Browse Articles

CAST-AI: Cystectomy after systemic therapy with ADC and immunotherapy.

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .

Quality of care (QoC) measures among patients with recurrent, papillary-only bacillus Calmette-Guérin (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC).

709 Background: QoC indicators, including those from the American Urologic Association Quality Registry (AQUA) and National Comprehensive Cancer Network (NCCN), have been developed to identify gaps in care for HR-NMIBC. HR-NMIBC carries high clinical and economic burden, and care often involves multiple interventions, including transurethral resection of bladder tumor (TURBT), routine cystoscopy, and intravesical therapy, which may impact quality of life. Although BCG is the recommended bladder-sparing therapy for HR-NMIBC, recurrence after treatment is common. This study described QoC measures following diagnosis among BCG-experienced patients with papillary-only HR-NMIBC with recurrence in the US. Methods: This retrospective cohort study included patients ≥65 years from the SEER-Medicare database (01/01/2007-12/31/2022) with HR-NMIBC (papillary carcinoma [stage T1 or high-grade Ta] without carcinoma in situ [Tis staging or diagnosis codes]) who were BCG-experienced (i.e., adequate induction; ≥5 instillations within 70 days) with recurrent disease, with recurrence defined as having BCG re-challenge, TURBT, biopsy, radical cystectomy, or treatment with other intravesical therapies, systemic chemotherapy, radiotherapy, or pembrolizumab any time after BCG discontinuation. A subgroup analysis was conducted among patients receiving subsequent treatment within 30 days of recurrence. QoC measures included monitoring, treatment, and health services-related indicators assessed from HR-NMIBC diagnosis to the earliest of 12 months, end of continuous enrollment, plan switch, death, or end of data. Results: Among 3,177 patients with HR-NMIBC who received BCG and had recurrence (overall), 166 patients received subsequent treatment within 30 days (subgroup). Mean age was 76 years, 78% were male, and 92% were White. For monitoring QoC measures, 42% (overall) and 41% (subgroup) did not have routine cystoscopy (every 3-4 months) after diagnosis. Repeat TURBT ≤6 weeks after initial TURBT occurred in 32% of the overall sample and 28% of the subgroup. For treatment QoC measures, 41% and 12% of the overall sample did not initiate BCG within 3 and 6 months of diagnosis, respectively; rates in the subgroup were 37% and 13%. For health-related services QoC measures, 21% (overall) and 18% (subgroup) had hospital readmissions ≤30 days after an initial hospitalization. Among patients with cystectomy, hospital readmission ≤3 months occurred in 32% (overall) and 28% (subgroup), while death ≤3 months after cystectomy was observed in 1% and 5%, respectively. Conclusions: QoC measures were not consistently achieved, suggesting persistent care gaps following diagnosis among patients with recurrent, papillary-only BCG-experienced HR-NMIBC, including those with subsequent treatment within 30 days of initial recurrence.

Elucidating the coordination of RNA processing using short-read and long-read RNA-sequencing methods

Construction and Microenvironment Regulation of Short Charge Transfer Tunnel at MOF/COF Heterointerfaces for Visible‐Light‐Driven Hydrogen Evolution

ABSTRACT Raising electron transfer efficiency is a crucial issue in improving photocatalytic productivity. Herein, we propose a strategy for anchoring single atoms and the establishment of a short‐distance electron transport pathway. By incorporating nitrogen‐containing monodentate ligands into UIO‐66‐NH 2 , Pt single atom could be co‐anchored by both the nitrogen atom and the vacant Zr‐oxo cluster. Subsequently, the Pt‐containing UIO was condensed with TpPa‐1. Thereby, a molecular‐level electron transfer pathway from TpPa to Pt has been established at the heterointerface between TpPa and UIO. By rationally adjusting the positions of the functional groups (‐H, ‐Cl, and ‐OCH 3 ) in the monodentate ligand, their involvement in the pathway was precisely regulated. They functioned as electron relays when positioned at the ortho‐position of the amino group, thereby facilitating the electron delivery. Cl exhibited a more pronounced effect compared to OCH 3 , UPT‐ o ‐Cl achieved the maximum H 2 yield of 14.21 mmol g −1 h −1 . Mechanism calculations revealed that the groups located along the pathway would regulate the microenvironment of the constructed tunnels, resulting in a higher electron density and enhanced ability to adsorb H intermediates of the Pt sites. This research reports a strategy for precisely regulating the microenvironment adjacent to the active site, providing new insights into enhancing carrier mobility and utilization efficiency.

