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Predictive value of early circulating tumor DNA (ctDNA) response in advanced urothelial carcinoma (aUC) treated with enfortumab vedotin plus pembrolizumab (EVP).
800 Background: EVP is active in aUC; however, biomarkers predicting early benefit are lacking. ctDNA is a noninvasive marker of tumor dynamics, but its predictive value in this setting is unknown. We hypothesized that early ctDNA response (ctDNA-R) predicts long-term outcomes with EVP. Methods: Patients (pts) who received EVP and had baseline ctDNA within the UNITE study were included. Early ctDNA-R was defined as reduction in ctDNA from baseline (−4/+2 weeks relative to EVP start) to the second measurement (through ≤3 months after EVP end or before subsequent therapy), with decline evaluated as continuous percent drop, ≥50% drop, and ≥90% drop. Associations with progression-free survival (PFS), overall survival (OS), and observed response rate (ORR) were assessed. PFS and OS were analyzed using Kaplan–Meier and Cox regression, and ORR using Firth logistic regression in pts with scans after ≥1 EVP cycle. Median baseline ctDNA was also evaluated for association with outcomes. Results: Among 48 pts treated with EVP across 3 US sites, 44 had measurable ctDNA at baseline (median 18.5, range 0 – 995), and 33 of these were evaluable for ctDNA dynamics with a second timepoint. Among the evaluable pts, median age was 72 years, 76% were male, 76% had pure urothelial histology, 97% had ECOG PS 0/1, 42% had visceral metastases, 82% were treatment naive in metastatic setting, and 30% had prior immunotherapy exposure in any setting. All pts had ctDNA measured using the Signatera assay, with a median baseline ctDNA of 29.5 MTM/mL (range 0.07 - 995). With a median follow-up of 12 months, median PFS and OS were 12 mos (95% CI 6–NR) and 23 mos (95% CI 12–NR), and ORR was 52% (16/31; 95% CI 39–64). The median time from baseline to the second ctDNA read was 7 weeks (range 3–25), with a median ctDNA-R of 96% (range 0–100) over this timeframe. Early ctDNA-R ≥50% occurred in 82% (27/33), ≥90% in 58% (19/33), and complete clearance in 30% (10/33). Greater ctDNA-R was associated with improved PFS, OS, and ORR across both continuous and categorical thresholds, while baseline ctDNA levels (above vs. below median) was not (Table). Conclusions: In this multi-site retrospective analysis, early ctDNA-R was associated with improved outcomes with EVP, supporting its potential as a predictive biomarker for early treatment monitoring. Despite potential selection bias, these hypothesis-generating findings merit validation in larger prospective cohorts. ORR: OR (95% CI) PFS: HR (95% CI) OS: HR (95% CI) Percent change (continuous) 1.05 (1.01 – 1.15), p = 0.002 0.96 (0.94 – 0.98), p < 0.001 0.97 (0.95 – 0.99), p = 0.001 ≥50% drop 22.6 (2.25 - 3069) , p = 0.005 0.06 (0.02 – 0.25), p < 0.001 0.07 (0.13 – 0.37), p = 0.002 ≥90% drop 7.36 (1.67– 40.02), p = 0.008 0.19 (0.07 – 0.55), p = 0.002 0.14 (0.03 – 0.61), p = 0.009 ≥ Median baseline ctDNA 1.53 (0.43 – 5.70), p = 0.5 0.89 (0.35 – 2.23), p = 0.8 0.60 (0.18 – 2.00), p = 0.4
PERSIAN trial (NCT03449719): Predictive features of complete biochemical response within a randomized phase II trial testing apalutamide and stereotactic body radiation therapy for low-burden, metastatic, hormone-sensitive prostate cancer.
157 Background: Apalutamide+androgen deprivation therapy (ADT) currently represents one of the accepted standards of care for systemic treatment for metastatic hormone sensitive prostate cancer (mHSPC). Stereotactic body radiotherapy (SBRT) on top of I line androgen receptor pathway inhibitors (ARPIs) treatment showed to significantly improve radiological progression free survival in castrate resistant setting and PERSIAN trial (NCT05717660) is a randomized phase II trial testing the benefit of concomitant ARPIs and SBRT in mHSPC setting. Methods: Patients affected by metachronous oligometastatic HSPC were randomized to standard of care with apalutamide+ADT (ARM A: Control) or the same systemic treatment combined with SBRT on all sites of metastatic disease evidenced on conventional imaging (ARM B: Treatment). Patients affected by de novo metastatic disease or > 5 distant metastases were excluded from the trial. Here is reported an early analysis focusing on rates of complete biochemical response (CBR: defined as PSA< 0.2 ng/ml) and predictive features of CBR at 6 months after treatment start in this population. Results: Sample size was completed in November 2024 after enrollment of 180 patients. Of these, 154 had at least 6 months of follow up data. In the overall population, CBR rate was 93.5%. Neither the presence of PSMA positive lesions undetected on conventional imaging or the presence of bone metastatic lesions affected the rate of CBR (OR 0.33, p=0.13 and OR 1.22, p= 0.77). Conversely, patients with <3 metastatic lesions had significantly improved complete biochemical response rate (OR 0.11, 95% CI 0.03-0.44, p-value 0.002). Conclusions: Rate of CBR was higher in oligometastatic HSPC if compared to unselected mHSPC enrolled in TITAN trial, especially in subgroup of patients with lower disease burden (e.g., < 3 metastatic lesions). This suggests improved outcomes in this population. Further analyses on the final sample size are awaited to explore the impact of SBRT on early and later clinical outcomes in control vs treatment arm. Clinical trial information: NCT03449719 .
