Conclusions: Perioperative SG+Pembro revealed a compelling cCR rate, with a manageable safety profile, allowing a bladder preservation with sustained remission in ~40% of pts. Pre-treatment biomarker analyses revealed an enrichment of putative biomarkers of response and outcome in Luminal subtypes. Clinical trial information: NCT05535218 .

Consensus guidance on early identification and management of peripheral neuropathy in patients with UC receiving enfortumab vedotin: A Delphi study.

661 Background: Peripheral neuropathy (PN) is a cumulative, debilitating, and potentially dose-limiting adverse event associated with enfortumab vedotin (EV) given either as monotherapy or with pembrolizumab (P). Due to the significant activity of EV+P in muscle-invasive bladder cancer and locally advanced or metastatic urothelial carcinoma (la/mUC), early identification and management of PN is a critical part of optimizing patient outcomes on EV+/-P. This study aims to develop consensus on best practices for early dentification and management of EV-associated PN, including how to counsel patients initiating EV and their caregivers on short/long-term PN monitoring. Methods: A RAND/UCLA modified Delphi panel included US-based, multidisciplinary healthcare professionals experienced in managing PN in patients with la/mUC treated with EV. A rating form (survey) informed by a targeted literature review (TLR) and individual expert interviews presented hypothetical patient scenarios and potential strategies for early identification, management of EV-associated PN, and counselling patients initiating EV and their caregivers on PN monitoring. Panellists independently rated strategy appropriateness using a 1–9 scale before and after an in-person meeting. Second-round ratings were analyzed using the RAND/UCLA Appropriateness Method to develop consensus-based clinical guidance. The Delphi panel is ongoing, and results will be reported at the time of presentation. Results: Here we present the findings of the TLR, which included 46 studies. Assessing PN is challenging as patients may underreport symptoms due to fear of treatment interruption, clinicians can underestimate symptom severity, and patient-reported outcomes may not correlate with objective findings. Functional assessments and screening questions at each treatment cycle can aid identification, while sensory assessments are performed selectively. There are no consensus guidelines for EV-associated PN. Dose modification is the primary management strategy, but evidence on outcomes after early intervention following PN emergence is limited. Pharmacologic interventions may be effective at reducing chemotherapy-induced neuropathic pain depending on whether the patient exhibits positive and/or negative PN-symptoms. Multidisciplinary approaches, including education or physical/occupational therapy may be beneficial. Conclusions: Early assessment, detection and proactive intervention are critical to improving outcomes in EV-associated PN in patients with UC. There are opportunities to further develop, educate and advance guideline-driven management of EV-associated PN. This ongoing Delphi study will provide the first expert consensus to guide clinical decision-making and address gaps in managing EV-associated PN in patients with UC.

Activity and biomarker analyses with casdatifan (cas), a next-generation HIF-2α inhibitor, in refractory clear cell renal cell carcinoma (ccRCC): Results from ARC-20.

493 Background: HIF-2α is a validated target in refractory ccRCC. ARC-20 is an open-label platform study evaluating Cas, a HIF-2α inhibitor, in metastatic ccRCC with prior anti–PD-(L)1 and VEGFR-TKI treatment. Cas elicits deep and enduring reductions in serum erythropoietin (sEPO). The approved HIF-2α inhibitor loses its effect on sEPO reduction after approximately 13 weeks (Choueiri, 2021). Here, we present updated efficacy with progression-free survival (PFS), safety, and exploratory biomarker findings including the relationship between sEPO changes and clinical outcomes. Methods: Data are reported from Cas monotherapy expansion cohorts from the phase 1 ARC-20 study (NCT05536141): Cas 100 mg QD (100QD) and a total group comprising all monotherapy cohorts (50 mg QD, 50 mg BID, 100 mg QD, 150 mg QD). Primary endpoint was safety. Secondary endpoint was ORR. PFS was an exploratory endpoint. Change in sEPO was assessed and correlated with efficacy. Results: As of August 15, 2025, median (range) follow-up was 12 (6–14) months (100QD; n=32) and 15 (6–26) months (all patients [pts]; n=127). At baseline, 72% (100QD) and 71% (all pts) had intermediate/poor IMDC risk score; all pts received prior IO/VEGFR-TKI therapy (median 3 prior lines; range: 1–6 [100QD], 1–11 [all pts]). The confirmed ORR was 35% (95% CI: 19, 55) in the 100QD cohort (all PR) and 31% (23, 40) in all pts (1 CR, 37 PR). Median PFS was not reached (95% CI: 5.7 months, not evaluable) and 12.2 (9.4, 20.6) months, respectively. Deep sEPO reduction was observed by study week 2 and sustained through study week 52. Deeper sEPO reduction was associated with higher rates of CR/PR and lower rates of PD (Table); sEPO reduction was significantly greater in those with disease control (CR, PR, SD) vs without ( P = .0018), with median best reduction of 86% vs 79%. Dose reductions due to Cas-related TEAEs occurred in 22% (100QD) and 24% (all pts). Most dose reductions were due to anemia (9% [100QD] and 14% [all pts]) and hypoxia (3% [100QD] and 7% [all pts]). Treatment discontinuation due to Cas-related TEAEs was infrequent in the 100QD cohort (3%) and in all pts (3%); no pts in the 100QD cohort discontinued due to anemia despite deep EPO suppression. No treatment-related deaths occurred. Conclusions: In heavily treated metastatic ccRCC, Cas monotherapy showed encouraging clinical activity and durable responses across cohorts. The extent of sEPO reduction correlated with clinical benefit, providing important linkage between tumor HIF-2α biology and clinical outcomes. The safety profile of Cas monotherapy remains manageable, supporting evaluation of the 100 mg QD dose now in phase 3 development. Clinical trial information: NCT05536141 . BOR by max sEPO reduction quartile. BOR < 25th (least deep)n = 29 25–50thn = 29 50–75thn = 29 ≥ 75th (deepest)n = 30 CR/PR 10% (3) 31% (9) 45% (13) 43% (13) PD a 38% (11) 21% (6) 7% (2) 10% (3) a Including 2 pts who had PD before 1st scan.