Resolving the mRNA Encapsulation‐Release Trade‐off via Compensatory Forces in Engineered Ionizable Lipids

Abstract A critical challenge in lipid nanoparticle (LNP) delivery of messenger RNA (mRNA) is the inherent trade‐off between stable encapsulation and efficient intracellular release. Here, this challenge is addressed through rationally engineering compensatory forces between mRNA and LNP, leveraging short‐range intermolecular interactions (van der Waals, hydrogen bonding) to dynamically balance long‐range Coulombic binding. Guided by a computational‐experimental framework, a “contact number” metric is developed to decipher mRNA and LNP binding hierarchies, enabling the strategic incorporation of short‐range‐interaction motifs (e.g., urea, carbamate) into ionizable lipid (IL) structures. These designs achieve optimal mRNA encapsulation while promoting endosomal escape and cytosolic release, resulting in enhanced mRNA translation. Compared to commercial mRNA vaccine counterparts, the engineered LNP (OT13‐LNP) induces a 1.7‐fold increase in antigen‐specific T cell responses and 77.9% tumor inhibition in melanoma. In hepatic gene editing, OT13‐LNPs achieve comparable transthyretin (TTR) on‐target editing efficiency to ALC0315‐LNPs (0.5 mg kg −1 ), but elicit a markedly stronger silencing effect, reducing serum TTR levels by over 90% compared with ≈58% for ALC0315‐LNPs. This study may highlights the potential of compensatory‐force engineering for next‐generation mRNA therapeutics in oncology, gene editing, and infectious diseases.

Effect of pH on small-molecule inhibitor binding to influenza virus hemagglutinin

HCRN GU22-598: Phase 2 trial of enfortumab vedotin plus pembrolizumab with selective bladder sparing for treatment of muscle-invasive urothelial cancer of the bladder.

TPS891 Background: Radical cystectomy is a standard potentially curative treatment for patients with muscle-invasive bladder cancer (MIBC). However, it is associated with challenges including the need for urinary diversion, a detrimental impact on patients’ psychosocial health and body image, and potential morbidity and mortality. Further, despite being performed with curative intent, a large subset of patients experience metastatic recurrence. Neoadjuvant systemic therapy has been integrated into treatment of MIBC in an attempt to eradicate micrometastatic disease and improve outcomes. With standard cisplatin-based neoadjuvant therapy, ~30-40% of patients achieve a pathological complete response (pCR). The KEYNOTE-905 trial further showed a 57.1% pCR rate among patients who were predominantly cisplatin-ineligible and who received neoadjuvant enfortumab vedotin (EV) plus pembrolizumab (Vulsteke et al, ESMO 2025). These findings have raised the question of whether cystectomy is needed in all patients to achieve cure. We previously showed that with a response-guided bladder-sparing approach, in which patients achieving a stringently defined clinical complete response (cCR) after systemic therapy could omit cystectomy, that durable bladder intact survival is achievable in a subset of patients (Galsky et al, Nature Medicine, 2023). Building on this approach requires integrating more effective and generalizable systemic therapy. The KEYNOTE-905 trial recently established a role for EV plus pembrolizumab as neoadjuvant therapy for MIBC. The current trial seeks to integrate this regimen into a response-guided bladder-sparing paradigm. Methods: The Hoosier Cancer Research Network GU22-598 is a single arm multi-center phase II trial, investigating the use of enfortumab vedotin and pembrolizumab with response-guided bladder sparing for the treatment of localized MIBC (cT2-T3N0M0). The study is enrolling at 5 institutions, with a planned sample size of 47 patients. The primary endpoint is clinical complete response rate, a stringently defined composite endpoint based on results of MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies using a recommended template. All patients receive three cycles of neoadjuvant EV and pembrolizumab, with patients achieving a cCR omitting cystectomy and proceeding with additional 14 cycles of maintenance pembrolizumab, with EV given along with the first 6 maintenance cycles. Patients without a cCR proceed with cystectomy. The planned sample size of 47 patients is based on a hypothesized cCR rate of 45%, ensuring the lower bound of the 95% confidence interval exceeds 30%. The study was open to accrual as of February 2025. Primary completion is estimated to be in November 2027. The ClinicalTrials.gov ID number is NCT06809140. Clinical trial information: NCT06809140 .