Survival outcomes of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving lutetium Lu 177 vipivotide tetraxetan (Lu) by prior taxane exposure.
101 Background: Lu is a prostate-specific membrane antigen (PSMA)-targeting radioligand therapy. Its approval was recently expanded to include all adults with PSMA-positive mCRPC who have been treated with an androgen receptor pathway inhibitor (ARPI) and are considered appropriate to delay taxane-based chemotherapy. With approval expanding to taxane-naïve pts, there is limited data to guide the sequencing of treatment in pts with PSMA-positive mCRPC after progression on ARPI. Thus, we sought to compare the survival of pts with mCRPC who received Lu based on the timing of taxane receipt. Methods: This is a retrospective cohort study using the US-based, electronic health record-derived deidentified Flatiron Health Research Database. We included pts diagnosed with mCRPC with prior ARPI treatment who initiated Lu from 12/19/2018 to 6/23/2025. The final cohort was divided into three categories based on the receipt of taxane relative to Lu: before Lu, after Lu, and never. Endpoints: median real world time to next therapy (rwTTNT) and median real world overall survival (rwOS) and were calculated from timing of Lu initiation, summarized by Kaplan-Meier estimates and their 95% confidence intervals (CIs). Results: Of the overall cohort of 27,979 pts with metastatic prostate cancer, 850 pts with mCRPC and prior treatment with an ARPI who received Lu were included in our analysis. The majority were White non-Hispanic (65.18%), treated in community practice (70.35%), and covered by commercial insurance (61.18%). 466 pts (54.82%) received taxane before Lu, 35 (4.12%) received taxane after Lu, and 349 (41.06%) received Lu and did not receive taxane. The median rwTTNT and rwOS by timing of taxane are summarized in the Table. Conclusions: Numerical differences in rwTTNT and rwOS were observed with Lu based on timing of taxane treatment. This may represent underlying patient and disease heterogeneity along with tumor evolution. Regardless of prior taxane exposure or not, Lu maintained effectiveness in pts with mCRPC. These results provide real-world data for patient counseling in clinic and emphasize the need for randomized clinical trials in this setting for optimal treatment sequencing. Median rwTTNT and median rwOS from first Lu initiation based on timing of taxane. N Median rwTTNT (months) (95% CI) Median rwOS (months) (95% CI) Taxane before Lu 466 8 (7.4-9.0) 12 (11-13) Taxane after Lu 35 6 (4.9-8.0) 16 (13-not reached) Never received taxane 349 10 (9.2-11) 14 (13-17)
TP53 mutations (TP53mut) as a predictive biomarker for lutetium-177-PSMA (Lu-PSMA) vs. docetaxel benefit in post-androgen receptor pathway inhibitors (ARPI) metastatic castration-resistant prostate cancer (mCRPC).
