Browse Articles
Discover research articles across all indexed journals
Harnessing Targeted Photodynamic Therapy to Synergistically Activate T Cell and NK Cell Responses in Multiple Myeloma
Abstract Multiple myeloma (MM) remains an incurable malignancy, with immune suppression in the bone marrow microenvironment playing a critical role in disease progression and relapse. Restoring both adaptive and innate immunity represents a promising therapeutic strategy. In this study, a novel photodynamic therapy (PDT) platform is developed that simultaneously activates both adaptive immunity through T cells and innate immunity through natural killer (NK) cells, thereby fostering a synergistic anti‐tumor immune response in MM. A series of aggregation‐induced emission luminogen (AIEgen)‐based photosensitizers is synthesized and compared, identifying a dual‐acceptor molecular design with superior PDT efficacy. The high‐performance AIEgen is formulated into nanoparticles and functionalized with B‐cell maturation antigen monoclonal antibodies for precise MM targeting. Upon photoactivation, the nanoagent triggers immunogenic cell death, dendritic cell activation, and T‐cell priming. Simultaneously, it induces DNA damage in MM cells, upregulating MICA/B expression via the ATM/SMAD1 pathway to activate NK cells through NKG2D receptor engagement. In vivo studies using an NSG mouse model demonstrate robust activation of patient‐derived T and NK cells, leading to potent anti‐MM effects. This work presents a dual‐pronged immunotherapeutic strategy to overcome immune suppression in MM, offering a synergistic approach to harness both adaptive and innate immunity for enhanced cancer immunotherapy.
Long-term oncological outcomes of prostate cancer upgrading following robot-assisted radical prostatectomy.
351 Background: Pathologic upgrading from biopsy to final pathology at the time of Robot-Assisted Radical Prostatectomy (RARP) is a frequent finding and may reflect more aggressive disease biology, potentially leading to adverse long-term oncologic outcomes. This study aimed to evaluate the association between upgrading and oncologic outcomes beyond five years after RARP. Methods: A retrospective review was conducted using an IRB-approved database to identify 4,910 consecutive patients who underwent RARP between 2015 and 2020. Patients were included if they had at least five years of postoperative follow-up. Biochemical recurrence (BCR) was defined according to AUA guidelines. Results: A total of 1,210 patients met inclusion criteria. Pathologic upgrading was identified in 361 patients (29.8%). While the upgraded and non-upgraded groups were similar in terms of adverse pathological features, the upgraded group had a significantly higher incidence of positive surgical margins (42.1% vs. 35.4%, p = 0.039). At a median follow-up of 82.4 months (IQR 69.5-97.4), these differences did not translate into a significant difference in BCR-free survival ( p = 0.32). Conclusions: Despite a relatively high incidence of pathologic upgrading in patients undergoing RARP, most of which originated from Grade Group 1, this finding was not associated with worse BCR outcomes. With long term follow-up, upgrading at the time of RARP did not significantly impact BCR-free survival, and overall BCR rates did not differ meaningfully between upgraded and non-upgraded patients. Baseline clinicodemographics and oncological outcomes of all included patients. Overall cohort ( n =1210) Equivocal ( n =841) Upgrading ( n =361) p Age (years) 63 (58 –68) 63 (59-68) 63 (58-67) 0.077 PSA (ng/mL) 5.7 (4.2 - 8.6) 6.5 (4.8-11.6) 7.3 (5.2-11.5) 0.201 Biopsy ISUP Grade Group <0.001 1 256 (21.2%) 66 (7.9%) 188 (52.1%) 2 517 (42.7%) 405 (48.2%) 108 (29.9%) 3 234 (19.3%) 195 (23.2%) 42 (11.6%) 4-5 203 (16.8%) 178 (21.1%) 25 (6.9%) RARP ISUP Grade Group <0.001 1 70 (5.8%) 70 (8.3%) 0 2 639 (53.2%) 474 (56.4%) 165 (45.5%) 3 300 (25.0%) 188 (22.4%) 112 (32.0%) 4 78 (6.5%) 51 (6.1%) 27 (7.5%) 5 114 (9.5%) 57 (6.8%) 57 (15.8%) Positive Surgical Margin 455 (37.6%) 298 (35.5%) 152 (12.6%) 0.039 Biochemical Recurrence (BCR) 321 (26.5%) 217 (25.8%) 102 (28.25%) 0.514 Distant Metastasis 145 (12.0%) 102 (12.14%) 41 (11.36%) 0.786 Follow-up Duration (months) 82.4 (69.5-97.4) 81.8(69.4-96.7) 84.7 (70.2 -101.8) 0.105 IQR = Interquartile Range; ISUP = International Society of Urological Pathology; BCR = Biochemical Recurrence; IQR = Interquartile Range; ISUP = International Society of Urological Pathology; BCR = Biochemical Recurrence; Categorical variables are presented as n (%), and continuous variables as median (IQR).
Determinants of treatment intensification in metastatic hormone-sensitive prostate cancer: Institutional vs patient-level factors in a diverse UK multicentre cohort.
