Browse Articles

TNF-alpha: Roles in pathogenesis and therapeutics in cancer

Artificial intelligence–based detection of treatment-emergent metastatic neuroendocrine carcinoma of prostate.

36 Background: Metastatic prostate carcinoma is a highly heterogeneous disease with a wide morphological spectrum and disease outcomes. While some retain adenocarcinoma morphology, some undergo lineage plasticity and transform into treatment emergent neuroendocrine carcinoma (t-NEPC) with morphology similarity to small cell carcinoma and highly aggressive disease behavior. We developed a morphology-based artificial intelligence (AI) tool applicable in real-world metastatic biopsies to assist the diagnosis of t-NEPC on digital whole-slide images (WSIs). Methods: Using a previously presented deep-learning based supervised learning algorithm, which was trained with localized prostate specimens with NEPC morphology in whole slide images (WSIs) using a custom-designed UNet model, here we fine tuned this algorithm using 62 metastatic biopsies from our institution with WSIs of H&E sections (enriched for t-NEPC, n=15, 24%), bench marking with GU pathologist’s diagnosis (adenocarcinoma vs. poorly differentiated carcinoma vs. t-NEPC) to generate a continuous t-NEPC score (range 0-1, with 1 most likely represent t-NEPC) for each slide. The algorithm was further tested in a non-overlapping external cohort (West Coast Dream Team and PROMOTE cohorts) of 167 metastatic biopsies with H&E WSIs (including 7 t-NEPC, 4%). Results: In our institutional cohort for fine tuning (n=62), t-NEPC score was significantly higher in 15 cases with a pathology diagnosis of t-NEPC compared to those with adenocarcinoma or poorly differentiated carcinoma. Using t-NEPC score >0.05 as a cutoff, the concordance rate between the AI t-NEPC score and pathologists was 94% t-NEPC and 56% for adenocarcinoma. In the validation cohort (West Coast Dream Team and PROMOTE, n=167), the algorithm still separated t-NEPC from adenocarcinoma, but not significantly in poorly differentiated carcinoma, with a concordance rate 71% for t-NEPC 77% for adenocarcinoma. Conclusions: As a proof-of-principle study, a morphology-based AI t-NEPC score established from a localized NEPC classifier was applicable towards the diagnosis of t-NEPC with a high concordance rate with GU pathologists. Adenocarcinoma Poorly differentiated Carcinoma t-NEPC Institutional cohort (n=62)  N, % 34, 55% 12, 19% 15, 24%  t-NEPC score (mean, +/- STD) 0.14, 0.20 0.09, 0.15 0.38, 0.21  Concordance (n, %) 19/34, 56% N/A 14/15, 94% West Coast Dream Team and PROMOTE cohorts (n=162)  N, % 100, 62% 60, 37% 7, 4%  t-NEPC score (mean, +/- STD) 0.05, 0.12 0.08, 0.17 0.24, 0.33  Concordance (n, %) 77/100, 77% N/A 5/7, 71%

Circulating tumor (ct)DNA-guided adjuvant atezolizumab (atezo) in muscle-invasive bladder cancer (MIBC): Exploratory analysis of ctDNA dynamics in the IMvigor011 trial.

633 Background: In the randomized, double-blind, Phase 3 IMvigor011 trial (NCT04660344), ctDNA-guided adjuvant atezo led to statistically significant improvements in investigator-assessed disease-free survival (INV-DFS) and overall survival (OS) vs placebo (pbo) after radical cystectomy (RC) in patients (pts) with MIBC. A higher proportion of pts in the atezo arm cleared ctDNA at either Cycle (C)3 or C5; all pts in the pbo arm who cleared ctDNA had low baseline concentrations (Powles, New Engl J Med 2025). Here we report exploratory analyses of ctDNA timing and concentration in ctDNA-positive (+) pts in surveillance, and on-treatment ctDNA dynamics in randomized pts, including correlation with clinical outcomes. Methods: Pts with MIBC and no radiographic disease were enrolled in surveillance within 6–24 weeks (wk) of RC. Serial ctDNA monitoring was done every 6 wk with imaging every 12 wk for up to 1 year post-RC. Pts who tested ctDNA+ at any time were screened for the treatment phase. Eligible pts were randomized 2:1 to atezo or pbo every 4 wk for 12 cycles or up to 1 year. Time to first ctDNA+ result and baseline ctDNA concentration were assessed in all pts who tested ctDNA+ during surveillance (n = 379); correlation with INV-DFS was evaluated in pts who did not receive active adjuvant treatment (n = 212). On-treatment ctDNA dynamics, including association with INV-DFS and OS, were evaluated in pts who received ≥1 dose of atezo (n = 165) or pbo (n = 83). Results: In pts who tested ctDNA+ during surveillance, the concentration of ctDNA at time of first + test ranged from 0.01–613.8 mean tumor molecules (MTM)/mL (median, 0.27 MTM/mL). The majority of pts (n = 281, 74.1%) tested ctDNA+ within 24 wk of RC. Early ctDNA-positivity and higher baseline ctDNA concentration were associated with higher tumor stage and/or node+ status at RC, as well as shorter INV-DFS. Late ctDNA-positivity was associated with low baseline ctDNA concentration (R = −0.28; P < 0.001). In randomized pts, atezo decreased ctDNA levels between C1 and C3 (log2 fold-change [FC] –0.4), while levels increased on pbo (log2FC 0.5; Wilcoxon P = 0.009). ctDNA clearance at C3 or C5 was associated with improved DFS and OS; landmark DFS and OS rates were numerically higher in atezo-treated pts (Table). Conclusions: For most pts identified as ctDNA+ via serial ctDNA monitoring after RC, positivity was evident ≤24 wk. Early positivity and high baseline concentrations were negative prognostic factors. Atezo treatment prevented the rapid increase in ctDNA levels observed in the pbo arm and led to enhanced ctDNA clearance, which was associated with superior clinical outcomes. Clinical trial information: NCT04660344 . Cleared ctDNA at C3 or C5 Did not clear ctDNA at C3 or C5 Atezo (n=42) Pbo (n=12) Atezo (n=123) Pbo (n=71) DFS, % 6 months (mo) 97.6 91.7 54.7 42.0 12 mo 84.4 62.9 31.2 23.7 OS, % 12 mo 97.1 100 80.8 65.4 24 mo 86.2 85.7 54.9 41.5 Median follow-up: 16.1 mo