28 Background: Predictive biomarkers are needed to help guide Lu-PSMA vs. taxane use in post-ARPI mCRPC. Randomized trials comparing Lu-PSMA to taxanes did not include extensive tissue NGS profiling. Kwan et al 2025 observed strong associations with ctDNA tumor fraction and differential benefit from Lu-PSMA and cabazitaxel in the TheraP trial. However, additional genomic assessments were limited by small numbers. TP53 is commonly mutated in advanced prostate cancer, affecting downstream responses to radiotherapy in preclinical models. Making use of a large real-world cohort, we sought to perform comparative effectiveness of these agents defined by TP53 status. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with metastatic prostate cancer treated with docetaxel or Lu-PSMA in the post-ARPI setting with tissue tumor genomic testing were eligible for analysis. PSA growth rate (g-rate) was calculated with R package ‘tumrg.’ Time to next treatment (TTNT) and overall survival (OS) were adjusted for between-group imbalances and for factors influencing their treatment assignment in routine practice via propensity weighting. Results: 561 patients were eligible for the cohort. Receiving docetaxel: 144 TP53mut(+) & 274 TP53mut(-). Receiving Lu-PSMA: 50 TP53mut(+) & 93 TP53mut(-). Patients receiving docetaxel vs. Lu-PSMA had faster PSA doubling times prior to treatment assignment, less prior lines of therapy, less prior docetaxel, and higher baseline PSA values. After propensity weighting, residual imbalances were largely mitigated (less than 0.1 SMD). Patients with TP53mut(-) had more favorable TTNT on Lu-PSMA vs. docetaxel (HR: 0.47, 95% CI 0.28 – 0.81, p = 0.006) while this was not observed in TP53mut(+) (HR: 1.09, 95%CI 0.61 – 1.93, p = 0.77). Similar associations were observed for OS. Significant treatment interactions were observed for Lu-PSMA vs. docetaxel by TP53mut status for TTNT (p = 0.034) and OS (p = 0.00070). Extensive sensitivity analyses observed similar results. Conclusions: In a large routine practice cohort, making use of best practices in causal inference, we observed the majority of clinical benefit from Lu-PSMA to be in the non-TP53 mutated group. Compared to similar patients who received docetaxel, we observe more favorable outcomes on Lu-PSMA only in the non-TP53 mutated group. Treatment assignments were consistent with more aggressive getting docetaxel and initial later line Lu-PSMA approval. However, now with earlier approval, TP53 status is a strong candidate predictive biomarker to guide Lu-PSMA vs. docetaxel decisions in mCRPC, warranting future studies.
Interface‐Engineered High‐Performance Flexible Thermoelectric Films for Self‐Powered Health Monitoring
ABSTRACT Harvesting low‐grade discrete heat through flexible thermoelectrics (TEs) offers a transformative route toward self‐powered wearable electronics, yet is hindered by the inherent trade‐off among electrical/thermal transport and flexibility, as well as lack of application‐driven co‐design between materials and devices. Herein, we counterintuitively incorporate an insulating polymer‐polyvinylpyrrolidone (PVP) into the flexible Ag 2 Se‐based matrix, leveraging its multifunctional interfacial effects to achieve carrier‐phonon decoupling. This yields a flexible TE film with record‐high power factor of 3328 ± 332 µW m −1 K −2 and a figure of merit ( ZT ) of 1.1 at 341 K. The high‐performance stems from the rational incorporation of PVP as a dual‐functional additive, which simultaneously promotes coherent grain boundaries and mitigates Fermi‐level pinning effect. The assembled flexible TE generator delivers a normalized power density of 81 W m −2 under a temperature gradient of 35 K. Moreover, a proof‐of‐concept TE‐cup that integrates physiological sensing and energy harvesting is demonstrated, which achieves 100%‐accurate user identification via thermal‐sensing signals and powers a physiological monitor using harvested energy (∼20 mV) through an ultra‐low‐power management circuit. Our work redefines the positive role of non‐conductive polymers in TE nanocomposites, establishes an effective strategy for structure‐property manipulation, and pioneers a self‐sustained platform for next‐generation healthcare monitoring.
A High‐Safety Solid‐State Thermally Responsive Separator‐Electrolyte Structure for Flexible Energy Storage Devices
ABSTRACT In the era of energy development, electrochemical energy storage devices are widely used for their high‐power density and long cycle life. However, rapid ion transport can cause excessive heat, accelerating degradation and raising safety risks. To address this, a high strength integrated smart separator‐electrolyte structure based on poly (N‐isopropylacrylamide) (PNIPAAm) is developed. The assembled supercapacitor achieves 81% capacitance retention after 5000 cycles at 1 A g −1 . By incorporation of hydrophilic (N‐vinylpyrrolidone) NVP monomer and high concentration salts, the hydrogen bonding network is precisely regulated, giving the structure exceptional mechanical robustness and anti‐freezing performance, enabling stable operation under deformation and extreme conditions. Leveraging the reversible phase transition of PNIPAAm, the electrolyte dynamically closes ion channels upon heating and reopens them upon cooling, achieving automatic shutdown and self‐recovery of device operation. Above 60°C, the electrolyte rapidly suppresses ionic transport (100% capacity loss), with full function recovery after cooling. In addition, the color change of the exclamation mark pattern on the outer packaging allows for quick and accurate identification of the overheating status. The synergistic integration of thermal responsiveness and visual alerting ensures ultra‐safe operation and provides a promising strategy for enhancing the operational safety of next‐generation flexible energy storage devices.
Prospective comparison of AR-V7 transcripts from whole blood and circulating tumor cells in castration-resistant prostate cancer patients undergoing treatment with androgen-receptor signaling inhibitors: The PEARL trial.