40 Background: In the United States, racial disparities in the use of treatment intensification (TI) for metastatic hormone-sensitive prostate cancer (mHSPC) have been documented, with Black men less likely to receive intensified therapy. Whether such disparities exist within the UK's National Health Service (NHS), which provides equal access to care, remains unclear. This study represents the first analysis outside the U.S. to evaluate determinants of TI in mHSPC across institutional practice and patient acceptance, within an equal-access healthcare system. Methods: A retrospective cohort study was conducted on all patients with mHSPC and ECOG performance status 0–2 discussed at multidisciplinary team meetings at Barts Health and Homerton NHS Trusts between March 2020 and December 2023. These centers serve one of the UK’s most ethnically and socioeconomically diverse populations; 36% of the cohort identified as Black. Mixed-effects multivariable logistic regression, with prescribing clinician as a random effect, was used to evaluate factors associated with TI offering and acceptance. Survival outcomes were assessed using Kaplan-Meier, Cox regression, and restricted mean survival time (RMST) analysis. Results: Among 173 eligible patients, TI was offered to 87% (151/173), with 79% (117/151) accepting—equating to 68% of the total cohort receiving TI. Ethnicity did not influence whether TI was offered. Older age was the only independent predictor of not offering TI (OR 0.87 per year; 95% CI 0.81–0.93; p<0.001), with minimal variation between clinicians (ICC 0.011). However, TI acceptance was significantly lower among Black men (OR 0.20; 95% CI 0.07–0.56; p<0.001), older patients (OR 0.90; 95% CI 0.85–0.95; p<0.001), and those with ECOG 2 (OR 0.27; 95% CI 0.10–0.77; p=0.01). Socioeconomic deprivation and comorbidities did not influence TI decisions. At five years, median overall survival was not reached; RMST was 52.1 months. Low disease volume was associated with improved survival (HR 0.27; 95% CI 0.10–0.71), while ethnicity had no effect on survival (HR 0.87; 95% CI 0.47–1.61; p=0.66). Conclusions: In this ethnically diverse NHS cohort with equal healthcare access, no evidence of institutional or physician bias was found in offering TI. However, Black men were less likely to accept TI when offered. These findings highlight the importance of culturally sensitive, shared decision-making to improve equity in mHSPC treatment uptake and outcomes.
Chromophobe renal cell carcinoma: Long-term survival and treatment patterns from a real-world cohort.
467 Background: Chromophobe renal cell carcinoma (chRCC) is an uncommon subtype of renal cell carcinoma (RCC), representing approximately 5-10% of kidney cancers. It shows distinctive morphologic and molecular features and generally favorable prognosis, but evidence on managing advanced disease remains scarce. This study evaluated clinicopathologic features and outcomes of localized and metastatic chRCC in a real-world setting. Methods: We conducted a retrospective cohort study including patients (pts) diagnosed with chRCC at a single tertiary cancer center from 2009 to 2024. Clinical, pathological, and survival data were extracted from electronic records. Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier; prognostic factors were assessed by univariate analyses Cox proportional hazards mode, separately for pts with localized and advanced disease. Results: Among 2,181 RCC pts, 792 (36.3%) had non–clear cell histology, including 170 (7.8%) chRCC. Twenty-three had advanced disease ( de novo metastatic, n = 9; relapsed, n = 14). Median age at diagnosis was 58.5 years (Interquartile ratio [IQR] = 50.0-68.0); 54.1% were female, 95.2% had ECOG performance status 0 or 1. Stages were T1–T2 in 60% and T3–T4 in 40%. A second malignancy occurred in 21.2%, including 9 pts with another RCC and 4 with thyroid cancers. In the advanced cohort, most common metastatic sites were bone (56.5%) and lymph nodes (43.5%). Systemic therapy was administered to 55% of pts (pazopanib 6, sunitinib 4, sorafenib 1), with a response rate as per RECIST 1.1 of 18.2%. Metastasis-directed therapy (MDT) was employed in 60.8% (surgery 9, radiotherapy 5, multimodal 2). The 5-year OS for all pts was 83.8% (95% CI 77.4–90.8%), after a median follow-up of 60.9 months. Shorter OS was associated with M1 stage (p < 0.001), T3–T4 (p = 0.02), and ECOG ≥ 2 (p = 0.03). Among advanced cases, 5-year OS was 19% (95% CI 7–52%), and MDT correlated with improved survival (HR 0.22, 95% CI 0.07–0.69) in univariate analysis. No OS benefit was observed in pts who underwent cytoreductive nephrectomy (p = 0.9). For pts with localized disease, the 5-year DFS was 84% (95% CI 77–91%), with no significant associations between DFS and stage (p = 0.18), ECOG-PS (p = 0.49), or histological grade (p = 0.13). Conclusions: Advanced chRCC is associated with limited survival and suboptimal responses to systemic therapy. Notably, pts receiving MDT achieved improved outcomes, although this observation may reflect underlying selection bias.
Scalable and Customizable Single‐Atom Coatings for pH‐Universal H <sub>2</sub> O <sub>2</sub> Electrosynthesis
ABSTRACT Achieving scalable fabrication of robust and uniform single‐atom catalyst‐based gas‐diffusion electrodes (SAC‐GDEs) remains challenging. Here, a universal one‐step soot‐deposition route was developed to convert various metal‐containing paraffins into conformal single‐atom catalyst (SAC) coatings on diverse electrodes (1D fibers, 2D plates, and 3D foams). The process provides multiscale control, from precursor‐defined molecular coordination to micropore wettability and macroscopic geometry, to collectively engineer hierarchical coating films that couple intensified mass transfer and high intrinsic catalytic activity for efficient H 2 O 2 electrosynthesis. As a device‐level demonstration, Pd‐SAC‐GDE delivers pH‐universal H 2 O 2 production under an industrial‐level current (500 mA cm −2 ) for 100 h, achieving a record‐high H 2 O 2 yield of 16.9 mol g −1 h −1 . A tip‐enhanced mechanism was proposed based on constant‐potential calculations. The results reveal that the curvature‐enhanced localized electric field promotes O 2 polarization and activation at the Pd‐O 3 sites, thereby facilitating both * OOH generation and adsorption and ultimately leading to highly selective H 2 O 2 production. This facile, broadly applicable fabrication strategy significantly advances the scalable manufacture of SAC‐coated GDEs for environmental and sustainable catalysis.