Comparative outcomes of radiotherapy and interventional therapy for adrenal oligometastases: A multicenter retrospective study.

1 Background: Adrenal oligometastatic disease (OMD) represents an intermediate state between localized and systemic malignancy, with adrenal involvement in 10–25% of carcinoma cases. Aggressive local therapy may achieve durable remission. While systemic therapy remains essential, local control often requires surgery, interventional therapy, or radiotherapy. Adrenalectomy offers survival benefit but carries morbidity; Radiotherapy and interventional therapy provide > 80% local control and > 50% 3-year OS with minimal toxicity. However, direct comparisons remain limited. This study compares radiotherapy and interventional therapy for adrenal OMD, assessing LPFS (Local Progression-Free Survival), OS (Overall Survival), and toxicity across tumor types and disease settings to define optimal management. Methods: This multicenter retrospective study compared radiotherapy and interventional therapy for adrenal oligometastases (≤5 lesions ≤3 organs) in 118 patients (2008–2024). Primary endpoint was OS; secondary LPFS. IPTW-adjusted Cox analysis showed balanced covariates (SMD < 0.10). Radiotherapy delivered median 40 Gy (BED10 = 60 Gy); interventional therapy median 1.17 h, 3-day stay. Outcomes and toxicity were compared using weighted models. Results: Between 2008–2024, 245 patients with adrenal metastases were analyzed (127 radiotherapy, 118 intervention). Baseline features were balanced after IPTW (SMD < 0.1). At 20.6 mo mean follow-up, local recurrence was 17.3% vs 22.0%; deaths 44.9% vs 70.3%. Unadjusted LPFS HR 1.29 (0.92–1.81) and OS HR 1.39 (0.96–2.00) showed no significant difference; adjusted LPFS HR 1.29 (0.91–1.84) and OS HR 1.30 (0.89–1.89) confirmed equivalence. Subgroup analyses revealed poorer outcomes with intervention among females (HR 2.29, P = 0.03) and lung primaries (interaction P = 0.03), while synchronous disease favored intervention (HR 1.99, P = 0.05). Multivariate Cox identified lung primaries (HR 2.68, P = 0.0003) and lesion > 42 mm (HR 2.25, P = 0.0009) as mortality predictors. Bilateral and medium lesions predicted LPFS failure (HR 2.80, P = 0.005). Toxicity was acceptable: radiotherapy led to more mild respiratory/hematologic events (6.9%, 3.5%), intervention to pain (10.2%), pneumothorax (3.7%), renal injury (5.7%). No procedure-related deaths occurred. Conclusions: In 245 patients with adrenal metastases, adjusted comparisons showed radiotherapy and interventional therapy had similar efficacy. Radiotherapy showed nonsignificant OS and LPFS benefits. Subgroups (female, synchronous, 42–80 mm lesions) showed distinct responses. Lung primaries and tumors > 42 mm predicted poor OS; bilateral or intermediate lesions impaired control. Toxicities differed but remained tolerable.

Metastatic progression and toxicity in high-risk clear cell renal cell carcinoma patients treated with adjuvant pembrolizumab at a tertiary care center.