253 Background: Androgen receptor splice variant 7 (AR-V7) messenger RNA (mRNA) from whole blood (WB) was reported to predict treatment resistance to androgen-receptor signaling inhibitors (ARSI) in metastatic castration-resistant prostate cancer (mCRPC). This prospective study aimed to validate AR-V7 mRNA from WB in comparison to AR-V7 mRNA from circulating tumor cells (CTCs) for prediction of treatment resistance to ARSI in mCRPC. Methods: PEARL is a prospective biomarker study of mCRPC patients starting ARSI treatment with abiraterone or enzalutamide (NCT03601143). Pretreatment blood samples were analyzed using droplet digital PCR for AR-V7 mRNA quantification in WB and Adnatest for quantitative PCR AR-V7 mRNA detection in CTCs. The primary objective was to validate the predictive ability of AR-V7 status in WB compared to CTCs for treatment response defined by PSA decline ≥50%. Secondary endpoints included PSA progression-free survival (PSA-PFS), clinical progression-free survival (PFS), and overall survival (OS). Results: Overall, 111 blood samples from 107 mCRPC patients were included. Test failure rates were 0% (0/111) for WB-based testing and 19% (21/111) for CTC-based testing. High AR-V7 expression in WB was detectable in 10% (11/111), while AR-V7 in CTCs was detectable in 31% (28/90). AR-V7 detection from WB-tests was significantly associated with treatment response (p=0.02), whereas CTC-based test results were not (p=0.06). In multivariable logistic regression models adjusting for key clinical covariates, AR-V7 status in WB remained an independent predictor of non-response with an odds ratio of 6.1 (95%CI 1.1-67.3; p=0.04) while CTC-based AR-V7 test results was not significantly associated (OR 1.7 95%CI 0.6-4.9; p=0.3). Among cases with positive AR-V7 status, only 1 (10%) achieved PSA decline ≥50% for the WB test vs. 8 (31%) for the CTC-based test. Regarding secondary endpoints, high AR-V7 in WB was significantly associated with shorter PSA-PFS (3.3 vs. 8.5mo, p<0.001), shorter cPFS (3.4 vs. 8.4mo, p<0.001) and shorter OS (12.2 vs. 23.8mo, p<0.001). AR-V7 detection in CTCs was also significantly associated with shorter PSA-PFS (4.8 vs. 8.9mo, p=0.008), shorter cPFS (4.8 vs. 7.5mo, p=0.03) and shorter OS (12.5 vs. 31.4mo, p<0.001). Conclusions: AR-V7 RNA level testing in WB was prospectively validated to predict poor treatment outcome in mCRPC cases undergoing treatment with abiraterone or enzalutamide. Compared to the CTC-based test, the WB-test showed a better test procedure success rate, lower AR-V7 detection rate, but better stratification of treatment resistance. Clinical trial information: NCT03601143 .
An artificial intelligence–digital pathology algorithm to predict outcomes in a cohort of men diagnosed with prostate cancer within a low resource setting.
399 Background: In the era of precision oncology, personalized prognostic biomarkers have demonstrated superior prostate cancer (PCa) risk stratification, but their deployment in low- and middle-income countries (LMICs) is limited by resource and infrastructure constraints. Although digital pathology-based multimodal artificial intelligence (MMAI) model offers a scalable, low-cost alternative using routine hematoxylin and eosin (H&E) slides, few studies have evaluated the performance of these models on samples from LMICs. Here, we report the first evidence of a prognostic MMAI in predicting biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) in a cohort of native African men (NAM) with PCa, aiming to bridge this gap and advance personalized care in low-resource settings. Methods: We performed a retrospective analysis of NAM with localized PCa who had available digital histopathologic images from biopsy (Bx) specimens. MMAI scores were generated by applying deep learning to digitized H&E Bx slides, integrating histopathologic features with clinical variables. This approach preserves tissue samples and can be readily implemented in LMICs. MMAI scores were evaluated as both continuous and categorical variables using pre-specified cutoff. The primary objective was to determine whether MMAI can predict BCRFS and DMFS using Harrell’s concordance index (C-index) derived from Cox proportional hazard models. Next, HTG EdgeSeq and gene set enrichment analysis (GSEA) was performed to identify distinct biological pathways that are associated with low/intermediate vs. high MMAI scores. Results: The final analytical cohort included 88 NAM with both MMAI and longitudinal clinical outcomes data. The median age of the cohort was 68 years (IQR: 63-73). The majority of patients (N=86, 98%) received radiation therapy as their primary treatment. The median follow-up time was 27 months (IQR: 13-44 months). Each 1–standard deviation (SD) increase in MMAI score was associated with higher risk of BCR (HR=4.38, 95% CI 1.87-10.27, P =.0007) with a C-index of 0.84, and DM (HR=2.68, 95% CI 1.14-6.32, P =.02) with a C-index of 0.86, indicating excellent discriminatory performance of MMAI. Lastly, GSEA revealed strong positive correlation between MMAI high and immune related pathways (NK cells, B cell markers, T cell markers) and negative correlation between MMAI high and MTORC1 Signaling, Unfolded Protein Response, and Androgen Response pathways. Conclusions: Our study provides the first evidence that MMAI score predicts BCRFS and DMFS in a native African PCa cohort. The performance and ease of deployment of MMAI in low resource settings has the potential to close the gap in personalized care for men with PCa globally.