Insulin pathway changes in localized prostate cancer: A multi-institutional analysis.

380 Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN , FOXO , and PIK3CA , are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF Cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan-Meier curves were used to assess median overall survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, Cluster 1 (n=96) and Cluster 2 (n=337). Compared with Cluster 2, Cluster 1 consisted of decreased expression of PTEN (P<0.001) and PIK3R1 (P<0.001) along with increases in the expression of AKT1 (P<0.001), IRS1/2 (P<0.001), FASN (P<0.001), IGFBP2 (P<0.001), and MTOR (P<0.001). GSEA analysis revealed increased expression of the following pathways in Cluster 1 relative to Cluster 2: MYC targets, PTEN regulatory signaling, and AKT signaling via MTOR . Median overall survival was estimated at 117 months and 232 months for Cluster 1 and Cluster 2, respectively (P<0.05). Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that were associated with worse survival outcomes. This finding suggests that early insulin pathway dysregulation may contribute to risk of metastasis and poor outcomes. These findings support larger studies to determine if insulin pathway changes represent prognostic biomarkers at the localized stage.

Complementary Anion‐Cation Modulated Electrolyte with Balanced Conductivities for High‐Performance All‐Solid‐State Lithium‐Metal Batteries

ABSTRACT Solid‐state electrolytes with superionic conductivity and high compatibility with lithium‐metal anode are essential for high specific energy all‐solid‐state batteries. Here, we develop an argyrodite‐type solid‐state electrolyte that enables fast Li + transport and excellent interfacial compatibility with Li metal through a cooperative anion–cation modulation strategy. A robust anodic interface is spontaneously formed via the in situ reaction between Li metal and the tailored electrolyte. The cation Mo introduced into the electrolyte can be reduced to form a lithiophilic Li‐Mo alloy, while the anion N is capable of forming highly Li‐compatible Li 3 N. These interfacial products promote uniform Li stripping/plating and suppress parasitic reactions at the anodic interface. Meanwhile, Mo incorporation weakens the strong N─Li electrostatic interaction, ensuring rapid Li + migration within the electrolyte. The modulated electrolyte exhibits high dynamic stability and Li reversibility at the anodic side, enabling Li//Li symmetric cells to cycle stably for over 3100 h at 0.5 mA cm −2 . The Li//LiNi 0.8 Co 0.1 Mn 0.1 O 2 batteries demonstrate an ultra‐stable long cycle life with 75% capacity retention over 1500 cycles at 4C (3.0 mA cm −2 ), accompanied by an outstanding average coulombic efficiency of 99.99%. This work highlights an anion–cation cooperative modulation strategy for designing electrolytes that enable high‐performance all‐solid‐state lithium‐metal batteries.

Bio‐inspired Displays: Toward Intelligent Systems With Active Perception and Adaptive Interfaces

ABSTRACT Under the backdrop of deep integration between digitalization and intelligence, conventional display technologies are confronted with multiple constraints, including rigid form factors, limited visual experience, restricted physical performance, and weak environmental interaction. Bio‐inspired display technology, which draws on the evolutionarily optimized structures and mechanisms of biological systems, offers groundbreaking concepts and innovative pathways for the development of next‐generation display systems. This review systematically introduces the concept of “bio‐inspired displays” and organizes current bio‐inspired strategies and research advances in information display devices from two dimensions: “human‐inspired” and “nature‐inspired” approaches. Human‐inspired displays focus on human visual behavior and perceptual mechanisms, aiming to achieve deep integration between devices and users and provide healthier visual services. Nature‐inspired displays leverage the optical properties of biological structures to overcome the inherent limitations of conventional materials and architectures. The synergistic evolution of display technology and bio‐inspired engineering will significantly enhance the natural interactivity, visual comfort, and environmental adaptability of display systems. This paper provides an in‐depth analysis of the latest progress, existing challenges, and future directions in the field of bio‐inspired displays, reviews emerging bio‐inspired technologies and related fabrication processes, and establishes a theoretical framework and technical roadmap for next‐generation display innovation. It is foreseeable that bio‐inspired display technology will advance human–computer interaction from “passive viewing” to “active perception,” enabling breakthrough applications in smart terminals, digital twins, remote collaboration, and beyond.