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HER2 and nectin-4 IHC expression and clinical outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

827 Background: Enfortumab vedotin and pembrolizumab (EV/P) is the standard of care for metastatic urothelial carcinoma (UC). Outcomes in UC based on HER2 IHC expression and correlation between membranous Nectin-4 and HER2 IHC expression have not been reported. Methods: A retrospective cohort of patients with metastatic UC treated with EV/P at Memorial Sloan Kettering Cancer Center was reviewed. Data were collected by chart review. HER2 and Nectin-4 IHC were performed on patients treated with EV+P and scoring was performed by MSK pathology. Response to EV/P was assessed using RECIST v1.1 and compared using Fisher’s exact test (unordered) and Cochran Armitage (ordered HER2 groups). Progression-free and overall survival (PFS, OS) were estimated from the start of EV+P using the Kaplan-Meier method and compared using logrank tests. Results: Of 232 patients treated with EV/P, 125 underwent both HER2 and Nectin-4 IHC. In the HER2 IHC cohort, the median age was 74 years; 71% were male; 30% had upper tract primary, and 43% had a component of variant histology. Median follow-up was 19 months (95% CI 16, 20). HER2 IHC distribution was 0-1+ 54%, 2+ 23%, and 3+ 23%. HER2 expression was associated with presence of membranous Nectin-4 expression ( P = 0.009). The presence (yes/no) of variant histologic features decreased across ordered HER2 categories, from 53% in HER2 0–1+ tumors to 45% in HER2 2+ tumors and 18% in HER2 3+ tumors (P = 0.0023). There was no significant association between baseline HER2 IHC status and best overall response (P = 0.077, Cochran-Armitage test) or OS (median OS HER2 0–1+: 26 months [95% CI 19, NR], 2+: 27 months [26, NR], 3+: 26 months [14, NR]; logrank p = 0.3). Median PFS was 8.1 months in HER2 0–1+ tumors and 12 months in HER2 2+ and HER2 3+ (logrank p = 0.3). Conclusions: In a large real-world cohort, HER2 and membranous nectin-4 co-expression were observed in the majority of tumors by IHC. Tumors with HER2 IHC 0 were also likely to have low Nectin-4 membranous expression. Clinical outcomes in HER2 0-1, 2+, and 3+ subgroups were similar, with no difference in PFS or OS observed based on HER2 clinical status. These data support that HER2 IHC expression is not prognostic for response to EV+P. Further follow-up and additional studies are needed for validation and to understand the landscape of HER2 expression following EV+P exposure. HER2 and nectin-4 IHC expression and clinical outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial cancer. Nectin-4 Membranous Expression Characteristic Overall N = 125 1 0 N = 14 1 > 0 N = 111 1 p-value 2 Her2 IHC Score 0.009  0-1 68 (54%) 13 (93%) 55 (50%)  2 29 (23%) 0 (0%) 29 (26%)  3 28 (22%) 1 (7.1%) 27 (24%) Clinical Outcomes with EV+P HER2 IHC Score mPFS p-value mOS p-value  0-1 8.1 m (5.1,10) 0.30 26.0 m (CI 19-NR) 0.30  2 12.0 m (7.1, —) 27.0 m (CI 26-NR)  3 12.0 m (6.9, —) 26.0 m (CI 14-NR) 1 n (%); 2 Fisher's exact test; **Cochran-Armitage test.

Efficacy and safety of belzutifan in patients with metastatic clear cell renal cell carcinoma (mccRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

479 Background: Belzutifan, a hypoxia-inducible factor 2α inhibitor (HIF2i), has been recently approved for the management of patients with advanced RCC following treatment with a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. We sought to assess the efficacy and safety of belzutifan in patients with mccRCC using the IMDC dataset. Methods: Patients with mccRCC treated with belzutifan monotherapy in the second-line setting or beyond were included. Cases were stratified by line of therapy (2-3L vers 4L+). Baseline demographic and clinical characteristics, as well as efficacy parameters and adverse events from belzutifan treatment were collected. Clinical outcomes included overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and overall survival (OS). TTF and OS were estimated using the Kaplan-Meier method. Results: Overall, 74 patients with mccRCC treated with belzutifan monotherapy were included, of whom 44 and 31 were treated in the 2-3L and 4L+ setting, respectively. Baseline characteristics were similar across subgroups stratified by line of therapy (Table 1). Median follow-up was 13.7 months. ORR was 10.7% (95% CI: 5.0-21.4%). In the 2-3L subgroup, ORR was 13.8%, while in the 4L+ subgroup it was 7.4%. DCR was 60.7% (95%CI: 47.6-72.4%) in the overall study population, with similar rates across line of therapy subgroups (i.e., 2-3L: 62.1% and 4L+: 59.3%). Median TTF was 7.72 months (95%CI: 4.17-12.0 months) in the overall population, reaching 10.81 (95%CI: 7.72-NR) and 3.68 (95%CI: 2.30-8.67) months in the 2-3L and 4L+ subgroups, respectively. The 12-month OS rate was 64.4% (2-3L subgroup: 80.8% and 4L+ subgroup: 40.3%). Among patients with available date for safety parameters (n=47), 38.2% experienced adverse events requiring belzutifan dose reduction, most commonly due to anemia or symptomatic hypoxia. Conclusions: In this retrospective analysis, belzutifan demonstrated lower efficacy compared to clinical trials, with poorer clinical outcomes identified towards later lines of therapy. However, higher rates of dose reduction (38.2%) suggest a need for proactive monitoring and management of adverse events. Larger studies with longer follow-up remain essential to identify optimal therapy sequencing schemes and help optimize the use of belzutifan in clinical practice. Summary of baseline characteristics in the study population, stratified by line of therapy subgroups. Total(n=74) 2-3L(n=44) 4L+(n=31) Age, median (IQR) 56.5 (51.0-63.9) 57 (49.9-64) 55.8 (52-63.7) Favorable IMDC Risk Group, n (%) 14 (25.4%) 7 (23%) 7 (28%) Intermediate IMDC Risk Group, n(%) 29 (52.8%) 17 (57%) 12 (48%) Poor IMDC Risk Group, n (%) 12 (21.8%) 6 (20%) 6 (24%) IQR: interquartile range.