Surface Oxophilicity Driven <sup>*</sup> N Pathway Tuning for Selective Nitrate Electroreduction to Nitrogen
ABSTRACT Electrochemical reduction of nitrate to nitrogen (N 2 ) offers a sustainable pathway to close the nitrogen cycle and mitigate nitrate pollution. However, for Cu, Co, and other transition‐metal catalysts, high N 2 selectivity has mainly relied on breakpoint chlorination, which consumes large amounts of chlorine and poses secondary contamination risks. Here, we introduce a surface‐oxophilicity strategy to steer the * N pathway, thereby enhancing both catalytic efficiency and intrinsic nitrogen selectivity. Among oxophilicity‐modified Pd, Sn doping emerged as the optimal configuration. The resulting PdSn metallene aerogels achieve remarkable NO 3 − ‐N conversion (∼97%) and N 2 selectivity (∼99%), together with long‐term stability (>600 h) and broad tolerance to variable nitrate concentrations. In situ characterization and theoretical analyses reveal that Sn‐induced oxophilicity strengthens nitrogen‐oxygen intermediate adsorption, ensuring sufficient * N availability for N‐N coupling while elevating the hydrogenation barrier of * N → * NH, thus suppressing NH 3 formation. Integrated into a Zn‐NO 3 − battery and a customized gas‐integrated flow electrolyzer, the catalyst enables efficient nitrate removal and nearly complete N 2 selectivity, offering a promising platform for sustainable nitrogen recycling and energy conversion.
Sacituzumab tirumotecan (Sac-TMT) plus pembrolizumab (Pembro) in participants (Pts) with advanced urothelial carcinoma (UC): Results from phase 2 2870-002/SKB264-II-06 study.
744 Background: There are limited 1L therapy options for cisplatin-ineligible patients with locally advanced or metastatic UC (la/mUC), indicating an unmet need for novel treatment strategies. Sac-TMT (MK-2870/SKB264) is a TROP2-directed ADC with a unique bifunctional linker that maximizes delivery of a novel belotecan-derived topo I inhibitor payload to tumor cells, that has shown promising antitumor activity in several tumor types, including as monotherapy in UC (Ye, D, et al. J Clin Oncol 2025;43[suppl 5]:796). We present efficacy and safety data for cohort B in 1L cisplatin-ineligible pts with la/mUC from the phase 2, open-label 2870-002/SKB264-II-06 study (NCT05642780) evaluating sac-TMT + pembro in pts with select solid tumors. Methods: Eligible pts in cohort B were aged ≥18 y, previously untreated, cisplatin-ineligible with la/mUC. Pts with prior adjuvant or neoadjuvant platinum-based therapy or nivolumab were eligible if they had disease recurrence >12 mo after completing therapy. Pts received sac-TMT 4 or 5 mg/kg IV (non-randomized) on days 1, 15, and 29 of each 42-day cycle + pembro 400 mg IV on day 1 of each 42-day cycle for up to 2 years until PD or unacceptable toxicity. Primary endpoints were safety and ORR per RECIST v1.1 by investigator assessment. Secondary endpoints included DCR, DOR, and PFS by investigator assessment. Results: As of May 21, 2025, 40 pts were treated with sac-TMT (26 pts at 4 mg/kg and 14 pts at sac-TMT 5 mg/kg) + pembro. Median follow-up was 14.5 (range, 11.6–21.8) mo. Median age was 66.5 y, 37 pts (93%) were Asian, and 24 (60%) had upper tract UC. Confirmed ORR was 68%, median DOR was 15.4 mo, and median PFS was 11.2 mo (Table). 39 pts (98%) experienced treatment-related AEs including 23 (58%) with grade 3 or 4 treatment-related AEs. Anemia (15%), decreased neutrophil count (15%), and stomatitis (10%) were the most common (incidence ≥10%) grade 3 or 4 treatment-related AEs. No treatment-related deaths occurred. Conclusions: Sac-TMT + pembro showed promising antitumor activity at both 4 and 5 mg/kg in previously untreated, cisplatin-ineligible pts with la/mUC, with a manageable safety profile consistent with that of the individual treatment components. Further studies are warranted. Clinical trial information: NCT05642780 . Outcome Sac-TMT 4 mg/kg + Pembro 400 mgn = 26 Sac-TMT 5 mg/kg + Pembro 400 mgn = 14 Total N = 40 Confirmed ORR, % (95% CI) 65 (44.3–82.8) 71 (41.9–91.6) 68 (50.9–81.4) DCR, % (95% CI) 89 (69.8–97.6) 86 (57.2–98.2) 88 (73.2–95.8) BOR, n (%) CR 0 (0) 1 (7) 1 (3) PR 17 (65) 9 (64) 26 (65) SD 6 (23) 2 (14) 8 (20) PD 1 (4) 1 (7) 2 (5) No assessment a 2 (8) 1 (7) 3 (8) Median DOR, mo (range) 15.4 (3.6–15.4) NR (2.0–17.7+) b 15.4 (2.0–17.7+) b Median PFS, mo (95% CI) 10.9 (5.7–NE) NR (3.7–NE) 11.2 (5.8–NE) NE, not estimable; NR, not reached. a Includes pts without post-baseline assessment on data cutoff date. b “+” indicates no event by time of last disease assessment.
Spatially mapping the prostate cancer tumor microenvironment to reveal immune cell drivers of aggressive disease.