OPTIMAS: A phase II randomized, decentralized, de-escalation trial in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) achieving optimal PSA response.
TPS288 Background: An optimal PSA response, defined as ≤0.2 ng/mL is achieved by ~51% of pts with mHSPC at 6–8 months after treatment (Rx) with androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) +/- docetaxel and is associated with a 61% reduction in risk of death (HR 0.39, 95% CI 0.30–0.50; Naqvi SAA ASCO GU 2023). Pts receiving continuous ADT experience numerous adverse effects including fatigue, loss of bone density, muscle loss, weight gain, gynecomastia, hot flashes, sexual dysfunction, increased cardiovascular risk and skeletal-related events. Since achieving optimal PSA response is prognostic of prolonged overall survival, these pts may be candidates for a de-intensified Rx strategy which may result in better quality of life. To investigate this, we initiated a de-intenstification trial in pts with mHSPC. Methods: This IRB approved, investigator-initiated, single-center, multi-cohort, phase 2, randomized, open-label study will enroll 160 pts. Cohort A will enroll 100 pts (step 1) with mHSPC who haven’t initiated systemic Rx for metastatic disease and will be treated with relugolix (R)+ARPI +/-standard of care Rx. Pts achieving PSA ≤0.2 ng/mL will be randomized (step 2) 1:1 to intermittent or continuous R+ARPI. Primary objective: To assess difference in fatigue at 6 months after randomization between intermittent vs continuous arms. In a prior study, pts with mHSPC who received ADT+ARPI had a mean baseline brief fatigue inventory worst fatigue (BFI3) score of 2.04 with a standard deviation (SD) of 2.176, and the SD was similar in control group. Null hypothesis: there is no difference in mean BFI3 in the control arm (continuous Rx) and experimental arm (intermittent Rx) 6 months after randomization. Alternative hypothesis: difference is ≥ 2 points. 52 pts (26 in each arm) are required to have 90% power at one-side 2.5% significance level, using two-sample t-test assuming equal variance. With 100 pts enrolled in Step 1 and expected 60% pts reaching PSA ≤0.2 ng/ml, 58 evaluable pts will be randomized at Step 2 to achieve 52 pts for primary analysis (assumed dropout rate 10%). Cohort B will enroll 60 pts with mHSPC who initiated ADT Rx for metastatic disease and achieved PSA ≤0.2 ng/ml. Pts will receive intermittent R+ARPI. Primary objective: To assess progression-free survival (PFS) on intermittent R+ARPI at 1 year. Assuming 1-year PFS rate of 92%, per Clopper-Pearson exact method with 60 pts, achieving expected 92% PFS rate provides 95% confidence that the true PFS rate is no lower than 83.3%. Secondary objectives for cohort A & B: To evaluate Rx effects on patient-reported outcomes (PROs) and efficacy of intermittent R+ARPI. Exploratory objectives: ecological momentary assessments, safety, PRO association with testosterone, tissue and blood biomarker assessment. Clinical trial information: NCT07216248 .
Contemporary outcomes of nephrectomy with IVC thrombectomy: Analysis from a large multi-institutional database.