A 3D‐Printed Piezoelectric Scaffold With Bio‐Inspired Gradient and Dynamic Adaptation for Tendon Regeneration

ABSTRACT Tendon regeneration requires materials that dynamically adapt to the healing stages, offering mechanical support, adhesion prevention, inflammation control, and collagen remodeling. We introduce a novel, dynamically adaptive piezoelectric hydrogel designed to address these requirements. The hydrogel features a bioinspired, anti‐adhesive lotus structure to minimize fibroblast and protein adhesion, preventing postoperative complications. Furthermore, it incorporates rationally designed gradients in piezoelectricity, mechanical properties, and degradation rate. These gradients allow the hydrogel to dynamically match the evolving needs of tendon healing, providing adjustable mechanical, electrical stimulation, and controllable degradation. The hydrogel demonstrably reduces inflammation (downregulating TNF‐α), promotes M2 macrophage polarization, inhibits bacterial growth, and stimulates endogenous tendon regeneration. This regeneration is characterized by increased collagen I deposition, improved fiber alignment, and enhanced biomechanical properties. Transcriptomic analysis revealed upregulation of genes associated with mechanotransduction, tissue remodeling, and anti‐inflammatory responses, alongside downregulation of fibrotic and oxidative stress pathways. This self‐powered, multi‐gradient scaffold represents a significant advancement in tendon tissue engineering, offering a promising strategy for tendinopathy treatment.

Sub‐Milliscale‐Resolution Bimodal Tactile Sensor Array with Human‐Skin‐Like Graphesthesia Sensation

ABSTRACT Multimodal sensory integration advances the development of embodied intelligent systems and robotics with human‐skin‐like tactile perception. However, the difficulties in simultaneously achieving high resolution and multimodality hamper the exquisite tactile perception to differentiate information through touching. In this study, we report a sub‐milliscale‐resolution bimodal tactile sensor array consisting of a piezoelectric sensor array for mapping pressure magnitude distribution and a triboelectric sensor array for contact height detection, enabling the calculation of Young's modulus distribution. As compared to existing studies, the bimodal tactile sensor array achieved sub‐milliscale spatial resolution of 700 µm and relatively high sensor density of 226 pixels/cm 2 , demonstrating fine‐grained multimodal perception. By combining the pressure mapping information from the piezoelectric sensor array and contact height information from the triboelectric sensor array, with a rapid response time of 50 ms, the Young's modulus distribution can be revealed. Furthermore, the tactile sensor array can achieve human‐skin‐like graphesthesia sensation and reconstruct the softness‐encrypted pattern with the assistance of deep learning algorithms, providing a paradigm‐shift strategy of sub‐milliscale‐resolution tactile perception toward embodied intelligence and robotics.

A high-throughput screen for nucleolar function reveals a role for the signaling protein, SPRR3, in ribosome biogenesis

Circulating tumor DNA dynamics as a predictive biomarker of response and survival in metastatic urothelial carcinoma treated with enfortumab vedotin and pembrolizumab.