400 Background: Cells of the tumor microenvironment (TME) have been implicated in prostate cancer (PCa) progression. However, the specific TME cell subtypes and cell–cell interactions driving disease progression in patients remains unclear. Traditional tumor profiling techniques lack the resolution needed to assess complex single-cell and spatial biomarkers. Imaging Mass Cytometry (IMC) can identify a much wider range of cancer, stromal and immune cell subtypes in patient tumors than previously possible using spatial proteomics. We profiled the tumors of a large prospective biopsy cohort with longitudinal clinical outcomes using two custom IMC assays to reveal potentially targetable TME cells driving localized PCa. Methods: Spatial single-cell expression profiling was performed on primary PCa tumor biopsies using two IMC assays (“Tumor Panel” enriched for PCa tumor markers and “TME Panel” enriched for stromal and immune cell markers). Cell subtypes were defined for both assays independently by clustering, then integrated using affine registration of paired images. Reference cell subtypes were defined using Tumor Panel, and TME cell subtypes were refined using co-registered TME Panel data. Per-sample “cell fraction” of each cell subtype was defined as cell count of that subtype divided by total cell count. Biochemical progression-free survival (bPFS) and cancer-specific survival (CSS) were prespecified clinical endpoints. Survival analyses stratified by cell fraction tertiles were performed using a Cox proportional hazards model. Cell–cell interactions were defined as colocalization using knn graphs, and significance was assessed using a permutation test (α=0.05). Results: Protein co-expression patterns in >6.4 million cells comprising 604 biopsy samples obtained from 393 patients were measured. Initial single-cell analysis of Tumor Panel data revealed 16 cell subtypes including luminal PCa cells, basal epithelial cells, lymphocytes, and MHC-II+ immune cells. Patients with tumors enriched for MHC-II+ immune cells demonstrated impaired bPFS ( P =0.001) and CSS ( P =0.002). Multivariable analysis including GS revealed MHC-II+ immune cell enrichment, Canary risk score, and Prolaris genomic risk score to be all independently prognostic of bPFS and CSS ( P <0.01). TME Panel showed the MHC-II+ cells to co-express CD68 and CD163, consistent with M2 macrophages. Spatial interaction testing revealed significant interaction between these cells and CD4+ FOXP3+ putative Tregs (P<0.05), suggesting they may cooperate to promote PCa progression. Conclusions: We identified a single-cell biomarker independently associated with poor prognosis in localized PCa. Validation in an independent cohort is needed. Our findings support new therapeutic strategies targeting TME immune cells and highlight the utility of spatial tumor profiling for discovering next-generation biomarkers.
Clinical outcomes of metastatic urothelial carcinoma patients discontinuing enfortumab vedotin due to toxicity and/or clinical response.
719 Background: Enfortumab vedotin (EV) monotherapy and its combination with pembrolizumab (EV/P) are established treatments for metastatic urothelial carcinoma (mUC). In clinical practice, patients who discontinue EV after achieving a complete or partial response (CR/PR), or to avoid excessive toxicity, may experience durable response. However, the treatment-free interval (TFI) after stopping EV has not been previously characterized. Methods: We retrospectively analyzed mUC pts treated with EV or EV/P at our institution. Pts receiving neoadjuvant EV/P for locally advanced disease or fewer than 2 cycles of EV or EV/P were excluded. The primary endpoint was TFI among pts who discontinued EV (with or without continuing pembrolizumab in EV/P pts) for > 8 consecutive weeks due to toxicity or CR/PR. Continuous variables were summarized using means, medians and ranges while categorical variables with frequencies and proportions. TFI was evaluated using cumulative incidence curves and Fine Gray models with treatment re-initiation and death as two competing events. Results: Among 146 pts (median age 72 years; 80% men), 78 received EV and 68 received EV/P. Seventy-two pts (49.3%) discontinued EV for >8 weeks due to toxicity and/or CR/PR (32 EV; 40 EV/P). Median treatment duration before discontinuing was 6.1 months (range, 1.4-15.4) with EV and 4.6 months (range, 1- 22) with EV/P. At 1 year after stopping EV, 43.75% of EV and 66.98% of EV/P patients remained alive and treatment-free (Table). Duration of EV prior to stopping did not predict TFI (EV: HR 1.02, p = 0.77; EV/P: HR 0.91, p = 0.33). Patients achieving CR had significantly longer TFI than those with PR (HR 5.06, p = 0.01). Among 22 patients who reinitiated EV at progression, 24% achieved PR, 33% stable disease, and 43% progressed. Conclusions: Nearly half of mUC patients stopping EV due to toxicity or clinical response remained treatment-free and alive at 1 year. Duration of prior EV exposure did not influence TFI, but achieving CR was associated with significantly prolonged TFI. Re-treatment with EV upon progression yielded disease control in over half of patients. Cumulative incidence at 1 year of stopping EV. EV Group (n = 32) EV/P Group (n=40) Alive and treatment-free 43.75% 66.98% Incidence of restarting any treatment 31.25% 24.66% Incidence of death 25% 8.36%
Machine Learning‐Informed Nano Co‐Assembly Inhibits Fibroblast Activation Protein and Improves Drug Delivery in Fibrotic Tissue
ABSTRACT Nanoparticle‐based drug delivery faces persistent challenges, including complex fabrication processes and limited lesional accumulation. Here we introduce SP‐13786 (SP), a precise small‐molecule inhibitor of fibroblast activation protein (FAP), as a universal and effective excipient enabling facile co‐precipitation into stable nanoparticles (SCAN) with diverse hydrophobic drugs. Screening of 861 compounds revealed a broadly enhanced colloidal stability and drug loading by SP. Corresponding simulations and explainable machine learning (XML) showed SCAN assembly hinges on balanced aromaticity, rigidity, and nitrogen‐mediated interaction, offering interpretable framework for co‐assembly nanomedicine. Biological assessment demonstrate that SCAN enhances drug delivery and therapeutic efficacy in FAP‐positive cells, therefore attentuate the fibrosis‐induced drug penetration barriers, increasing drug accumulation within the fibrotic tissue. The improved bioavailability correlate with superior therapeutic outcomes in multiple disease models with progressive fibrosis. Overall, we establish SP as a versatile nanotherapeutic platform combining simplicity in preparation, mechanistic insights provided by XML, and broad applicability for diseases characterized by pathological fibrosis and impaired drug delivery.