Design and implementation of a patient-centric expanded access program with cretostimogene grenadenorepvec in non-muscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin.

TPS897 Background: Current guidelines recommend radical cystectomy for High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (HR BCG-UR NMIBC). However, many patients are unwilling or unfit for this intervention due to medical risks. Thus, there is a need for effective, well-tolerated, and accessible bladder-sparing treatments. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, while simultaneously amplifying an anti-tumor immune response, further mediated by the GM-CSF transgene. Results from the Phase 3 BOND-003 study led to cretostimogene receiving Fast Track and Breakthrough Therapy Designations by the US FDA for BCG-UR NMIBC with CIS. The cretostimogene Expanded Access Program (CRETO-EAP) (NCT06443944) an open-label, expanded access clinical trial provides cretostimogene to real-world patients who may not qualify for current clinical trials or are unable to access or tolerate currently available options. Methods: The eligibility criteria are pragmatic and inclusive of the at-risk population seen in real-world practice: ECOG PS 0-3, pathologically confirmed BCG-UR CIS +/- Ta/T1 after completion of adequate BCG treatment. The protocol has been amended to improve flexibility and include patients who received prior therapies for HR BCG-UR NMIBC, including investigational agents. Intravesical cretostimogene is administered in combination with n-dodecyl-β-D-maltoside (DDM), an excipient that enhances adenoviral delivery for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then biannually through Month 24. Re-induction is permitted. Additionally, patients with partial response, defined as persistent but improved disease at Week 25 or subsequent timepoints, may receive continued 3-weekly doses of cretostimogene at the discretion of the investigator. As per routine NMIBC surveillance, primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and bladder biopsies when clinically indicated, with pathologic samples reviewed locally. Co-primary endpoints include safety and complete response at any time. The incidence of adverse events will be reported using the Medical Dictionary for Regulatory Activities (MedDRA) and CTCAE v5.0. Secondary outcomes include Duration of Response, Progression-Free Survival, Cystectomy-Free Survival, Patient Reported Outcomes and Health-Related Quality of Life measures. A broad cross-section of geographically diverse clinical sites that serve socioeconomically diverse patients has been identified. The study is actively enrolling, with initial patients treated. Clinical trial information: NCT06443944 .

Extended multi-centre review of adjuvant pembrolizumab for renal cell carcinoma.