860 Background: On treatment biomarkers that connect molecular clearance to clinical outcomes are needed in metastatic urothelial carcinoma (mUC). We tested whether circulating tumor DNA (ctDNA) kinetics, especially ctDNA negativity, track response and survival during enfortumab vedotin plus pembrolizumab (EV+pembro) treatment. Methods: This single-center retrospective study included 25 mUC patients treated with EV+pembro at The Ohio State University Comprehensive Cancer Center between August 2023 and August 2025. A tumor informed assay (Signatera) measured ctDNA longitudinally. Metrics included baseline detectability, early decrease (≤60 days), ctDNA negativity (0 MTM/mL) at any time, and rise after nadir. PFS and OS were measured from treatment start using Kaplan Meier and log rank methods. Hazard ratios were derived from univariate Cox regression analysis. Fisher’s exact test was used to assess associations with the ORR. Results: Median age 69 yrs; 68% male; ECOG 0–1 = 80%. Primary tumor site was bladder (80%) or upper tract (20%). Median follow up was 15.4 months. Baseline ctDNA was available for 18/25 patients and was detectable in all 18 (100%). Among those with baseline ctDNA, an on-treatment decrease occurred in 15/18 (83%) patients, including 13/18 (72%) within ≤60 days. Overall, ctDNA negativity was achieved in 15/25 (60%) patients. The best overall response was 5 CR, 14 PR, 4 SD, and 2 PD, for an ORR of 76%. ctDNA negativity aligned with response: the ORR was 100% (15/15) in patients who achieved ctDNA negativity versus 40% (4/10) in those who did not (p = 0.0012). ctDNA negativity was also associated with significantly improved PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021). Early decrease (≤60 days) showed non-significant trends toward improved PFS (HR 0.88, 95% CI 0.22–3.47; p = 0.86) and OS (HR 0.46, 95% CI 0.05–4.12; p = 0.49). The median PFS for the entire cohort was 9.59 months; median OS was not reached. Among 13 patients with a ctDNA rise after nadir, the median time from nadir to rise was 126 days, and the median time from rise to radiographic progression was 115 days, indicating potential lead time. In exploratory analyses, TP53 mutations (n = 11) trended toward shorter PFS (HR 4.44; p = 0.061) and lower ctDNA negativity (45.5% vs 88.9% without mutation; p = 0.07). TSC1 mutations (n = 3) trended toward shorter PFS (HR 4.51; p = 0.095) but showed no association with ctDNA negativity (p = 1.0). Conclusions: In EV+pembro treated mUC, achieving ctDNA negativity is a powerful on treatment biomarker, coinciding with a near universal radiographic response and substantially longer PFS and OS. An early decrease in ctDNA similarly indicated treatment activity and trended toward improved outcomes. These hypothesis generating findings support the prospective validation of ctDNA guided management strategies.

Duplex-Seq derived urinary cell-free DNA of Lynch syndrome patients with upper tract urothelial carcinoma.

838 Background: There is a critical need to develop urinary biomarkers for upper tract urothelial carcinoma (UTUC), especially for patients with Lynch Syndrome (LS), who have a 22-fold higher risk of developing UTUC. Urinary cell-free DNA (uDNA) represents a promising biomarker, but its utility has been limited thus far in predicting UTUC. However, LS-associated UTUC has three unique genomic features that may be targeted to improve biomarker capabilities; (1) somatic inactivation of the functional allele, (2) hypermutator phenotype, and (3) microsatellite instability (MSI). Herein, we apply Duplex-Seq, which is an ultra-accurate next-generation sequencing technology, to assess genomic alterations in uDNA with the goal of developing a more reliable biomarker for LS-associated UTUC. Methods: We performed Duplex-Seq on uDNA from 17 participants enrolled in a prospectively maintained biorepository at the University of Washington. The cohort included MSH2- mutated LS patients with active UTUC (LS+UTUC) (n = 3), MSH2 -mutated LS patients without UTUC (LS-UTUC) (n = 8), and non-LS patients with active UTUC (NonLS+UTUC) (n = 6). Sequencing targeted the 10 most frequently mutated genes in UTUC, MSH2 , and 17 poly-G microsatellites. Results: All LS+UTUC patients (3/3) exhibited second-site somatic inactivating mutations consistent with biallelic loss (VAF range: 0.00031-0.00075), and demonstrated markedly elevated mutation burdens (6.18±1.97x10 -8 ) indicative of a strong hypermutator phenotype. In contrast, none of the LS−UTUC patients (0/8) had second-site mutations; seven also had substantially lower mutation burdens (2.13 ± 1.60×10⁻⁸). NonLS+UTUC patients (6/6) had no MSH2 inactivating mutations and minimal mutation loads (1.26 ± 0.35×10⁻⁸). MSI status was inconclusive between LS+UTUC and LS-UTUC but suggested a slight increase relative to NonLS+UTUC patients. Conclusions: Duplex-Seq identified distinct mutational profiles in uDNA from LS-associated UTUC, distinguishing them from LS patients without UTUC and non-LS UTUC cases. These findings support the potential of uDNA as a non-invasive biomarker for early detection and surveillance of UTUC in LS patients, potentially guiding screening and clinical management in this high-risk population.

Trends in overall survival with evolving systemic therapies for metastatic non–clear cell RCC: An analysis over two decades.