Synergistic Ternary Heterostructures Cathode With “Electron‐Complementation” Bridging Interfaces Enable High‐Performance Zinc‐Ion Batteries
ABSTRACT Constructing multiphase heterostructures by interweaving characteristically complementary oxides, sulfides, and metals is promising for advancing aqueous battery electrodes, yet versatile synthesis and heterointerface insight pose significant challenges. Traditional methods often suffer from specificity optimization and non‐redox‐active substrate dependency, compromising performance. Herein, we overcome these limitations with a versatile overpotential‐driven synthetic strategy that enables precisely engineering ternary all‐component‐active heterostructures for compromise‐free high‐performance aqueous zinc batteries. Analysis of localized structure and first‐principles calculations in the model integrated V 2 O 5 @Cu 2 S@Cu heterostructure strongly suggest the formation of amorphous/crystalline bridging interfaces with electronic complementarity, which facilitates deep charge transfer and superior kinetics. In situ synchrotron X‐ray diffraction and ex situ X‐ray absorption spectra reveal the synergistic multi‐electron redox merging anion coordination, collectively enabling the all‐component redox activity and preferred rate capability. As results, V 2 O 5 @Cu 2 S@Cu delivers a high reversible capacity of 492 mAh g −1 , enabling 9000 cycles at 5 A g −1 with 90% capacity retention, greatly surpassing those of any single component. Such synthesis method has been further extended to other accessible vanadium‐based, manganese‐based and bismuth‐based ternary heterostructures, representing an important yet unexplored path to the fabrication of high‐performance aqueous battery cathodes featuring elaborate heterointerface manipulation.
Impact of abiraterone versus enzalutamide on depression and anxiety in hormone-sensitive prostate cancer (HSPC).
147 Background: Abiraterone (A) and enzalutamide (E) are now standard of care options for localized high risk and metastatic HSPC. Prior work in castration resistant disease suggested increased risk for depression with E compared to A. The impact of A v. E on depression and anxiety in HSPC where A/E are used for longer and have greater survival benefit is unknown. Methods: We used clinical data from an academic health system to identify patients who received ADT and either A or E as first-line therapy for HSPC from 2018-2024. Baseline characteristics were compared using t-, Chi-square, and Fisher’s exact tests. Outcomes were 1) clinical encounters for depression or anxiety and 2) psychotropic drug fills while on A/E. We restricted the cohort to those without baseline depression or anxiety diagnoses or psychotropic drug fills. Using logistic regression, we compared the odds of having the outcomes as a function of receiving A v. E; we controlled for age, race, cancer stage (N0/N1 v. metastatic), Charlson comorbidity index (CCI), year of A/E initiation, and time on A/E. We fitted a second logistic regression model to the full cohort and added baseline depression or anxiety and psychotropic drug fills as covariates. Results: Out of 412 patients with HSPC, 342 received A and 70 E. Patients who received E were more likely to have metastatic HSPC (89 v. 71%, p<0.01), start treatment later during the study period (56 v. 52% in 2022-2024, p=0.03), and have baseline depression (14 v. 4%, p<0.01). There was no difference in age, race, CCI, baseline anxiety, or time on A/E. In the subgroup without baseline depression or anxiety or psychotropic drug fills, patients on E had higher odds of a new depression diagnosis (aOR 3.12, 95% CI 1.10-8.88) than those on A (Table). There was no difference in odds of a new anxiety diagnosis (aOR 1.29, 95% CI 0.42-3.99) or psychotropic drug fill (aOR 2.08, 95% CI 0.79-5.45). When accounting for baseline depression or anxiety and psychotropic drug fills in the full cohort, patients on E had higher odds of a clinical encounter for depression (aOR 3.07, 95% CI 1.22-7.74, p=0.02) and a psychotropic drug fill (aOR 2.26, 95% CI 1.03-4.95, p=0.04) than those on A. There was no difference in odds of a clinical encounter for anxiety (aOR 1.69, 95% CI 0.67-4.28, p=0.27). Conclusions: Patients who received E for HSPC were more likely to experience clinically relevant depression, but not anxiety, than those who received A. Incident depression and anxiety in patients on A v. E for HSPC. Abiraterone(n, %) Enzalutamide(n, %) Adjusted OR (95% CI) Adjusted p-value DepressionA: n = 330, E: n = 60* 20 (6%) 8 (13%) 3.12 (1.10-8.88) 0.03 AnxietyA: n = 324, E: n = 63 20 (6%) 5 (8%) 1.29 (0.42-3.99) 0.66 Psychotropic drug fillA: n = 257, E: n = 50 25 (10%) 9 (18%) 2.08 (0.79-5.45) 0.14 *Cohort sizes differ for each outcome as analyses were restricted to patients without that outcome at baseline.
Homologous recombination repair gene alterations and outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.