458 Background: In patients at increased risk of recurrence following surgical resection of RCC, adjuvant pembrolizumab has been shown to lower the risk of recurrence and improve overall survival. This treatment is now the standard of care in the UK. In the KEYNOTE 564 trial 96.3% of patients who received pembrolizumab experienced at least one adverse event and 32.4% of patients experienced an adverse event of grade 3-5. 38.9% of trial patients discontinued treatment early; 21.3% due to adverse events and 10.5% due to disease recurrence. 7.4% of patients who were treated with pembrolizumab required treatment with high dose systemic steroids (≥40mg prednisolone per day). Aims: To assess how real-world data from UK centres aligns with the outcomes reported in the KEYNOTE-564 trial. Methods: A retrospective analysis was conducted of 293 patients who received adjuvant pembrolizumab following surgical resection of RCC across 11 UK centres between 2022 and 2025. Data was collected on treatment-related toxicities, discontinuation rates, steroid use, and disease recurrence. Results: Between 2022 and 2025, 293 patients received adjuvant pembrolizumab. The median follow-up period was 11 months (range: 16–855 days). A total of 28 patients (9.6%) experienced disease recurrence, of which 16 (57.1%) occurred during treatment. At the time of analysis, 74 patients (25.3%) were still undergoing treatment, 107 patients (36.5%) had completed the full course, and 107 patients (36.5%) discontinued treatment early. Of those who discontinued, 89 patients (30.4%) stopped due to toxicity and 16 patients (5.4%) due to recurrence. Among patients who did not complete treatment, the mean number of cycles received was 4 (range: 1–8). Toxicities were varied, with the most commonly reported all-grade events being endocrine (27.6%), skin (23.6%), and arthralgia (11.3%). Grade 3 toxicities were observed in 39 patients (13.3%), and Grade 4 toxicities in 4 patients (1.4%). The most frequent toxicity leading to treatment discontinuation was colitis. Steroid use for toxicity management was reported in 100 patients (34.1%), with 57 patients (19.5%) receiving high-dose steroids. Additionally, 9 patients (3.1%) required further immunosuppression, including mycophenolate mofetil (4), methotrexate (3), and infliximab (2). Hospitalisation due to toxicity occurred in 43 patients (14.7%). There were three treatment-related deaths, attributed to pneumonitis, Triple M syndrome, and complications from nephritis and colitis. Conclusions: Data from 11 UK treatment centres indicate that discontinuation rates of adjuvant pembrolizumab due to toxicity are comparable to those reported in the KEYNOTE-564 trial. However, a higher proportion of patients in the real-world setting received high-dose steroid treatment (19.5%) compared to the trial population (7.4%).

Broadband Excitation of Antiferromagnetic Dynamics by Acoustic Phonons

ABSTRACT Excitation of antiferromagnetic dynamics is at the core of ultrafast spintronics. Coherent excitation of antiferromagnetic magnons is typically monochromatic, confined at dispersion intersections between antiferromagnetic magnons and the excitation source. Broadband excitation can be enabled by introducing electron spins in an incoherent manner, albeit accompanied by high energy consumption from Joule heating. Here, we demonstrate a broadband excitation of antiferromagnetic dynamics of 2D antiferromagnet CrSBr without Joule heating, by Rayleigh‐type surface acoustic wave (R‐SAW). Incoherent magnons are efficiently excited via the angular momentum transfer from acoustic phonons, across a wide range up to the spin‐flop field. The collinear alignment between the Néel vector and phonon angular momenta induces strong excitation of magnons with high phonon dissipation, whereas orthogonal alignment suppresses dissipation, as revealed by R‐SAW transmission. Our work uncovers a mutual interplay between phonon transport and antiferromagnetic order parameters, offering a broadband, low‐loss route to manipulate antiferromagnetic dynamics.

Reversible Metal Coordination Switch Enables Activatable Sonodynamic Therapy via Dual‐Death and Immune Synergy

ABSTRACT Sonodynamic therapy (SDT) holds great potential for disease treatment, yet its efficacy is limited by constitutive reactive oxygen species (ROS) generation and poor selectivity. Herein, we report a generalizable strategy using reversible metal‐ion coordination to regulate the sonodynamic activity of semiconducting polymers (SPs). A diketopyrrolopyrrole (DPP)‐based polymer (SPC) serves as the coordination scaffold, where binding with transition metal ions (Cu 2+ , Co 2+ , Zn 2+ , Fe 3+ ) redistributes electron density and increases the singlet–triplet energy gap (Δ E ST ), thereby effectively suppressing ROS generation. Among them, Cu 2+ is selected as a model ion due to its reductive responsiveness to glutathione (GSH) in the tumor microenvironment (TME). This enables SPCu to remain inactive during systemic circulation and become selectively reactivated within the TME. Released copper further induces mitochondrial dysfunction and cuproptosis, synergizing with ultrasound‐triggered ROS‐driven PANoptosis. Together, this dual‐death mechanism elicits robust tumor ablation, immunogenic cell death, and immune cell activation, leading to systemic antitumor immunity. Collectively, this study presents a reversible, metal coordination–based platform for constructing activatable organic sonosensitizers, offering precise SDT with immuno‐therapeutic synergy.

Phosphorylation-dependent regulation of serine/arginine-rich proteins and U2AF1 interactions in early spliceosome assembly

Phase 1B/2 study of combination ¹⁷⁷ Lu girentuximab plus cabozantinib and nivolumab in treatment-naïve patients with advanced clear cell RCC.