474 Background: Metastatic non–clear cell renal cell carcinoma (nccRCC) is a rare, heterogeneous disease historically underrepresented in trials. Over the past two decades, systemic therapies including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (IO), and IO/TKI combinations have expanded, but their impact on survival in nccRCC remains poorly defined. Methods: We included patients diagnosed with metastatic nccRCC between 2004-2020 from National Cancer Database. We stratified patients based on therapy eras: pre-TKI, TKI, IO, and IO–TKI. We utilized Kaplan-Meier analysis and Cox proportional hazard models to study overall survival (OS)in patients with nccRCC. Results: We included 2,753 patients diagnosed with metastatic nccRCC from the NCDB. Among patients with nccRCC, those who did not receive systemic therapy had a median survival of 3.29 months (95% CI: 2.99–3.55 months). In contrast, patients who received systemic therapy had a longer median survival of 7.62 months (95% CI: 7.26–7.98 months). At 6 months, patients who did not receive systemic therapy had a survival probability of 32.9% (95% CI: 29.9–35.9%). By 12 months, survival declined further to 16.9% (95% CI: 14.7–19.5%). In contrast, patients who received systemic therapy demonstrated significantly better outcomes. At 6 months, survival probability was 62.1% (95% CI: 59.5–64.6%), and at 12 months, survival remained 27.6% (95% CI: 25.3–30.0%). Patients who received systemic therapy had 18% less risk of death compared to patients who did not receive systemic therapy. Additionally, each subsequent year of diagnosis had HR of 0.96 (95% CI: 0.95–0.97, p = 0.00) compared to previous year. Conclusions: Patients with metastatic nccRCC who received systemic therapy lived longer than those who did not (median 7.6 vs 3.3 months; ~18% lower mortality risk). Year-over-year survival gains (HR 0.96; p<0.001) align with wider use of TKIs, IO, and IO–TKI regimens. Given persistently modest survival, prioritizing enrollment in subtype-specific trials and ensuring timely access to active combinations should be central to care. Cox proportional hazards model evaluating factors associated with overall survival among patients with metastatic nccRCC. Variable Comparator HR (95% CI) P-value Age ≥65 years vs <65 years 1.02 (0.91–1.13) 0.78 Private insurance vs Uninsured 0.78 (0.60–1.01) 0.06 Non-academic facility vs Academic 1.13 (1.04–1.23) <0.001 Comorbidity ≥1 vs 0 1.07 (0.98–1.17) 0.13 Distance ≥50 miles vs <50 miles 0.87 (0.79–0.96) <0.001 Poor/Undifferentiated grade vs Well/Moderate 1.72 (1.50–1.97) <0.001 Cytoreductive nephrectomy: Yes vs No 0.46 (0.41–0.53) <0.001 Each Year of diagnosis vs Previous Year 0.96 (0.95–0.97) <0.001 Systemic therapy: Yes vs No 0.82 (0.76–0.89) <0.001

Bulk Passivation of Molybdenum Trioxide Enables Inverted Organic Photovoltaics with Significantly Enhanced Stability under Extreme Conditions

ABSTRACT While organic photovoltaics (OPVs) have achieved remarkable efficiencies, their practical deployment remains hindered by insufficient stability. Herein, we find that degradation is strongly associated with diffusion‐driven intermixing and redox chemistry at the buried molybdenum trioxide (MoO 3 )/photoactive materials contact region. To address this issue, we incorporate 1H‐isoindole‐1,3(2H)‐dione, 2,2’‐(oxydi‐4,1‐phenylene) bis[3a,4,7,7a‐tetrahydro‐(9CI)] (IPE) into the bulk heterojunction as a bulk passivator that interacts with diffusing MoO 3 species by passivating oxygen vacancies in MoO 3 , thereby suppressing redox reactions between MoO 3 and photoactive materials. The IPE‐containing devices achieve a champion efficiency of 19.06% alongside exceptional thermal robustness, retaining 87.5% of their initial efficiency after thermal aging at 170°C for 5 h (vs. 48.8% for control devices). Critically, under harsh environmental stressors, these devices maintain >80% of their initial efficiency after 500 thermal cycles (−40°C to 85°C, ∼60% relative humidity, ISOS‐T‐3) and over 1150‐h continuous maximum power point tracking under 1 Sun illumination (65°C, ∼50% relative humidity, ISOS‐L‐3). This represents one of the highest stability levels reported for OPVs under the stringent ISOS‐T‐3 and ISOS‐L‐3 protocols. This work provides a generalizable bulk modification strategy to mitigate diffusion‐ and redox‐driven degradation at buried contacts, paving the way for the practical deployment of stable, high‐efficiency OPVs.

A new family of TonB-dependent copper transporters linked to respiratory oxidase function

Germline DNA repair gene (gDRG) variants in BCG un-responsive patients: A potential genetic implication for risk stratification and target therapy.