829 Background: Enfortumab vedotin plus pembrolizumab (EV-P) represents the standard of care first-line therapy for patients with metastatic urothelial carcinoma (mUC). Homologous recombination repair (HRR) gene alterations are known to confer sensitivity to platinum-based regimens; however, their impact on outcomes in patients treated with EV-P remains elusive. Methods: We retrospectively identified patients with mUC treated with EV–P at the Oncology Institute of Southern Switzerland between December 2023 and August 2025. Targeted sequencing was performed on diagnostic FFPE tissue samples using the Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific). Clinical data, including objective response rate (ORR) and progression-free survival (PFS) on EV-P (PFS1) and on subsequent platinum-based chemotherapy (PFS2), were extracted from electronic medical records. Results: Nineteen patients received EV–P during the study period. Median age was 74.6 years; 42.1% had primary upper tract tumors; 68.4% had visceral metastases; median follow-up was 7.6 months. Six patients (31.6%) carried HRR-associated alterations: 4 carried BRCA mutations, 1 FANCA and 1 FANCD2 pathogenic variants. All patients received EV–P as first-line therapy, followed by second line carboplatin–gemcitabine in eligible patients. No patients with HRR-altered tumors achieved an ORR to EV-P versus 63.6% in patients with HRR–wild-type tumors (p = 0.034), including three complete responses. Median PFS1 was numerically shorter for the first group (4.3 vs 10.7 months, HR: 3.54, 95% CI: 0.83-15.09 p = 0.0874). Two patients without HRR alterations received second-line carboplatin–gemcitabine and had a PFS2 of 2 and 4 months, shorter than those observed in the three HRR-altered patients who received the same regimen (5, 9, and 14 months, respectively). Among them, the two BRCA2-mutated patients achieved longer PFS on platinum-based chemotherapy (9 and 14 months) than during EV–P treatment (≤6 months). Conclusions: In this small, single-institution retrospective cohort, HRR gene alterations were associated with lower ORR and shorter PFS under first-line EV–P. Patients with BRCA2-mutated tumors had a longer response with second-line platinum-based chemotherapy than with first-line EV-P. These findings require validation in larger cohorts and prospective trials. Characteristic HRR-altered, N=6 Others, N = 13 Median age, y (range) 71.5 (61-80) 76 (60-83) Male sex, n (%) 5 (83.3) 11 (84.6) Primary bladder cancer, n (%) 3 (50.0) 8 (61.5) Prior local treatment, n (%) 3 (50) surgery; 1 (16.7) trimodal 6 (46.2) radical surgery ECOG PS (0 / 1 / ≥2), n (%) 3 (50.0)/ 3 (50.0)/ 0 (0.0) 7 (53.8%)/ 4 (30.8)/ 2 (15.4) Visceral metastasis, n (%) 4 (66.7) 9 (69.2) Other somatic gene alterations, n FGFR3: 0ERBB2: 1CDKN2A/B: 0TERT: 3TP53: 4ARID1A: 0RB1: 1 FGFR3: 1ERBB2: 2CDKN2A/B: 0TERT: 4TP53: 2ARID1A: 3RB1: 0
Biomarker analysis of neoadjuvant atezolizumab in upper-tract urothelial carcinoma: Results from the ABACUS-2 trial.
832 Background: High-risk upper-tract urothelial carcinoma (UTUC) is associated with poor clinical outcomes and there are no standard neoadjuvant therapy options currently. ABACUS-2 evaluates two cycles of neoadjuvant atezolizumab prior to radical nephroureterectomy (RNU). Here, we report circulating (ctDNA) and urinary tumour DNA (utDNA) findings. Methods: ABACUS-2 (NCT04624399) is a single-arm phase II study of atezolizumab (1200 mg IV Q3W × 2) prior to RNU in patients with high-grade or high-risk (hydronephrosis, tumour > 2 cm, multifocality, variant histology, or prior RC for UC) UTUC (cT1-4a N0-1 M0). Co-primary endpoints were pathological complete response (pCR; pT0N0) and predefined biomarker analyses on serial liquid biopsies. For these analyses, baseline genomic profiling was performed using the PredicineWES+ assay to identify somatic variants, followed by longitudinal minimal residual disease (MRD) monitoring with the PredicineBEACON platform. Correlations were explored between pCR, relapse-free survival (RFS) and overall survival (OS) with ctDNA/utDNA dynamics. Results: 27 pts received at least 1 cycle of atezolizumab. 4 pts did not undergo RNU (3 due to disease progression, 1 unfit for RNU). pCR occurred in 7% (2/27). After a median follow-up of 18.9 months (95% CI 13.9 –25.6), disease recurrence was observed in 26% (6/27) and 15% (4/27) had died. Treatment was well tolerated, with no surgery delays reported. 24 pts had successful MRD tests in at least one of the time points from screening to end of follow-up and were included in this biomarker evaluable subset. At baseline 25% (5/20) of pts were ctDNA(+) and all pts (100%, 14/14) were utDNA(+). After neoadjuvant atezolizumab and RNU, 80% (4/5) pts had ctDNA clearance. Only 1 pt demonstrated utDNA clearance following neoadjuvant atezolizumab, which correlated with pCR on RNU. Post-RNU, 3 pts were ctDNA(+) and subsequently developed metastatic disease. Among 17 pts with post-RNU utDNA monitoring, 29% (5/17) showed repeated utDNA positivity at multiple follow-up timepoints, correlating with bladder tumour recurrence. ctDNA(-) status post neoadjuvant atezolizumab correlated with significantly longer RFS (p = 0.024) and OS (p = 0.048). Conclusions: Neoadjuvant atezolizumab was feasible and well tolerated in patients with high-risk UTUC, but pathological complete responses were infrequent. Post-operative liquid biopsy analyses revealed that ctDNA and utDNA provide complementary information on systemic and local disease, respectively. Persistent or recurrent ctDNA positivity post-RNU was strongly associated with metastatic relapse and inferior survival, while utDNA positivity during follow-up correlated with intravesical recurrence. These findings support the utility of plasma and urine MRD monitoring for risk stratification and early relapse detection in UTUC. Clinical trial information: NCT04624399 .