469 Background: Nephrectomy with IVC thrombectomy for renal cell carcinoma remains one of the most technically demanding procedures in urologic oncology. Despite advances in surgical technique and perioperative management, these operations carry substantial morbidity. Existing literature includes predominantly single-institution series with variable sample sizes, limiting comprehensive risk stratification for patient counseling. We present perioperative outcomes from the largest contemporary multi-institutional analysis to provide evidence-based benchmarks for this high-risk population. Methods: We analyzed the 2019-2023 ACS-NSQIP database for patients undergoing radical nephrectomy with IVC thrombectomy, identified using appropriate CPT codes. Pathologic staging determined thrombus level, with T3b correlating with level II-III thrombi and T3c with level IV thrombi. Demographics, comorbidities, and 30-day perioperative outcomes including major and minor complications, operative time, length of stay (LOS), readmissions, and mortality were analyzed. Results: Among 439 patients 362 had level II-III (T3b) thrombi and 77 had level IV (T3c) thrombi. Robotic surgery was utilized in 20.1% of level II-III cases and 9.6% of level IV. Demographics were similar across groups, though level IV patients had higher ASA class and lower preoperative hematocrit. Complication rates increased with advancing thrombus level: minor complications occurred in 58.5% of level II-III and 74.4% of level IV patients. Major complications occurred in 18.8% of level II-III and 29.9% of level IV patients, with level IV cases experiencing high rates of pulmonary embolism (9.1%), deep vein thrombosis (5.2%), myocardial infarction (2.6%), and cardiac arrest (3.9%). Bleeding requiring transfusion was the most frequent overall complication, affecting 51.9% of level II-III and 64.9% of level IV patients. LOS increased: level II-III 6.9±5.3 days, level IV 10.5±6.9 days. 30-day mortality rates were 1.9% for level II-III and 10.4% for level IV. Conclusions: This analysis demonstrates the significant morbidity associated with IVC thrombectomy. Level II-III operations carry significant complication rates, while level IV procedures involve even greater morbidity, with particularly high rates of bleeding, cardiovascular complications, and mortality. These outcome data provide evidence-based benchmarks for patient counseling and informed consent discussions. IVC thrombectomy patient outcomes. T3bN = 362 T3cN = 77 Minor Complications 213 (58.52%) 58 (74.36%) Other Bleeding 188 (51.93%) 50 (64.94%) Major Complications 68 (18.78%) 23 (29.87%) PE 15 (4.14%) 7 (9.09%) Operative Time (minutes) 291 ± 89 354.18 ± 145.02 Length of Total Hospital Stay (days) 6.88 ±5.27 10.48 ± 6.92 Return to operating room 7 (1.93%) 7 (9.09%) Readmission 34 (9.39%) 3 (3.9%) Death 7 (1.93%) 8 (10.39%)
Fusion Peptide‐Incorporated Lipid Nanoparticles Boost Endosomal Escape and Enhance Cytosolic mRNA Delivery
ABSTRACT The endosomal escape capability of current mRNA‐loaded lipid nanoparticles (mRNA‐LNPs) is generally low, which restricts their overall delivery efficiency. To address this limitation, we adopted a strategy inspired by the viral infection mechanism, utilizing fusion peptides to enhance the intracellular release of mRNA. Nine viral‐derived and artificial fusion peptides were co‐encapsulated within mRNA‐LNPs respectively, termed FP‐LNPs, and systematically assessed their efficacy in improving mRNA delivery. Notably, the HA2 fusion peptide from the influenza virus demonstrated a marked enhancement in mRNA delivery efficiency both in vitro and in vivo. Under acidic conditions of endosomes, HA2 collaborates with ionizable cationic lipids to facilitate endosomal membrane rupture, thereby promoting the release of mRNA into the cytoplasm and enhancing protein expression. Moreover, the incorporation of fusion peptides into various types of mRNA‐LNP formulations significantly improved their in vivo delivery efficiency of mRNA, resulting in improved gene editing outcomes in the liver and lungs. Furthermore, in a Hereditary Tyrosinemia Type 1 (HT‐1) mouse model, HA2‐LNP significantly boosted FAH protein expression in the liver and more effectively prevented body weight loss and reduced liver fibrosis. Overall, this approach offers a promising strategy for enhancing endosomal escape and boosting the delivery efficiency of mRNA, underscoring its enhanced therapeutic potential.
Van der Waals Ferroelectric CuInP <sub>2</sub> S <sub>6</sub> ‐based Multi‐slope In‐memory Probabilistic Computing
ABSTRACT Probabilistic bit (p‐bit) is the fundamental building block and core element of probabilistic computing (p‐computing). However, physical separation of bit generation and memory storage creates a memory bottleneck in conventional p‐computing architectures. We report on experimentally integrating voltage‐tunable stochastic bit generation and non‐volatile memory functionalities within a single in‐memory device to realize a p‐bit with van der Waals ferroelectric CuInP 2 S 6 (CIPS). Leveraging the stochastic displacement of Cu + ions and the material's remanent polarization under an external electric field, the proposed device achieves stable random bit retention (>1000 s) with low power consumption (∼75 nW). This eliminates the need for data transfer between separate memory and logic units, thereby enabling efficient in‐memory p‐computing with improved system‐level performance. In‐memory p‐computing outperforms conventional p‐computing in device‐to‐system‐level NP‐hard simulations, reducing time‐complexity from O(n 2 ) to O(n 1.5 ). Notably, the sigmoid slope of the probabilistic output is dynamically tuned by varying the CIPS layer thickness, enabling adaptive control over exploration–exploitation characteristics. Broader slopes facilitate initial exploration, whereas steeper slopes support rapid convergence in later stages. Sigmoid slope tunability over a wide dynamic range (6.17–38.41) reduces convergence steps by 400‐fold, highlighting the potential of CIPS‐based p‐bit as a compact, energy‐efficient platform for scalable and adaptive p‐computing.