808 Background: The introduction of the “BCG-unresponsive” definition by the U.S. Food and Drug Administration (FDA) has provided a structured framework for classifying patients unlikely to benefit from BCG therapy, accelerating the approval of novel therapeutic agents. There is an urgent need to improve tools predicting BCG failure. To address this unmet need, we investigated the predictive role of gDRG pathogenic variants (PVs), likely pathogenic variants (LPVs) and variants of unknown significance (VUS) in patients who received BCG. Methods: This is a nested case-control study, within an ongoing prospective single center trial, which includes patients with NMIBC who have received BCG and developed a recurrence. The study was founded by AIRC - Fondazione AIRC per la Ricerca sul Cancro, supported by the Italian Ministry of University and Research (MUR) under the National Recovery and Resilience Plan (PNRR), and registered in Italy (amendment number: ID-IG-25027-V1.3). This study was Naïve patient who received BCG treatment for HG-NMIBC from June 2023 to March 2025 underwent whole-exome sequencing. They were investigated for PVs, LPVs and VUS (including TM, ATR, MRE11A, BAP1, BARD1, BRCA1, NBN, BRCA2, PALB2, BRIP1, CHEK2, RAD51C, FAM175A, RAD51D, GEN1, XRCC1, and the mismatch repair genes MLH1, PMS2, MSH2, and MSH6). The primary endpoint was to describe the prevalence of PVs, LPVs and VUS in BCG un-responsive and responsive patients. Results: From January to June 2024 to August, a total of 18 naïve patients were enrolled. Seven patients (mean age 57.5 yrs – range 38-74) showed a recurrence during the follow-up and were defined “BCG un-responsive”. The median follow-up at the time of testing was 14 months. All patients had a history of high-grade bladder cancer and received intravesical BCG adjuvant treatment according to the SWOG protocol. None of the responders harbored PVs-LPVs, while two (18.1%) had VUS. In un-responsive group 2 over 7 (71.4%) presented at least a PV, and 5 a VUS; one of this was reclassified as LPVs by literature. The main variants were: ATM, BRCA2, MSH6, ATR, BARD1 and PALP2. The two BCG-unresponsive patients with more than one variant had a significant lower age at the diagnosis: 38 and 52 yrs old, and presented carcinoma in situ at recurrence. Conclusions: These very preliminary findings seem suggesting that gDRG variants could matter in patients who failed BCG course and underscore the need for further investigation into the utility of germline genetic risk stratification as crucial role in refining patient selection for BCG and new target therapies.

The molecular mechanism of lymph node metastasis driven by B lymphocyte FOXO1 palmitoylation induced by ACSL5 deficiency in bladder cancer cells.

835 Background: Bladder cancer (BLCA) is one of the most common malignancies of the urinary system, with muscle-invasive bladder cancer (MIBC) characterized by high aggressiveness and a strong tendency for lymph node metastasis. However, the molecular mechanisms underlying lymph node metastasis remain largely unclear, and there is currently a lack of safe and effective therapeutic strategies targeting this process. Methods: We established a murine popliteal lymph node metastasis model using MB49 bladder cancer cells. Through iterative in vivo selection over five consecutive rounds, we successfully generated a highly metastatic subline, MB49-LN5. Subsequently, we performed integrative analyses combining full-length transcriptomic sequencing, proteomic profiling, clinical BLCA tissue samples, and patient prognostic data, and identified ACSL5 as a potential key gene involved in lymph node metastasis. Further mechanistic studies were conducted using MB49 cells stably overexpressing wild-type or enzymatically inactive ACSL5. These cells were subjected to the popliteal lymph node metastasis model, along with in vivo tumor assays and flow cytometry analysis, to systematically assess the function and molecular mechanism of ACSL5 in BLCA metastasis. Results: Downregulation of ACSL5 markedly promoted lymph node metastasis of BLCA and was accompanied by a significant increase in tumor-infiltrating B cells within both primary tumors and metastatic lymph nodes. Functional assays demonstrated that the inhibitory effect of ACSL5 on lymph node metastasis was dependent on its enzymatic activity. Mechanistically, loss or inactivation of ACSL5 led to the accumulation of palmitic acid (PA) in the tumor microenvironment, which activated B cells and enhanced VEGF-C secretion, thereby promoting lymphangiogenesis and accelerating metastatic dissemination. Further molecular analyses revealed that PA induced palmitoylation of FOXO1, altering its subcellular localization and enhancing its cytoplasmic colocalization with AKT, leading to increased FOXO1 phosphorylation and suppression of its transcriptional activity. Reduced FOXO1 activity resulted in the downregulation of pro-apoptotic and cell cycle arrest–related genes, thereby facilitating B-cell proliferation and activation and accelerating lymph node metastasis. Conversely, mutation of the Cys111 site on FOXO1 reduced its palmitoylation, restored transcriptional activity, suppressed B-cell activation and lymphangiogenesis, and consequently diminished metastatic potential. Conclusions: Collectively, We revealed that ACSL5 modulates palmitic acid metabolism through its enzymatic activity, thereby shaping the tumor microenvironment by promoting B-cell proliferation and activation to facilitate lymphangiogenesis and metastasis.

Subclinical hepatic injury and risk of nonalcoholic steatohepatitis after adjuvant systemic therapy in early-stage testicular cancer survivors.