In Situ Synthesis of Biocompatible and Functionalizable Core–Shell Conductive Nanocomposites for Stretchable Electronics
ABSTRACT Stretchable electronics are poised to revolutionize smart wearables and biomedical implants, yet their progress is hindered by the lack of biocompatible and easily functionalized conductors. While silver nanowire (Ag NW)‐based composites show promise, their cytotoxicity and chemical instability often require complex passivation with noble metal coatings. Here, we introduce a scalable in situ synthesis that directly converts a patterned blend of Ag NWs and carbon nanotubes (CNTs) into a hierarchical core–shell architecture. The resulting material features a conductive nanocomposite core enveloped by a protective, CNT‐rich shell, achieving high conductivity (5100 S/cm), stretchability (>200% strain), and carbon‐like biocompatibility. Its broad electrochemical stability window permits direct electroplating of active materials required for physical and chemical sensing. We demonstrate the utility of this platform via soft electronic patches that conform to dynamic skins and organs. In a compelling in vivo application, these patches successfully recorded pathological electrograms and terminated arrhythmia via closed‐loop pacing therapy on a rabbit heart. This work establishes a general strategy for creating biocompatible compliant conductors as a key enabler for stretchable devices in health monitoring, medical therapies, and human‐machine interfaces.
Perspective on Aqueous Batteries: Historical Milestones and Modern Revival
ABSTRACT Aqueous batteries have played a pivotal yet fluctuating role in the evolution of electrochemical energy storage. From their foundational success in lead–acid and nickel‐based chemistries to their eclipse by lithium‐ion batteries, aqueous systems were long regarded as technologically inferior due to limited energy density and poor cycling stability. However, the urgent demand for safe, low‐cost, and sustainable storage has sparked a renaissance, fueled by breakthroughs in electrolyte engineering and advanced electrode materials for both anodes and cathodes. This review revisits the historical trajectory of commercialized aqueous batteries, extracting lessons from past successes and failures while highlighting the technological advances that now enable extended voltage windows, improved cycling stability, and scalable manufacturing. We argue that the future of aqueous batteries lies not in directly competing with lithium‐ion in high‐energy applications, but in complementing them across grid‐scale storage, uninterruptible power supplies, and decentralized energy systems where safety, cost, and recyclability are paramount. By connecting history with current progress, we reflect on how these insights reshape expectations for the next generation of aqueous batteries and their role in a more diversified and sustainable energy storage landscape.
Updated clinical results and associated biomarkers from an ongoing phase 1 study of FX-909, a first-in-class peroxisome proliferator-activated receptor gamma (PPARG) inhibitor, in patients (pts) with advanced urothelial carcinoma (adv UC).
LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .
The impact of rising PSA during salvage radiotherapy post radical prostatectomy on relapse.
365 Background: Salvage radiotherapy (RT) is an effective curative salvage of relapse after radical prostatectomy (RP). CAPRA S score predicts for relapse after salvage RT. The DADSPORT meta-analysis suggests those with low CAPRA S score do not benefit from benefit of androgen ablation (AA) to salvage RT. A rising PSA during salvage RT may be important in predicting which patients may benefit from treatment intensification such as addition of AA to salvage RT. Herein we report on outcomes of salvage RT without AA in relation to rising PSA during RT. Methods: 32 patients were treated with salvage RT alone without AA (either because of low risk or patient preference) for rising PSA rising post RP. All patients had a PSA prior to and at least twice during RT at least 3 weeks apart. Patients were treated with 66 Gy in 33# to prostate bed. Patients were followed for PSA q 6 months post RT. Those with a PSA rising to over 0.2 were considered to have relapsed. Actuarial outcomes for relapse were assessed with multivariate analysis including CAPRA S score (low, intermediate, and high), and by 6 year progression free survival estimate from MSKCC nomogram (dichotomized around the median). Results: Median and IQR of PSA at time of salvage RT were 0.24 (0.2-0.55). 19% of patients had rising PSA during RT. 19 patients (60%) also received 46 Gy in 23# to pelvic nodes in phase 1 of RT. 34% of patients had PSMA PET prior to RT (none showing involved nodes or metastases). CAPRA S scores were low (15%), intermediate (69%), and high (15%). Relapse rates did not differ by CAPRA S score, although numbers were small. Three-year freedom from relapse rates were 16% for those with rising, and 49% without rising PSA during RT respectively (p=0.006). Three-year freedom from relapse rates were 9% for those below the median MSKCC nomogram risk, and 68% for those above the median respectively (p<0.001). Only rising PSA during RT was significant on MVA. Three patients had a rising PSA and a negative PSMA prior to salvage RT: all three relapsed within 1 year of RT. Of eight patients who had a falling PSA during RT and a negative PSMA PET prior to salvage RT: only 1 relapsed within 3 years of salvage RT. Conclusions: A rising PSA during salvage RT without AA is prognostic for relapse, and may be particularly relevant in the PSMA PET era. This may be a factor to considered when deciding whether to intensify therapy during salvage RT, either by adding adjuvant ADT, and/or using a PSMA PET to guide dose escalation.
Multidimensional profiling of clinical trial cohorts and the characterization of radiotherapy/immunotherapy response biology in localised and metastatic muscle-invasive bladder cancer.