471 Background: Pembrolizumab was approved in 2021 as adjuvant therapy for high-risk clear cell renal cell carcinoma (ccRCC) after benefit was shown in the KEYNOTE-564 (KN564) clinical trial. Limited institutional data are available to evaluate subsequent patient selection for adjuvant therapy, efficacy, or toxicity in broader clinical practice. This study assessed disease-free survival (DFS) and adverse events (AEs) among patients treated at a high-volume U.S. institution, using KN564 eligibility criteria. Methods: We included ccRCC patients who underwent nephrectomy from 2021 to present meeting high-risk criteria (pT2 grade 4, ≥pT3 any grade, N1, or M1 with no evidence of disease [NED]) in a prospective institutional database. Clinical characteristics were compared between adjuvant and surveillance cohorts. DFS was estimated using Kaplan–Meier methods; Cox regression adjusted for tumor grade, tumor size, and venous thrombus. AEs were graded by Common Terminology Criteria for Adverse Events (CTCAE). Results: Among 195 high-risk ccRCC patients, 134 (67%) were referred to medical oncology for adjuvant therapy. 72 (37%) received adjuvant pembrolizumab and 123 (63%) underwent surveillance with a median follow-up of 21 vs 15 months respectively (P=0.20, Table 1). Per KN564 criteria, within the surveillance cohort, 96 (78%) were M0 intermediate-to-high risk, 16 (13%) M0 high risk, and 11 (9%) M1 NED; corresponding proportions in the pembrolizumab group were 64 (89%), 5 (7%), and 3 (4%), respectively (P=0.28). Pembrolizumab improved DFS (adjusted HR 0.34; 95% CI 0.17–0.66; P = 0.001). Two-year DFS was 84% with pembrolizumab versus 65% with surveillance (absolute risk reduction 19%; number needed to treat = 6). Only 37/72 (51%) completed 12 months of pembrolizumab. Treatment-related AEs were the main cause for discontinuation: 41/72 (57%) experienced any grade AEs including 17/72 (24%) who experienced a grade 3 or 4 AE. The most common high-grade AEs included pneumonitis, dermatitis, acquired type 1 diabetes presenting with ketoacidosis, myocarditis, and colitis. Conclusions: In contemporary practice, adjuvant pembrolizumab confers a measurable DFS benefit for high-risk ccRCC. Serious adverse events occurred in 24% of patients and were a frequent reason for treatment discontinuation. These data provide further real-world evidence and support pragmatic, shared decision-making when considering adjuvant pembrolizumab. Disease-free survival and toxicity. Surveillance(N=123) Adjuvant Pembrolizumab(N=72) Median follow-up, months (IQR) 15 (5–31) 21 (11–28) 1-yr DFS 76% 91% 2-yr DFS 64% 84% DFS HR (95% CI) Ref 0.34 (0.17-0.66); P=0.001 2-yr Absolute Risk Reduction — 19% Any Grade AEs, % 41 (57) Grade 3–4 AEs, % — 17 (24) Number needed to treat to prevent 1 recurrence or death 6 Number experiencing an adverse event for 1 recurrence prevented — 3

Flow‐Induced Microdomain Alignment During Block Copolymer Graphoepitaxy

ABSTRACT Block copolymer (BCP) graphoepitaxy provides a strategy for advanced nanofabrication based on self‐assembly. However, the polymer flow processes that occur due to the topography of the substrates and their effects on the self‐assembled microdomain patterns are not well understood. Here, by analyzing film thickness profiles and microdomain morphologies as a function of time during solvent vapor annealing, the time scale of the flow processes (capillary flow and dewetting) and how they determine the in‐plane orientation of cylindrical microdomains with respect to the sidewalls of trenches etched in the substrate are revealed. Capillary flow in the first minute of annealing planarizes the film into an incommensurate thickness. The film then dewets through nucleation and growth of islands and holes, which extend either isotropically or anisotropically along the trench axis, depending on film thickness. Isotropic dewetting produces microdomains, which are primarily transverse to the trench sidewalls, whereas anisotropic dewetting promotes alignment parallel to the trench walls. This study demonstrates an intriguing connection between flow‐induced microdomain alignment, film thickness, and trench depth during BCP graphoepitaxy, revealing general principles for controlling BCP microdomain orientation over topographical templates.

High‐Modulus and High‐Damping Ionic Polymers Enabled by Cohesive Entanglement

ABSTRACT High‐modulus polymers typically derive their properties from high crosslinking density and strong intermolecular interactions. In contrast, high‐damping polymers primarily dissipate energy via the sliding and friction of mobile molecular segments. This fundamental contradiction creates an inherent trade‐off, rendering the simultaneous achievement of high modulus and high damping a significant challenge. Herein, we report rigid‐damping amphoteric ionic polymers (AIPs) developed through a cohesive entanglement strategy governed by side‐chain ionic interactions. Synthesized via acid–base neutralization, these AIPs simultaneously achieve a high Young's modulus of 0.9 GPa and a damping coefficient (loss factor, tan δ) of up to 1.5. This breakthrough proposes a strategy to balance the modulus‐damping trade‐off and highlights the material's potential for advanced impact‐resistant applications, such as transparent coatings for electronic devices and vibration‐damping systems.

Emerging biologic modalities for targeted protein degradation

<i>ERBB3</i> -altered clinically advanced urothelial bladder cancer: Genomic landscape study and therapeutic possibilities.