607 Background: Patients with early-stage TGCT have an excellent long-term prognosis. Guidelines recommend active surveillance (AS) or adjuvant chemotherapy (CT) or radiation therapy for patients with high-risk features. However, long-term treatment-related toxicities are an increasing concern, especially with a rise in cardiometabolic disease. Subclinical hepatic injury leading to non-alcoholic steatohepatitis is an underreported complication. We aim to evaluate the impact of adjuvant systemic therapy on liver function in early-stage TGCT survivors. Methods: We conducted a retrospective cohort study of consecutive patients with clinical stage I and IIa testicular germ cell tumors treated at a tertiary care center in Mexico between 2015 and 2024. Patients who received adjuvant systemic therapy were compared with those managed through active surveillance. Hepatic injury was assessed using the non-invasive FIB-4 (Fibrosis-4) and APRI (AST-to-Platelet Ratio Index) scores, which estimate the extent of liver fibrosis based on routine biochemical and hematologic parameters. Both scores were calculated at diagnosis and at the last follow-up. Changes in metabolic syndrome components, including overweight or obesity, hypertension, dyslipidemia, and insulin resistance, were analyzed. Statistical analysis was conducted using chi-square tests and Student’s t-tests to determine differences between groups. A linear regression model was employed to identify predictive factors. Statistical significance was determined using both a p-value <0.05. Results: We included 142 eligible patients. Most were managed with AS (N = 96, 68%), while 46 received systemic adjuvant treatment (32%). The mean age at diagnosis was higher in the adjuvant group (31.4 ± 7.7 vs. 28.5 ± 8.7 years, p = 0.049), with similar distributions of smoking status and clinical stage between the groups. Seminoma histology was more common among patients receiving adjuvant therapy (76.1% vs. 43.8%, p = 0.001). In multivariable analysis, adjuvant therapy was independently associated with increases in FIB4 score (β = 0.18, 95% CI 0.05–0.32, p = 0.009) and APRI score (β = 0.10, 95% CI 0.02–0.18, p = 0.019) at follow-up, after adjusting for baseline values. There was a clear trend toward a higher prevalence of metabolic syndrome risk factors, particularly overweight and dyslipidemia, in the AS and adjuvant CT groups, although these associations did not reach statistical significance in the regression analysis. Conclusions: Exposure to adjuvant systemic therapy seems to be an independent risk factor for long-term subclinical hepatic injury in survivors of early-stage TGCT. The observed metabolic changes also merit clinical attention. These results could support integrating non-invasive screening methods like FIB-4 and APRI for long-term follow-up.

Exceptional Thermal Switching Performance in 2D MoS ₂ Due to Hexagonal to Rhombohedral Phase Transition and Polarization Switch

ABSTRACT Active control of heat flow is crucial for managing thermal energy in sustainable technologies. However, current technologies are limited by the small switching ratio and narrow operating temperature range of thermal switching materials. Herein, we demonstrate that molybdenum disulfide (MoS 2 ) exhibits an excellent thermal switching performance across an ultra‐wide temperature range of 300–1573 K, based on a reversible transition between the non‐polarized hexagonal (2H) and electronically polarized rhombohedral (3R) phases. This phase transition is kinetically limited, and the presence of electric field lowers the transition barrier, dramatically reducing the temperature and pressure required to drive the phase transition. The application of the electric field results in a vertical flip from the out‐of‐plane alignment along the pressure direction in the 2H phase (“off” state) to an in‐plane polarization alignment along the electric field direction in the 3R phase (“on” state). This phase transition and polarized orientation switching, in conjunction with the significant anisotropic thermal transport properties of both phases, lead to a record‐high thermal switching ratio of 15.2 at 300 K and maintains 6.6 at 1573 K. Our findings provide a new avenue for exploring high‐performance thermal switch material triggered by phase transition and orientation changes in highly anisotropic materials.

A Soft Microrobot for Single‐Cell Transport, Spheroid Assembly, and Dual‐Mode Drug Screening

Abstract Physiologically relevant 3D cellular in vitro systems have enabled disease modeling and drug screening, yet these approaches remain hindered by stochastic self‐assembly, structural heterogeneity, and limited diffusion. While hydrogel scaffolds, 3D bioprinting, and microfluidic platforms have improved spatial organization and environmental control in such systems, these approaches often lack real‐time adaptability. This work introduces a soft and untethered hydrogel microrobot enabling targeted single‐cell delivery, spheroid self‐assembly, photothermal actuation, and sensing. The microrobot is composed of an alginate hydrogel network carrying gold nanorods for plasmonic heating and Rhodamine B for real‐time temperature sensing. Microfluidic encapsulation is used to fabricate uniform spherical microrobots. Microrobot locomotion is achieved through thermophoretic convection, allowing precise manipulation within 3D workspaces in an externally controlled manner. The microrobots facilitate single‐cell pick‐up and spheroid formation through carefully designed surface coatings. The microrobots simultaneously function as localized heaters, modulating the cell microenvironment via photothermal actuation, and as sensors, providing real‐time feedback on local changes in temperature. Combining photothermal stimulation with chemotherapeutic testing reduces the invasive behavior of fibrosarcoma cells in proof‐of‐concept studies, demonstrating the system's capability to function as a drug screening tool.

A brain-gut excitatory peptide/CCHamide homolog regulates satiation and motivational state transitions in the Aplysia feeding circuit

The association of androgen deprivation therapy with time to dementia: A large competing risk analysis.