824 Background: Whilst combined radiotherapy/immunotherapy shows promising clinical potential, biological determinants of response are poorly understood. In RADIO (chemoradiotherapy ± durvalumab in localised MIBC, ISRCTN43698103) and PLUMMB (hypofractionated radiotherapy + pembrolizumab in metastatic MIBC, NCT02560636) trials, baseline tumour and longitudinal blood was profiled to investigate response biology. Methods: Whole exome sequencing, bulk RNAseq, T-cell receptor (TCR)seq and multiplex immunofluorescence (mIF) were used to profile n=12 RADIO and n=21 PLUMMB tumours, and longitudinal blood. Outcomes included RECIST criteria, disease-specific survival at 21 weeks (PLUMMB) and recurrence data at 6 months (RADIO) follow up. Results: Tumour mutational burden (TMB)-high PLUMMB patients survived longer (p=0.027), and TMB correlated with APOBEC enrichment (p<0.0001). However, neoantigen burden and APOBEC score were not associated with survival or response, and did not correlate with each other in either trial. PLUMMB tumours were enriched for carbohydrate metabolism (FDR<0.01) and TGF-β signalling (FDR<0.00005) transcriptomic pathways compared to RADIO, where TGF-β signalling associated with unfavourable outcomes (FDR=0.0452). Radioresistance pathways including cell cycle, hypoxia and epithelial to mesenchymal transition characterised progressive disease in PLUMMB. Durable response in RADIO was characterised by more intratumoural B and T-cells (mIF, p=0.024, p=0.008), with more unique TCRs in the tumour (p=0.049) and baseline blood (p=0.04), which reduced upon response (p=0.0357). PLUMMB patients had more peripheral TCR clones (p=0.0006) and clonotypes (p=0.03) with lower tumour similarity than in RADIO. High peripheral baseline TCR count associated with PLUMMB PD (p=0.044), indicating extensive but ineffective immunity. Conclusions: This unique multidimensional dataset revealed established biology associated with response to single agent therapies, in addition to novel parameters characterising localised and metastatic MIBC response to radiotherapy/immunotherapy combinations. As bladder-sparing chemo/radio/immunotherapy options show promising potential, comprehensive profiling of bladder cancers with multiple orthogonal methods reveals complex multimodal response biology. Ultimately, multidimensional research is essential for developing combination therapy biomarkers, where those for single agents may not suffice.
Prognostic utility of neutrophil:lymphocyte ratio (NLR) in patients receiving 177Lu-PSMA-617 (LuPSMA) for metastatic castration resistant prostate cancer (mCRPC).
207 Background: LuPSMA has a proven clinical benefit in mCRPC, but there is a need to develop predictive and prognostic biomarkers of response. Neutrophil:lymphocyte ratio (NLR) has shown prognostic value across a range of therapies for solid tumors, but there is limited data on its utility in mCRPC patients receiving LuPSMA. Methods: Patients with mCRPC who received ≥2 cycles (C) of LuPSMA therapy at Dana-Farber Cancer Institute between June 2022 and December 2024 were included. NLR at C1 and C2 of LuPSMA was categorized as ≤3 or >3, based on the cutoff used in the VISION trial (Wei et al, ESMO 2023). Efficacy endpoints included PSA50 (≥50% reduction in PSA from C1) and overall survival (OS). The association of NLR with outcomes was evaluated by logistic regression for PSA50 and Cox regression for OS, adjusted for age, visceral disease, number of prior taxanes and log-transformed C1 PSA. For C2 NLR or the change from C1 to C2, OS was calculated from the C2 date under a landmark analysis. Results: 265 patients were included, all of whom had received ≥1 taxane and ≥1 androgen receptor pathway inhibitor (ARPI). Median age was 72 years (IQR, 66-78), 80 (30%) had received 2 taxanes, 149 (56%) had received ≥2 ARPIs and 29 (11%) had liver metastases at baseline. Overall, 133 patients (50%) achieved a PSA50; with no significant difference in PSA50 rates based on NLR >3 (n=178) versus ≤3 (n=87) at C1 (OR=0.79 [0.47-1.35], p =0.39) or C2 (OR=0.69 [0.40-1.19], p =0.18). In the entire cohort, 63 deaths were observed, with a 6-month OS rate of 87% (95% CI 82-91). High NLR (>3) at C1 was associated with shorter OS compared to those with NLR ≤3 (6-month OS: 84% vs 93%, adjusted HR=1.87 [1.02–3.45], p=0.04); a similar trend was observed for elevated NLR at C2 (6-month OS from C2: 78% vs. 83%, adjusted HR=1.72 [0.93–3.18], p=0.08). When assessing change in NLR between C1 and C2, patients with persistently elevated NLR (>3 at C1 and C2) had the poorest outcomes, intermediate in those with change from >3 to ≤3 and best in those with NLR ≤3 at C1 (Table). Conclusions: In this large institutional cohort, baseline NLR was prognostic in patients receiving LuPSMA, with elevated NLR (>3) at C1 and C2 associated with the poorest outcomes to therapy. Baseline and early NLR dynamics may be helpful in identifying patients with poor outcomes on LuPSMA, for whom early treatment modification or intensification may be warranted. Change in NLR between C1 and C2 N OS (landmark analysis from C2) 6-mos OS from C2 (%, 95% CI) Adjusted HR (95% CI) <3 to <3 60 84 (71-92) Ref. >3 to ≤3 19 76 (41-92) 1.57 (0.42-5.85) ≤3 to >3 27 92 (57-99) 1.04 (0.29-3.78) >3 to >3 159 77 (69-84) 2.00 (1.00-4.00)