799 Background: ERBB3 is often altered ( ERBB3 -alt) in advanced urothelial bladder cancer (aUBC) and its activation may drive tumor growth and treatment resistance, thus it may serve as a putative biomarker and therapy target. We explored the genomic landscape of ERBB3 -alt and ERBB3 -wild type ( ERBB3 -WT) aUBC. Methods: 9,969 cases of clinically aUBC underwent comprehensive genomic profiling (CGP) using a hybrid-capture based FDA-approved assay (FoundationOneCDx) to assess all classes of genomic alterations (GA). MSI status, TMB, HRD signature, genetic ancestry and COSMIC signature were all calculated from sequencing data for research use-only purposes in the context of this study. PD-L1 expression was determined by IHC using Dako 22C3 TPS assay. PD-L1 IHC was performed on a subset of samples for ERBB3- WT (N=136) and ERRB3 -alt (N=9). Results: 636 (6.4%) aUBC cases featured GA in ERBB3 including 90.2% short variant mutations, 8.8% amplifications and 1% had both. Compared to ERBB3 -WT aUBC, patients with ERBB3 -alt were slightly more often male (78.6% vs 74.7%). Both groups had similar genomic ancestry profiles (European range 84.9% to 86.6%). Median TMB was higher in ERBB3-alt aUBC (12.5 vs 6.3 mutations/Mb) as was TMB ≥10 mut/Mb (61.2% vs 33.0) and ≥20 mut/Mb (28.6% vs 11.1) (Table). APOBEC cosmic genomic signature was more frequent in the ERBB3 -alt aUBC (50.0% vs 30.3%). PD-L1 expression was higher in ERBB3 -WT aUBC with high positive (≥50% TPS) 19.1% vs 11.1% (not significantly different). Individual GA more frequent in the ERBB3 -alt cases included AKT2 (6.8% vs 3.5%), ARID1A (38.4% vs 24.4%), ERBB2 (24.2% vs 18.0%) and TERT (87.1% vs 77.5). GA more frequent in ERBB3-WT aUBC included CDKN2A (38.8% vs 27.2%), CDKN2B (31.2% vs 20.1%), FGFR3 (18.1% vs 14.6%) and MTAP (25.7% vs 16.4%). Conclusions: ERBB3 GA in aUBC identify a subset of cases with relatively distinct genomic characteristics, including higher median TMB and frequency of APOBEC signature as well as potential “targetable” pathways. CGP can help identify putative biomarkers for treatment selection and may inform clinical trial designs. Study limitations include retrospective nature, lack of clinical outcomes data annotation, selection and confounding biases. Genomic and molecular features associated with ERBB3 -altered versus ERBB3 -wildtype tumors. ERBB3-WT ERBB3-alt P-value† N 9333 636 Median TMB 6.3 12.5 &lt;.0001 TMB≥20 mut/Mb 11.10% 28.60% &lt;.0001 APOBEC Signature 30.30% 50.00% &lt;.0001 ARID1A 24.40% 38.40% &lt;.0001 CDKN2A 38.80% 27.20% &lt;.0001 ERBB2 18.00% 24.20% 0.0006 FGFR3 18.10% 14.60% 0.0482 KMT2D 23.60% 16.70% 0.0002 MTAP 25.70% 16.40% &lt;.0001 TERT 77.50% 87.10% &lt;.0001 †FDR corrected using Benjamini/Hochberg adjustment.

Healthy donor fecal microbiota transplantation combined with immunotherapy in metastatic renal cell carcinoma: Results from the phase I PERFORM trial.

559 Background: Despite advances with immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF)–targeted tyrosine kinase inhibitors, outcomes in metastatic renal cell carcinoma (mRCC) remain variable, with primary resistance and treatment-limiting toxicities The gut microbiome influences both ICI response and immune-related toxicity. The PERFORM trial (NCT04163289) is a single-arm, phase I study evaluating the safety of healthy-donor fecal microbiota transplantation (FMT) given before and during first-line ICI-based therapy in patients with mRCC. Methods: In this trial, 20 untreated mRCC patients received encapsulated healthy-donor FMT (LND101) prior to standard ICI-based regimens (ipilimumab–nivolumab, pembrolizumab–axitinib, or pembrolizumab–lenvatinib). The primary endpoint was safety. Secondary clinical endpoints included objective response (ORR), clinical benefit (complete or partial response or stable disease lasting six months or longer), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). Results: FMT was well-tolerated with no FMT-related serious toxicity. Median follow-up was 21.9 months (range, 5.6–53.3). One patient (5%) experienced grade 1 gastrointestinal event attributed to FMT. Any-grade irAEs occurred in 95%; grade ≥3 in 50%, consistent with historical ICI rates. No grade 4–5 toxicities related to FMT or systemic therapy were observed. Among 18 evaluable patients, the ORR was 44% (n = 8) including two complete responses (11%). Primary progressive disease occurred in five patients (28 %). Clinical benefit was achieved in 72% (n = 13). Only 1 of 8 responders (12.5%) developed grade ≥3 irAEs vs 8 of 10 non-responders (80%) (p = 0.018). Median PFS and OS were 11.15 and 36 months, respectively. QoL remained stable over the first four treatment cycles without evidence of decline attributable to FMT. Conclusions: Encapsulated healthy-donor FMT administered before ICI-based therapy was safe and feasible in patients with previously untreated mRCC. Clinical activity was consistent with contemporary regimens, and severe immune-related toxicity was uncommon among responders. These data support further evaluation of FMT with ICI therapy in larger, multi-center trials to validate safety and clinical benefit. Clinical trial information: NCT04163289 .