TPS582 Background: Complete response (CR) remains a rare outcome in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab and cabozantinib was approved for first-line treatment of ccRCC, demonstrating an improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR remains low, at only 12%. Strategies to enhance T cell anti-tumor activity may improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising immunomodulatory mechanism. 177 Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells expressed in >90% ccRCC to deliver targeted beta radiation to cancer with minimal off-target toxicity. As monotherapy in metastatic ccRCC, 177 Lu-girentuximab was safe and effective and stabilized disease in 57% of patients. We hypothesize 177 Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to enhance activated T cell trafficking and infiltration, thereby increasingCR rates. Methods: Up to 100 treatment naive, biopsy-confirmed ccRCC patients with adequate organ/marrow function and at least one evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety and futility monitoring will employ a Bayesian approach. The sample size was chosen to provide reasonable operating characteristics to distinguish a clinically meaningful CR rate of 18%(primary endpoint) from 9%, using a beta (0.09, 0.91) prior distribution. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab will be administered at 1480 MBq/m 2 (61% of single agent MTD)every 12 weeks for up to 3 cycles with 24-hour post treatment SPECT/CT imaging. Starting with cycle 2, patients will also receive standard-dose nivolumab and cabozantinib. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET/CT with 18 F-FAraG radiotracer as along with tumor biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05663710 .

Induction enfortumab vedotin plus pembrolizumab followed by maintenance pembrolizumab in first-line metastatic urothelial carcinoma (IMPROEV).

TPS893 Background: Enfortumab vedotin plus pembrolizumab (EV/P) is the preferred first-line regimen for metastatic urothelial carcinoma (mUC), demonstrating significant improvements in overall survival (OS) and progression-free survival (PFS) compared with platinum-based chemotherapy. However, continuation until disease progression or unacceptable toxicity leads to cumulative adverse events, particularly peripheral neuropathy, which is a common cause of treatment discontinuation. Post-hoc exposure–response analyses indicated that early EV dose intensity was associated with response, while declining serum EV concentrations over time did not compromise efficacy. In EV-103 and EV-201, 38–50% of patients who discontinued EV or EV/P maintained disease control for years, suggesting durable benefit after treatment cessation. These data support a finite-duration, induction–maintenance strategy over the traditional “treat-to-toxicity” approach. We hypothesize that induction EV/P followed by pembrolizumab maintenance in responders will preserve durable oncologic control while reducing cumulative toxicity and improving quality of life. Methods: IMPROEV is a single-arm, open-label, nonrandomized phase II trial enrolling 97 previously untreated patients with locally advanced or metastatic UC across four centers. Patients who received prior neoadjuvant or adjuvant checkpoint inhibitor therapy ≥12 months before enrollment are eligible. Patients receive EV 1.25 mg/kg IV on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 of each 21-day cycle for 6 cycles (18 weeks). Patients achieving confirmed complete or partial response per RECIST v1.1 transition to P 400 mg IV every 6 weeks for up to 2 years. Those with stable disease may continue EV/P or transition to P alone at investigator discretion. The primary endpoint is 18-month PFS. Secondary endpoints include OS, duration of response, treatment-free interval, incidence of peripheral neuropathy, and quality of life (EORTC QLQ-C30, BLM30, CIPN20). Exploratory analyses will evaluate ctDNA dynamics from baseline through progression. The trials uses a one-arm, two-stage design testing the null hypothesis that the proportion of patients who progress or die within 18 months ( p 0 ) is ≤0.56 versus the alternative ( p a ) of 0.67, with 11.4% type I error and 80.3% power. Stage I will enroll 31 evaluable patients; if >22 progress or die within 18 months, accrual will stop. Otherwise, 66 additional patients will be enrolled in stage II. Enrollment is expected to begin in Fall 2025. Clinical trial information: NCT07221942 .

Real-world survival outcomes with single-agent erdafitinib (Erda) in patients (pts) with advanced urothelial carcinoma (aUC) based on line (L) of therapy and prior enfortumab vedotin (EV) treatment (Rx).