136 Background: Androgen deprivation therapy (ADT), used for advanced prostate cancer (PC), has shown mixed associations with dementia in previous studies. We evaluated whether ADT for PC raises the risk of dementia in a large, real-world sample, hypothesizing that patients receiving ADT for PC would have higher odds of dementia compared with PC patients not treated with ADT. Methods: A de-identified open-claims real-world database (NorstellaLinq) included patients age ≥40 years, diagnosed with PC between August 1, 2015, through December 31, 2021, with follow-up data through March 31, 2023. We used target trial emulation, treating the date of PC diagnosis as day 0 and examining whether receiving ADT within 180 days was associated with risk of dementia at ≥365 days. Death was inferred for patients with no claims for ≥12 months. We used competing risk analyses, accounting for death as a competing risk. Covariates included age, presence of metastatic PC, other non-PC cancers, medical comorbidities, and race, derived using an algorithm based on Bayesian Improved Surname Geocoding. Results: Of the 1,495,181 patients who met the study criteria, 9.4% received ADT within 180 days after PC diagnosis; 16% died during the study. Dementia diagnoses after day 365 were observed among 4.2% of ADT recipients and 4.2% of patients not treated with ADT. Using ADT within 180 days after PC diagnosis was not associated with dementia (aHR [adjusted hazard ratio]=0.993, 95% CI 0.97–1.02, p=0.639); ADT was associated with higher adjusted risk of death (aHR=1.268, 95% CI 1.25–1.28, p=3.5e –285 ). Sensitivity analyses found similar results. Compared with White patients, Black (aHR=1.40, 95% CI 1.34–1.46, p=8.9e −54 ) and Hispanic patients (aHR=1.26, 95% CI=1.21–1.32, p=6.7e −23 ) had higher risk of dementia. In analyses examining dementia risk among patients receiving various classes of ADT, patients receiving gonadotropin-releasing hormone agonists had higher risk of dementia (aHR=1.05, 95% CI 1.02–1.090) compared to patients not receiving ADT, and patients who received androgen receptor inhibitors (aHR=0.91, 95% CI 0.86–0.95) or androgen synthesis inhibitors (aHR=0.85, 95% CI 0.77–0.95) had lower risk of dementia than patients not receiving ADT. Conclusions: Contrary to our hypotheses, we found no increased risk of dementia among PC patients treated with ADT compared with those not treated with ADT in this large, real-world sample. However, future studies should further examine the findings of higher dementia risk among Black and Hispanic patients and among patients receiving gonadotropin-releasing hormone agonists.

Induction ipilimumab plus nivolumab followed by consolidating chemoradiotherapy as bladder-sparing treatment in stage II/III urothelial carcinoma of the bladder: The phase 2 Indi-Blade trial.

LBA637 Background: Radical cystectomy remains the most commonly used curative treatment for muscle-invasive bladder cancer (MIBC). Bladder-sparing options are typically for patients (pts) with limited tumors, or those unfit for cystectomy. Effective systemic induction therapy could broaden the population eligible for bladder-sparing treatment. The NABUCCO trial showed promising pathological complete responses (43-46%) and a 5-year overall survival (OS) of 70% using neoadjuvant ipilimumab (ipi) + nivolumab (nivo) in stage III MIBC pts. We hypothesize that induction immune checkpoint inhibition (ICI) followed by chemoradiotherapy (CRT) is an effective bladder-sparing approach in MIBC pts. Methods: Indi-Blade is a multicenter, single-arm, phase-II trial, enrolling cT2-4aN0-2 MIBC pts. Treatment consists of ipi 3mg/kg (day 1), ipi 3mg/kg + nivo 1mg/kg (day 22) and nivo 3mg/kg (day 43), followed by standard-of-care CRT using mitomycin C and fluoropyrimidines (5FU or capecitabine. The primary endpoint is two-year bladder-intact event-free survival (BI-EFS), estimated by Kaplan-Meier analysis. Events are defined as muscle-invasive, nodal or distant recurrence; cystectomy; switch to chemotherapy or death by any cause. With a two-sided alpha of 0.05, a sample size of n = 50 has 81.3% power to exclude an estimated BI-EFS of 50% (median 24 months), with a target two-year BI-EFS of 70% (median 46.6 months). Secondary endpoints include OS, toxicity and circulating tumor DNA (ctDNA) analysis. Results: 50 pts were enrolled between February 2022 and February 2024. Pts had cT2N0 (22; 44%), cT3N0 (21; 42%) and cN+ (7; 14%) MIBC. 45/50 pts (90%) proceeded to CRT following induction ICI. After a median follow-up of 28.7 months (interquartile range 22.6 – 34.7), the primary endpoint of estimated two-year BI-EFS was met at 76% (95%CI 0.65-0.89; p < 0.001). Estimated two-year OS was 96% (95%CI 0.9-1.0). Grade ≥3 immunotherapy-related AEs occurred in 24% of pts; grade ≥3 CRT related AEs occurred in 6%. ctDNA positive status was associated with significantly shorter BI-EFS compared to ctDNA negatives at both baseline (HR = 4.5, p = 0.02) and after induction ICI (HR = 6.1, p = 0.02). Pts who were ctDNA negative at baseline or post-ICI had an 88.6% and 88.4% two-year BI-EFS, respectively. ctDNA clearance in baseline ctDNA positive pts occurred in 76.9% (10/13 evaluable pts) post-ICI and 91.7% (11/12) post-CRT. Conclusions: Induction ipi + nivo followed by CRT provided encouraging two-year BI-EFS and OS in MIBC pts. ctDNA negative pts at either baseline or post-ICI had high rates of BI-EFS. Potent systemic induction ICI followed by CRT is an effective bladder-sparing treatment strategy for a broad population of MIBC pts. Clinical trial information: NCT05200988 .