Ferroptosis suppression and its association with chemoradiotherapy resistance in muscle-invasive bladder cancer.

839 Background: Chemoradiotherapy (CRT) within trimodality therapy (TMT) offers a curative-intent, bladder-preserving option for patients with muscle-invasive bladder cancer (MIBC), yet its long-term efficacy is limited by treatment resistance. While alterations in DNA damage response genes have been proposed as candidate radiosensitivity biomarkers, the broader molecular landscape influencing CRT outcomes remains unclear. Methods: We conducted comprehensive transcriptomic profiling of pre-treatment tumors from 179 patients undergoing TMT, representing the largest and most uniform bladder-preservation cohort analyzed to date, to delineate molecular determinants of CRT response. To complement the clinical analysis, CRT-resistant bladder cancer cell models were used to perform integrative RNA sequencing, lipidomic profiling, and genome-wide CRISPR/Cas9 loss-of-function screening. Results: Patients with disease progression showed significantly poorer survival than progression-free cases, accompanied by distinct immune- and lipid metabolism–related transcriptional programs. Integrating these findings, we derived a ferroptosis suppressor signature (FSS). High FSS expression correlated with poor CRT response, immune-excluded microenvironments, and inferior survival, and was enriched in Basal/Squamous subtypes, whereas FSS-low tumors were predominantly Luminal Unstable and immune-inflamed. Resistant cells mirrored these transcriptomic and metabolic traits and exhibited restored radiosensitivity upon ferroptosis induction. A CRISPR/Cas9 screen further identified key ferroptosis suppressor genes—including GPX4 , SLC7A11 , and NFE2L2 —as radiosensitizing vulnerabilities. Conclusions: This integrative clinical and functional analysis highlights ferroptosis suppression as a central molecular determinant of CRT resistance in bladder preservation therapy. Incorporating ferroptosis suppressor status alongside molecular subtype and immune contexture may enhance patient stratification and support personalized treatment decision-making in bladder-preserving approaches. Multivariable Cox regression for rPFS and OS. Variable HR (95% CI) for rPFS HR (95% CI) for OS FSS-high 2.73 (1.76–4.25) *** 2.83 (1.71–4.71) *** LVI (+) 1.76 (1.06–3.01) * 2.36 (1.25–4.45) ** Ba/Sq 1.88 (1.17–3.01) ** 1.21 (0.72–2.01) cT ≥T3 1.28 (0.82–2.00) 　 1.23 (0.74–2.03) Invasive (+) 1.68 (0.40–7.03) 　 0.95 (0.24–3.72) Grade (+) 1.62 (0.59–4.47) 　 1.08 (0.35–3.34) Age ≥75 0.59 (0.34–1.02) 　 0.73 (0.40–1.33) Concomitant CIS (+) 0.64 (0.34–1.20) 　 0.43 (0.18–1.02) 　 HR, hazard ratio; CI, confidence interval; rPFS, radiographic progression-free survival; OS, overall survival; FSS, ferroptosis suppresive signature; LVI, lynphvascular invasion; Ba/Sq, basal/squamous subtype; CIS, carcinoma in situ; *** P &lt; 0.001; ** P &lt; 0.01, * P &lt; 0.05.

Comparing NCCN-based risk groups to the PROTEUS definition of high-risk localized prostate cancer to inform peri-operative care.