Outcomes of [ <sup>177</sup> Lu]Lu-PSMA-617 ( <sup>177</sup> Lu-PSMA-617) after sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC): A real-world prostate cancer disease observation (PRECISION) data platform analysis.
88 Background: The VISION (NCT03511664) and PSMAfore (NCT04689828) clinical trials have demonstrated the effectiveness of 177 Lu-PSMA-617 in patients with mCRPC who have previously received androgen receptor pathway inhibitors (ARPIs) with or without taxane-based chemotherapy. Sipuleucel-T is used for treatment of mCRPC in routine clinical practice, particularly among community urologists; however, to date, there are no data available to understand the effectiveness of 177 Lu-PSMA-617 in patients previously treated with sipuleucel-T. Methods: This was a retrospective, observational study of adult patients with a diagnosis of mCRPC who received 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, and had a history of treatment with sipuleucel-T. Data were obtained from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US that integrates electronic health records and claims data from community, academic, urology, and medical oncology settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and prostate-specific antigen (PSA) response rates were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was analyzed using Kaplan–Meier curves. Results: A total of 290 patients met the inclusion criteria, of whom 72% were White and 12% were Black. At index, 32% of patients were treated in urology and 68% in oncology settings. The median age was 74 years, the median baseline PSA was 35.3 ng/mL (interquartile range [IQR] 10.0–99.2 ng/mL), and 57% of patients had a Gleason score of ≥8. In addition to sipuleucel-T, prior to 177 Lu-PSMA-617, 97% of patients had received ≥1 ARPI and 79% had received ≥1 taxane. The median follow-up for this cohort was 9.4 months (IQR 5.3–17.5 months). Among 144 patients with available PSA values both before and during 177 Lu-PSMA-617 treatment (representing 50% of the cohort), PSA response rates were as follows: a ≥50% reduction in PSA from baseline (PSA50) was observed in 60%, PSA80 in 42%, and PSA90 in 33% of patients. Overall, the median PFS was 15.2 months (95% confidence interval [CI] 11.6–19.4 months). Conclusions: In this real-world analysis of patients who received 177 Lu-PSMA-617 after sipuleucel-T treatment, the median PFS was similar to that observed in clinical trials, suggesting that 177 Lu-PSMA-617 can be sequenced after sipuleucel-T treatment in appropriate patients.
Real-world survival disparities and comorbidity predictors with Lu-177–PSMA-617 and PARP inhibitors in metastatic prostate cancer.
125 Background: Lu-177–PSMA-617 (Pluvicto) and PARP inhibitors represent distinct targeted treatment paradigms in metastatic prostate cancer (mPCa). Real-world comparative data describing their impact on survival and comorbidity-related outcomes remain limited. We utilized the TriNetX global federated database to evaluate mortality associations and clinical predictors among patients receiving these therapies. Methods: We conducted two retrospective cohort analyses using the TriNetX Research Network (110 healthcare organizations, 2010–2025). Patients with mPCa (ICD-10 C61 plus C77–C79) were grouped by receipt of Lu-177–PSMA-617 (vipivotide tetraxetan) or PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib). Cox proportional hazards models assessed all-cause mortality, adjusting for age, race, ethnicity, and comorbidities (hypertension, diabetes, liver disease, dementia, thromboembolic events, cerebrovascular disease). Results: The Lu-177–PSMA-617 cohort included 2,009 patients vs 119,042 controls; the PARP inhibitor cohort included 1,830 vs 119,221. 1) Lu-177–PSMA-617 was associated with lower mortality risk (HR 0.76; 95% CI 0.70–0.82; p <0.001). 2) PARP inhibitors were linked to higher observed mortality (HR 1.21; 95% CI 1.14–1.30; p <0.001), likely reflecting later-line or biomarker-selected use. 3) Age was predictive in both models (HR 1.04 per year; p <0.001). Diabetes (HR ≈ 1.15), hepatic disease (HR ≈ 1.41), and thromboembolic events (HR ≈ 1.29) increased mortality risk, while Hispanic ethnicity was protective (HR ≈ 0.62; p <0.001). Conclusions: In this real-world analysis, Lu-177–PSMA-617 improved survival, whereas PARP inhibitor–treated patients had higher mortality, likely reflecting more advanced disease. Cardiometabolic and hepatic comorbidities independently predicted poorer outcomes, emphasizing the need to account for comorbidity burden in managing advanced mPCa. Cox proportional hazards model for mortality in metastatic prostate cancer (TriNetX 2010–2025). Variable Hazard Ratio (HR) 95% CI p-Value Interpretation Lu-177–PSMA-617 (vs no Lu-177–PSMA-617) 0.76 0.70–0.82 <0.001 24% lower mortality risk PARP inhibitor (vs no PARP) 1.21 1.14–1.30 <0.001 21% higher mortality risk* Age (per year increase) 1.04 1.03–1.04 <0.001 Increased risk with age Type 2 diabetes mellitus 1.15 1.12–1.17 <0.001 Adverse impact Hepatic disease (fibrosis/cirrhosis) 1.41 1.31–1.53 <0.001 Adverse impact Thromboembolic disease (DVT/PE) 1.29 1.23–1.35 <0.001 Adverse impact Cerebrovascular disease 1.16 1.11–1.22 <0.001 Adverse impact Hispanic ethnicity 0.62 0.59–0.66 <0.001 Protective association Male sex 0.88 0.74–1.06 0.18 NS Black race 1.08 1.04–1.13 <0.001 Modestly higher risk Asian race 1.24 1.18–1.31 <0.001 Higher risk vs White *Likely reflects later-line therapy and selection for biomarker-positive advanced disease.