Prognostic significance of the preoperative De Ritis ratio and its association with sarcopenia in muscle-invasive bladder cancer: A multicenter retrospective study.

859 Background: The De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) has been reported as a prognostic biomarker in various malignancies. Given the role of hepatic glucose metabolism in bladder cancer cells, the De Ritis ratio may also serve as a prognostic indicator in muscle-invasive bladder cancer (MIBC). However, its impact on oncological outcomes and its association with sarcopenia in patients undergoing radical cystectomy (RC) remain poorly understood. Methods: This multicenter retrospective study included 881 patients with MIBC who underwent RC. The De Ritis ratio was measured preoperatively. The optimal cut-off value for recurrence was determined using receiver operating characteristic curve analysis. Patients were stratified into two groups based on the De Ritis ratio: lower and higher. Multivariable Cox proportional hazards regression analyses were conducted to assess the impact of a higher De Ritis ratio on recurrence-free survival (RFS) and overall survival (OS). Muscle quantity was evaluated using the psoas index (PI) derived from preoperative computed tomography images, with lower PI values indicating sarcopenia. The association between the De Ritis ratio and PI was analyzed using Spearman’s rank correlation test. Results: The median age and follow-up duration were 70 years and 55 months, respectively. The optimal cut-off value for the De Ritis ratio was 1.40. Of the 881 patients, 244 (28%) had a higher De Ritis ratio. Both RFS and OS were significantly shorter in the higher De Ritis ratio group compared to the lower group ( P < 0.001 for both). After adjusting for confounding variables, a higher De Ritis ratio remained significantly associated with shorter RFS ( P = 0.017; hazard ratio [HR]: 1.394; 95% confidence interval [CI]: 1.060–1.834) and OS ( P < 0.001; HR: 1.548; 95% CI: 1.221–1.961). The De Ritis ratio was not significantly correlated with PI in female patients (ρ = –0.049, P = 0.516), but showed a significant negative correlation in male patients (ρ = –0.233, P < 0.001). Conclusions: The preoperative De Ritis ratio may serve as a prognostic biomarker for oncological outcomes in patients undergoing RC. Additionally, it may function as a simple surrogate marker for sarcopenia in male patients. Multivariable analysis for RFS. Factor P value HR 95% CI Age Continuous 0.866 0.999 0.983–1.015 Performance status Continuous 0.090 1.301 0.960–1.764 NAC Received 0.196 1.203 0.909–1.593 Tumor grade Grade 3 0.075 1.377 0.969–1.957 Pathological T stage ≥ pT3 <0.001 2.504 1.482–2.846 LVI Positive 0.002 1.719 1.223–2.414 Pathological N stage ≥ pN1 0.008 1.583 1.125–2.227 Surgical margin Positive 0.263 1.322 0.811–2.156 Urinary diversion Neobladder 0.041 0.750 0.568–0.989 De Ritis ratio ≥ 1.40 0.017 1.394 1.060–1.834

Falcon Vision‐Inspired Ultrafast Traffic Obstacle Avoidance Based on 2D Edge‐Rich van der Waals Heterostructures

ABSTRACT Ultrafast and reliable visual perception is essential for obstacle avoidance in autonomous driving, where split‐second decisions must be made in complex, high‐speed environments, yet remains constrained by the limited temporal resolution and processing latency of conventional devices. Here, inspired by the exceptional temporal resolution of falcon vision systems (>150 Hz), we develop a neuromorphic vision sensor capable of ultrafast, edge‐selective perception for dynamic traffic scenarios. The sensor leverages vertically stacked, edge‐rich SnS 2 /MoS 2 van der Waals heterostructures, in which a high density of atomic‐scale interfaces and defective edges enables enhanced light‐matter interactions and rapid carrier dynamics. These structural advantages endow the Falcon Vision Sensor (FVS) with synaptic plasticity (PPF = 201%, LTP = 1300s), high refresh rate (250 Hz), and intrinsic erasure behaviors, closely mimicking the temporal precision and motion discrimination features of falcon vision. When the synaptic devices are integrated with computing modules, the system achieves real‐time obstacle detection, along with a directional motion recognition accuracy of 98.89%. This work demonstrates a robust biologically inspired visual intelligence, offering a compact, low‐latency solution for next‐generation autonomous vehicles and edge AI applications requiring rapid environmental responsiveness.