344 Background: There are varying definitions of high-risk prostate cancer. The most commonly used is the NCCN definition which defines patients as having high- or very-high-risk disease if they have any of clinical T3 or greater disease, Gleason Grade Group 4 or 5, or PSA &gt; 20ng/mL. Recent studies of androgen receptor signaling inhibitors have employed alternative definitions of baseline risk. Herein, we compared patient distributions and oncologic outcomes for patients undergoing radical prostatectomy according to two definitions of high-risk disease. Methods: Using an institutional database of patients undergoing radical prostatectomy, we characterized patients as having high-risk disease either by using NCCN risk groups (any of Gleason grade group [GGG] 4 or 5; or Clinical T3 or T4; or PSA &gt;20 ng/mL) or using the definition employed in the PROTEUS trial (overall GGG ≥3 and at least one of the following: GGG5 in at least one core; or GGG4 in at least 2 cores, each with &gt;80% involvement; or GGG3+ in ≥6 systematic cores; or GGG3+ in ≥3 systematic cores and PSA ≥20 ng/mL). Descriptive statistics were used to compare patient distributions. Area under the receiver operating curve (AUC) were compared between NCCN- and PROTEUS-based definitions of high-risk disease for oncologic outcomes including extra-prostatic extension, positive surgical margins, and PSA &gt;0.1 or &gt;0.2 at 12 months post-operatively. Results: Among 424 patients undergoing radical prostatectomy in the dataset, 358 had complete pathological biopsy data allowing for nuanced pre-operative risk stratification. Of these, 62 (17%) were classified as high-risk per NCCN criteria while 44 (12%) were classified as high-risk per PROTEUS criteria. Among 62 patients classified as high-risk per NCCN criteria, 38 met the PROTEUS criteria and 24 did not. Conversely, among 44 patients classified as high-risk per PROTEUS criteria, 38 met the NCCN high-risk criteria and 6 did not. Using AUC, the two definitions were comparably predictive of extra-prostatic extension (NCCN 0.56, 95% CI 0.52-0.60; PROTEUS 0.56, 95% CI 0.53-0.60; p=0.96), positive surgical margins (NCCN 0.54, 95% CI 0.49-0.58; PROTEUS 0.52, 95% CI 0.49-0.56; p=0.44), PSA &gt;0.1 at 12 months post-operatively (NCCN 0.54, 95% CI 0.46-0.62; PROTEUS 0.59, 95% CI 0.51-0.67; p=0.22), and PSA &gt;0.2 at 12 months post-operatively (NCCN 0.59, 95% CI 0.49-0.69; PROTEUS 0.64, 95% CI 0.54-0.75; P=0.32). Conclusions: This comparative analysis based on highly granular data shows that prostate cancer patients defined as high-risk based on NCCN risk groups, or high-risk criteria employed in the PROTEUS clinical trial, have comparable outcomes. Therefore, identifying patients suitable for treatment intensification with peri-operative systemic therapy is critical in this evolving clinical landscape.

Exploring Co, Fe, and Ni Reference Layers for Single‐Pulse All‐Optical Reversal in Ferromagnetic Spin Valves

ABSTRACT We investigate the magnetization reversal process induced by a single femtosecond laser pulse in ferromagnetic spin valves by systematically comparing reference layers composed of pure Co, Ni, and Fe. To circumvent the loss of perpendicular magnetic anisotropy associated with changes in reference layer material and thickness, we design spin valves with in‐plane magnetizations. While antiparallel‐to‐parallel switching is observed for all three elements, parallel‐to‐antiparallel switching occurs only with a Co reference layer and is absent with Ni and Fe. This difference is attributed to the distinct ultrafast magnetization dynamics of the reference materials. Our results support the hypothesis that parallel‐to‐antiparallel switching requires a rapid remagnetization of the reference layer, which generates a substantial negative spin current polarized opposite to the free layer magnetization—an essential condition for triggering its reversal.

Divergent pathways of surfactant protein C maturation for disease-associated isoforms

Liquid biopsy-based detection of MTAP gene loss in non-muscle invasive bladder cancer.

844 Background: MTAP, located at chromosome 9p21.3 adjacent to CDKN2A/B, is frequently co-deleted with the CDKN2A in cancer. Homozygous 9p21 deletions (encompassing CDKN2A/MTAP) occur in ~15% of all cancers, and MTAP loss is observed in ~30% of bladder cancers. MTAP deletion creates a therapeutic vulnerability through dependence on the PRMT5/MAT2A pathway, a target of emerging synthetic-lethal therapies. A non-invasive liquid biopsy assay to detect MTAP loss may enable biomarker-driven patient selection in clinical drug development. Methods: Urine samples from patients with non-muscle invasive bladder cancer (NMIBC) were analyzed using the PredicineCARE 200-gene NGS assay, which covers MTAP and CDKN2A coding regions and includes a genome-wide SNP backbone, enabling detection of MTAP gene deletion events independent of CDKN2A. Results: MTAP gene loss was identified in 137/409 (33%) and CDKN2A loss in 141/409 (34%) selected patient urine samples. Results of a subset urine samples with matched tissues were confirmed by tissue NGS results. The assay distinguished MTAP-specific deletions from CDKN2A deletions despite their &lt; 30 kb proximity. Notably, four patients showed MTAP deletions with intact CDKN2A, and seven patients had CDKN2A deletions with preserved MTAP. Both heterozygous (HETD) and homozygous (HOMD) deletions were resolved, including 15 cases with CDKN2A homozygous deletion and MTAP heterozygous loss. Conclusions: This study demonstrates the feasibility of urine liquid biopsy-based detection of MTAP gene loss in bladder cancer, differentiating MTAP deletions from adjacent CDKN2A losses and resolving both HETD and HOMD events. These findings highlight the potential of liquid biopsy-based cancer diagnostics for patient selection and therapy monitoring in clinical drug development and personalized patient care.

Succinate dehydrogenase B deficient renal cell carcinoma (RCC): A genomic landscape study.