694 Background: Erda, a pan fibroblast growth factor receptor (FGFR) inhibitor, has been approved since 2019 for pts with aUC harboring FGFR3 alterations. However, data on uptake and outcomes of erda, including its effectiveness before and after EV, are limited. We aimed to evaluate real-world survival outcomes and Rx patterns of single-agent erda in pts with aUC in a large database. Methods: This study used the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Eligibility: diagnosis of aUC between 1/13/2013 and 11/4/2024 and receipt of single-agent erda. Pts on clinical trials were excluded. The data cutoff date was 6/30/2025. The L numbers for single-agent erda were summarized using frequency and percentages. Time to next therapy (TTNT) was defined as time from erda initiation to the next L of Rx or death and censored at the lost to follow up. Overall survival (OS) was defined as time from the erda initiation to death and censored at the lost to follow up. For stratified analysis, pts who received any EV-containing Rx before or after erda were included. Kaplan-Meier method was used to estimate median TTNT and OS, and their 95% confidence intervals (CIs). Results: Of 15,236 pts with aUC in the dataset, 180 who received single-agent erda were eligible and included in the analysis. Start date for erda was between 5/1/2019 and 5/15/2025. Median age was 73 years (IQR 66 – 78); most were White non-Hispanic (73%), male (67%), and treated in community practice (78%). Erda was given in 2L for 36% of pts and in 3L for 32%. At a median follow up of 35.3 months, 76% of pts died, median TTNT was 5.3 mo (95% CI 4.9 – 6.2) and median OS was 9.1 mo (95% CI 6.9 – 12). Median TTNT and OS by L of Rx are summarized in Table. Among 180 pts, 107 also received EV: 45 received erda followed by EV and 62 received EV followed by erda. Median TTNT and OS was 5 mo (95% CI 4.5 - 7.9) and 17 mo (95% CI 14 – 21) when pts received erda followed by EV and was 4.9 mo (95% CI 3.8 - 6.2) and 5.4 mo (95% CI 4.9 – 9.7) when EV followed by erda. Conclusions: In this large real-world cohort, single-agent erda was mostly used in 2L-3L and associated with modest survival outcomes. Erda demonstrated sustained effectiveness regardless of L of therapy and prior EV exposure. These findings may help answer sequencing questions in clinical practice and help provide survival estimates for clinical trial design. Median TTNT and OS by line of Rx in pts with aUC receiving single-agent erda. Line of Rx Number of pts, n (%) Median TTNT (mo) (95% CI) Median OS (mo) (95% CI) 1 21 (12) 6.3 (3.5, 15) 21 (6.4, -) 2 64 (36) 5.6 (5.1, 7.5) 12 (8, 19) 3 57 (32) 5 (4.4, 7.2) 7.1 (5.8, 11) 4 24 (13) 4.4 (3, 15) 6.4 (4.3, -) 5 8 (4) 2.5 (1.3, -) 2.5 (1.6, -) 6 5 (3) 2.9 (1.9, -) 5.6 (5.1, -)

Multilineage differentiating stress-enduring cells alleviate neuropathic pain in mice through TGF-β and IL-10-dependent anti-inflammatory signaling

Preoperative CT radiomics–deep learning signature for lymphovascular invasion in bladder cancer: External validation and clinical utility.