551 Background: In addition to the association of SDHB genomic alterations (GA) with paraganglioma and pheochromocytoma, SDHB GA are also linked to a rare form of RCC with inactivation or homozygous deletion (complete loss) of the SDHB gene (SDHBdef-RCC) which carries a high risk for metastasis and adverse prognosis. We studied the GA landscape of SDHBdef-RCC and compared it to RCC lacking SDHB GA (SDHBwt-RCC) . Methods: 9,462 cases of clinically advanced RCC underwent hybrid capture based comprehensive genomic profiling (CGP) using the FoundationOneCDx assay to identify all classes GA. Microsatellite instability status (MSI) and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by IHC using the Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). All cases had relapsed either loco-regionally or with metastatic disease at the time sequencing. Results: 17 (0.6%) of the sequenced advanced RCC were SDHBdef-RCC) and included 7 (41.2%) with germline short variant (SV) SDHB mutations, 6 (35.5%) with somatic SV SDHB mutations and 4 (23.5%) with homozygous SDHB deletions (complete loss of 8 of 8 exons). Their histologic RCC subtypes included 5 sarcomatoid, 5 high grade NOS, 4 oncocytic, 2 clear cell and 1 collecting duct RCC morphology; 10 RCC were sequenced using the primary kidney tumor and 7 from a metastatic site biopsy for CGP. Patients with SDHBdef-RCC were younger (mean age 45.9 yrs vs 62.5 yrs; p&lt;.0001) and had a similar gender distribution (29.4% - 30.9% female). Biomarkers of checkpoint inhibitor efficacy including MSI-high status (0% - 0.6%), TMB level (mean 3.6 to 3.9 mutations/Mb) and any level of PD-L1 expression (40.0% vs 35.7%) were similar in both groups. Noteworthy GA summaries are shown in attached Table. Conclusions: SDHBdef-RCC is a rare form of clinically advanced RCC with predominantly oncocytic and sarcomatoid non-clear cell histology featuring either inactivating short variant SDHB germline or somatic mutations or homozygous deletion of SDHB gene. When compared with SDHDwt-RCC, SDHBdef-RCC occurs in younger patients, features non-clear cell histology, less frequent GA in tumor suppressor genes ( VHL , PBRM1 , SETD2 , BAP1 ), less frequent GA in cell cycle regulatory genes ( CDKN2A / B , T P53 ) and significant increased GA in NF2 . Further investigation of GA in this rare RCC type for clinical trial design and germline screening strategies is warranted. Limitations of this study include its retrospective nature, potential selection bias, and lack of clinically relevant data. Genomic alteration summaries of sequenced advanced RCC. SDHBmut RCC (N=17) SDHBwt RCC (N=9445) P value VHL 23.5% 43.7% NS PBRM1 0.0% 24.9% .011 SETD2 0.0% 17.0% NS BAP1 0.0% 11.3% NS CDKN2A 11.8% 25.6% NS CDKN2B 11.8% 20.1% NS MTAP 7.7% 15.0% NS TP53 5.9% 21.1% NS NF2 23.5% 6.7% .024

Real-world (RW) outcomes associated with enzalutamide (enza) vs apalutamide (apa) in metastatic castration-sensitive prostate cancer (mCSPC): Analysis of United States (US) oncology electronic health record (EHR) data.

180 Background: RW data comparing first-line (1L) androgen receptor pathway inhibitors for mCSPC treatment (tx) are limited and misclassification of disease state can complicate interpretation. This RW study compared outcomes in patients (pts) with mCSPC who initiated 1L enza or apa. Methods: Flatiron Health EHR data (January 2013–May 2025) were analyzed for males in the US with chart-abstracted evidence of mCSPC who initiated index tx (1L enza or apa) on/after January 1, 2020, and had no evidence of metastatic castration-resistant prostate cancer (mCRPC) within 3 months post 1L tx initiation. Outcomes included duration of tx (DoT), time to next tx (TTNT), and time to mCRPC. Cox proportional hazards models with inverse probability of tx weighting (IPTW) compared outcomes between enza and apa in the overall population, adjusting for baseline characteristics. Sensitivity analyses were restricted to pts who received 1L tx in the mCSPC setting only (i.e., no evidence of mCRPC while on 1L tx). Results: Overall, 864 pts had enza and 410 pts had apa as 1L mCSPC tx. Median follow-up was 23 (enza) and 24 (apa) months. Baseline characteristics were balanced after IPTW: mean age was 73 years, 80% of pts received tx in community oncology practices, and 68% had de novo metastatic disease. All IPTW-adjusted outcomes were comparable for enza and apa (Table). Similar proportions of pts in the enza and apa cohorts discontinued index tx (56% vs 58%), initiated next tx (30% vs 31%), and progressed to mCRPC (25% vs 25%). Sensitivity analyses yielded consistent results. Conclusions: In pts with mCSPC (defined stringently to minimize bias) who were treated in US oncology practices, 1L enza and apa showed comparable DoT, TTNT, and time to mCRPC, which supports similar effectiveness of enza and apa. Disclosure: A genAI tool (09/23/25; Pfizer; GPT-4o) developed the first draft; authors assume content responsibility. IPTW-adjusted outcomes in pts with mCSPC. Overall Sensitivity analysis Enza(N ‡ = 861) Apa † (N ‡ = 407) Enza(N ‡ = 738) Apa † (N ‡ = 355) Outcome § Median (95% CI), mo Median (95% CI), mo aHR (95% CI) Median (95% CI), mo Median (95% CI), mo aHR (95% CI) Time to tx discontinuation ║ 22 (19, 25) 19 (16, 24) 0.95 (0.81, 1.12) 25 (22, 29) 22 (17, 30) 0.90 (0.75, 1.08) Time to next tx ¶ NR (46, NE) NR (51, NE) 0.98 (0.78, 1.22) NR (NE, NE) NR (53, NE) 0.93 (0.72, 1.21) Time to mCRPC # NR (NE, NE) NR (NE, NE) 1.03 (0.81, 1.32) NR (NE, NE) NR (NE, NE) 0.87 (0.61, 1.24) † Apa was the reference group. ‡ N for IPTW-weighted sample. § IPTW-adjusted by baseline characteristics. ║ Time from index date to the discontinuation of index tx (next tx, tx gap &gt;90 days, death). ¶ Time from index date to the earliest initiation of next tx. # Time from index date to mCRPC date. aHR, adjusted hazard ratio; CI, confidence interval; mo, months; NE, not evaluable; NR, not reached.

TROPION-Urothelial03: A phase 2/3 study of datopotamab deruxtecan (Dato-DXd) + platinum chemotherapy (CT) vs gemcitabine + platinum CT in participants with locally advanced or metastatic urothelial carcinoma (la/mUC) with progression on or after enfortumab vedotin (EV) + pembrolizumab (pembro).

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( &lt; 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

Bioinspired Cross‐Modal Self‐Adaptive Machine Intelligence for Event‐Driven and Ultrahigh‐Precision Underwater Grasping

ABSTRACT Embodied intelligent agents, which represent the future of robotics, demand precise perception and real‐time decision‐making capabilities to achieve natural environmental interactions. However current systems face inherent limitations in unimodal sensing and cross‐modal coordination, which hinder their performance in dynamic contact‐rich operations. Herein, we present a fabric‐based event‐driven tactile interface that features an innovative woven structure with cross‐fiber electrodes. It achieves breakthroughs in sensitivity (246.3 kPa −1 ), pressure detection (&gt;450 kPa), and waterproof robustness. This interface enables millisecond‐level pressure/slip dual‐mode feedback for self‐adaptive grasping, thereby improving the dexterous manipulation of fragile or slippery objects. For underwater scenarios, a bio‐inspired visual–tactile fusion (VTF) architecture leverages tactile perception to compensate for visual limitations, demonstrating a high accuracy of 97.7% in complex tasks, including underwater transparent object manipulation and recognition of similar objects. Event‐driven tactile feedback is merged with visual semantics for decision‐level optimization, thereby enhancing the autonomy and adaptation of humanoid machine intelligence. It creates an innovative closed‐loop cross‐modal perception–decision system that builds a direct link between environmental interaction and autonomous decision‐making for intelligent agent development in open‐world scenarios. The superior performance of the VTF architecture dynamic interaction tasks represents a crucial step toward robotic systems with advanced intelligence.

Continuous Surface Strain Regulation in Trimetallic PtPbRu/Pt Nanoplates for Promoted Formic Acid Oxidation Catalysis

ABSTRACT Regulating surface strain of platinum (Pt)‐based nanomaterials to achieve efficient formic acid oxidation reaction (FAOR) catalysis for direct formic acid fuel cell (DFAFC) is crucial yet challenging. Herein, we adopt a continuous surface tensile strain modulation strategy to realize the superior activity, excellent stability, strong CO resistance, and high direct pathway selectivity for DFAFC. Atomic‐level analysis reveals that controlling the partial substitution of Pb with Ru atoms modulates the lattice constant of the intermetallic core, thereby enabling precise control of biaxial strain in the Pt shell. The optimized 2.4%‐PtPbRu/Pt nanoplates/C exhibits a mass activity of 10.0 A mg Pt+Ru −1 for FAOR, 100.0 times higher than that of commercial Pt/C. Furthermore, its membrane electrode assembly achieves a high power density of 465.4 W g Pt+Ru −1 , 3.2 times greater than that of commercial Pt/C, along with an unprecedented lifetime at 0.4 V for 469.1 h with only 7.4% power density decay, representing the best FAOR catalysts reported to date. The introduced Ru increases tensile strain and downshifts Pt‐5 d orbitals, enhancing d ‐ d orbital coupling, weakening CO * adsorption, and promoting the HCOO * adsorption to facilitate the direct formate pathway. It breaks through the strain‐performance relationship bottleneck of traditional Pt‐based catalysts, providing an atomic‐scale design blueprint of efficient anodic catalysts for DFAFC.