857 Background: Lymphovascular invasion (LVI) critically guides neoadjuvant therapy, cystectomy timing, and surveillance in bladder cancer, yet it is rarely known preoperatively. We developed and externally validated lymphovascular invasion radiomics–deep learning signatures (LRDs) to noninvasively predict LVI and provide a clinicopathologic+LRDs nomogram. Methods: Retrospective two-center cohort of 302 bladder cancer patients with preoperative contrast-enhanced CT and pathologic LVI reference. QLYY split 7:3 (train/internal); TCIA external. CTs standardized; radiomics+DL features stacked. Performance (AUC, calibration, DCA) and survival (KM/Cox) evaluated. Results: 302 patients (training/internal/external 174/75/53; male 76%/87%/81%). Baseline features were comparable; the external cohort was older (69.3 y; SMD_age≈0.30) with higher LVI (54.7% vs 41–43%), more MIBC (54.7% vs 37–41%) and N+ disease (34% vs 19–25%), forming a tougher validation set. Among single-source models, radiomics-MLP outperformed DL-only (AUC 0.856/0.859/0.832 train/internal/external vs 0.758/0.746/0.773 for DL-LR). The stacked LRDs improved discrimination to 0.859 (95%CI 0.806–0.913) in training, 0.872 (0.792–0.952) internally, and 0.872 (0.773–0.972) externally, with ΔAUC vs radiomics +0.003/+0.013/+0.040 and vs DL +0.101/+0.126/+0.099. DeLong favored LRDs over DL and showed gains over radiomics (largest externally). DCA showed highest net benefit at pt = 0.20–0.60 with near-ideal calibration; results were stable in NMIBC/MIBC. Clinically: ≤0.20 rule-out (bladder-sparing), ≥0.60 rule-in (early RC/NAC). NRI confirmed incremental value (LRDs vs DL +0.159/+0.200/+0.075; vs radiomics +0.015/+0.044/+0.055 for train/internal/external). A clinicopathologic+LRDs nomogram achieved AUC 0.912 (95%CI 0.871–0.954) in training and 0.886 (0.808–0.965) internally. In multivariable analysis, MIBC, nodal positivity, HER2 overexpression, and LRDs (per-SD) were independently associated with LVI (all p < 0.05). LRDs generated clinically meaningful probabilities (e.g., 0.28 in pathologic LVI−, 0.65 in LVI+), aligning with the rule-out/rule-in cut points above. Prognostically, high LRDs predicted worse outcomes (PFS HR 2.35, 95%CI 1.55–3.57; OS HR 3.10, 1.90–5.06; both p < 0.001), with time-dependent AUCs 0.698/0.718/0.724 (PFS) and 0.730/0.741/0.781 (OS) at 1/3/5 years. Conclusions: The integrated CT-based LRDs accurately estimates preoperative LVI, is externally validated in a harder cohort, and adds independent value beyond pT/pN/HER2. With strong calibration and higher net benefit than single-source models, and deployable from routine CT via a clinicopathology+LRDs nomogram, it enables individualized counseling, guides perioperative planning, and stratifies PFS/OS risk.

Real-world outcomes of clear-cell renal cell carcinoma (ccRCC) patients treated with belzutifan stratified by von Hippel-Lindau (VHL) status.

475 Background: Belzutifan is a HIF-2a inhibitor with demonstrated efficacy in ccRCC associated with VHL syndrome. Belzutifan was also recently approved for sporadic advanced ccRCC after PD-1/PD-L1 inhibitor and VEGF-TKI therapy following the positive LITESPARK-005 trial. VHL inactivation results in constitutive activation of HIF-2a in VHL syndrome and also in sporadic ccRCC, providing clear mechanistic rationale for belzutifan. To date, no real-world data on belzutifan treatment correlated with genomic findings have been presented. We hypothesize that ccRCC patients with somatic alterations in VHL will experience superior response to belzutifan. Methods: Veterans included in the central cancer registry (VACCR) were queried for somatic tumor testing within the National Precision Oncology Program (NPOP) and treatment was obtained from VINCI (Veterans INformatics and Computing Infrastructure). Genomic results from commercial NGS assays were used to identify VHL alterations of any type. The Kaplan-Meier method was used to determine overall survival and time on treatment, defined as initial dispense of belzutifan to last dispense. Results: One-hundred nineteen (119) patients (pts) met inclusion criteria and were selected for analysis. Pts were predominantly male (116/119, 97.5%). Median age at initiation of belzutifan was 72.5 years. Median follow-up from initiation of belzutifan was 218 days (range 8 - 1431 days). Overall survival data (OS) were available for all patients. Genomic results were available for 39/119 pts (32.8%). Of these, VHL alterations were present in 30/39 pts (76.9%). Median time on treatment (TT) was 107 days (112 days for pts w/ genomic results). Median OS was 484 days (356 days for pts w/ genomic results). Among evaluable pts, median OS was 96 days when VHL alteration was absent and 484 days when VHL alteration was present (K-M p = 0.17). TT was 95 days when VHL alteration was absent and 113 days when VHL alteration was present (K-M p = 0.41). Conclusions: In this study of Veterans with ccRCC treated with belzutifan, pts with somatic VHL alterations may respond more favorably to belzutifan compared to pts without VHL alteration. A trend towards improved OS and time on treatment was seen in this cohort, but did not reach statistical significance. Further study is warranted to determine the benefit of belzutifan in ccRCC patients with somatic VHL alterations, as well as identify additional genomic correlates which may assist in patient selection or risk stratification.

Histopathologic and spatial transcriptomic analyses of en bloc resections of de novo and recurrent bladder tumors.

864 Background: En bloc transurethral resection of bladder tumors (ERBT) is a safe and effective treatment for non-muscle invasive bladder cancer (NMIBC). ERBT additionally preserves the relationship of the tumor, margin, and surrounding urothelium, enabling better evaluation of lateral extension (LE) of atypia and molecular changes in nearby tissues. Analyses of these specimens may provide unique insights into mechanisms of tumorigenesis and recurrence. Methods: En bloc specimens from de novo and recurrent high-grade papillary NMIBC were obtained via ERBT. H&E slides were prepared and reviewed to characterize LE, which was defined as atypical urothelium extending > 1 mm from the tumor base. Targeted next generation sequencing (NGS) of cancer-related genes was performed on tumor and LE samples. Spatial transcriptomic analyses were performed with the 10X Genomics Xenium platform. Results: 37 specimens from 26 patients (10 de novo, 16 recurrent) were obtained for analysis. 13 patients had multifocal tumors, and 35% of tumors had LE. 9/11 cases with LE were de novo tumors, whereas 14/15 cases without LE were recurrent tumors. Of those with LE, the surrounding atypia was generally low-grade (77%). 70% of LE extended to the ERBT resection margin with a mean length of 4 mm. NGS demonstrated overlap between tumor mutations and LE mutations in 8 samples (72%). 3 LE samples (all low-grade) had no identified mutations. Preliminary spatial transcriptomic analyses on 8 tumors (6 with LE) demonstrated differences with and without LE in terms of margin cell types and organization. With LE, there are cells that cluster with tumor cells throughout, compared to distinct cell-type clusters in margins without LE. Furthermore, ranking cells from basal to luminal subtypes showed normal urothelial organization in margins without LE and a disorganized structure in LE. Conclusions: ERBT preserves spatial relationships between NMIBC and surrounding tissue, permitting more informed analyses. These results suggest significant differences in the surrounding urothelium for patients with and without LE. The pattern of prevalence vs absence of LE in de novo vs recurrent cases suggests distinct biology between these entities, such as a field effect for initial tumorigenesis compared to reimplantation in recurrence. Clinically, the frequency of LE extending to the margin in de novo tumors argues for obtaining wider margins during initial resections. Total cohortN = 2637 tumors Lateral extension absentN = 15 (58%)24 tumors (65%) Lateral extension presentN = 11 (42%)13 tumors (35%) De novo 10 (38%) 1 (7%) 9 (82%) Multifocal 13 (50%) 9 (60%) 4 (36%) Mean tumor size (range) 1.1 (0.1-2.6) 0.9 cm (0.1-2.5) 1.4 cm (0.3-2.6) Mean LE size (range) - - 4.1 mm (1-10.8) LE at margin - - 9 (70%) NGS overlap (tumor vs LE) - - 8 (72%) Cell-clustering - Margin and tumor distinct LE and tumor overlap Basal to Luminal organization - Organized Disorganized

Solar‐Powered Radiation Cooling/Heating for Advanced Thermal Management of Wound

ABSTRACT Active heating and cooling techniques are widely used in biological tissue regeneration. However, given the growing emphasis on environmental sustainability, heat exchange without additional energy input is receiving increasing attention. This Perspective examines the influence of temperature on wound healing and explores the potential of passive radiative cooling and passive radiative heating for thermal wound management. The advantages are highlighted, relevant application scenarios outlined, and current challenges identified, with the aim of proposing novel zero‐energy wound treatment strategies for the biomedical field.