Perioperative outcomes from a randomized controlled trial comparing MRI-guided transurethral ultrasound ablation (TULSA) to robot-assisted radical prostatectomy (RARP).
369 Background: MRI-guided transurethral ultrasound ablation (TULSA) uses MRI to target, monitor, and control thermal ablation of prostate tissue with high intensity directional ultrasound, demonstrating favorable histologic control and preservation of genitourinary function in single-arm studies [1,2]. CAPTAIN (NCT05027477) is a post-market, multi-center randomized controlled trial (RCT) of TULSA vs RARP for intermediate-risk prostate cancer, and is the first such study to meet its enrolment target. Here we compare baseline patient characteristics, treatment parameters, and periprocedural outcomes. Methods: CAPTAIN enrolled men with treatment-naïve, organ-confined, Grade Group 2 or 3 prostate cancer at 23 centers including academic and private clinics in the USA (20), Canada (2), and Finland (1). Patients were randomized 2:1 to TULSA or RARP, without crossover. Endpoints include pad-free urinary continence (EPIC) and erections sufficient for penetration (IIEF Q2) at 1 year, salvage treatment at 3 years, and survival to 10 years. Periprocedural metrics include length of stay, blood loss, catheter time, and 30-day patient diary (EQ-5D-5L, NRS pain score). Results: 211 patients were treated from Jan 2022 to Aug 2025 (70% TULSA, 30% RARP), surpassing the enrolment target of 201. Arms had similar baseline characteristics: median (IQR) age for TULSA vs. RARP was 63 (58–68) vs 65 (60–69) years (p=0.12), PSA was 6.5 (4.9–9.6) vs 7.2 (5.6–9.7) ng/mL (p=0.63), Grade Group 2/3 proportions were 76%/24% vs 77%/23% (p=0.88). RARP involved bilateral, unilateral, or no nerve sparing in 89%, 5.7%, and 5.7% of cases. TULSA ablation plans included whole-gland (68%) and ≥hemi-ablation (32%). Median (IQR) blood loss was lower during TULSA vs RARP: 0 (0–0) vs 100 (100–200) mL (p<0.001). Hospital stay was shorter for TULSA: 0.29 (0.27–0.32) vs 1.24 (1.12–1.36) days (p<0.001). Catheter duration was longer post-TULSA: 13 (11–15) vs 8 (8–10) days (p<0.001). Patients reported lower NRS pain scores after TULSA to post-operative day 6, and less decline in overall health on the EQ-5D-5L 0-100 visual analog scale over 30 days (p<0.05). Fewer patients reported extreme inability on EQ-5D-5L after TULSA vs RARP over the first month for mobility (0% vs 15%), self-care (1% vs 18%), and usual activities (18% vs 38%) (all p<0.05). Conclusions: CAPTAIN is the first multicenter RCT comparing ablation to radical prostate cancer treatment to meet its enrollment target. Early perioperative results from CAPTAIN demonstrate that TULSA had no blood loss or overnight hospitalization, reduced post-procedural pain, and faster return to baseline activities and overall health. Data collection to 1 and 3 years post-treatment continues to readout of the primary safety and oncological outcomes. [1] Klotz et al 2021, JUrol 205(3):769-779. [2] Eggener et al 2024, UrolOnc 42:S83. Clinical trial information: NCT05027477 .
Treatment patterns, attrition, and survival outcomes in patients with metastatic unclassified renal cell carcinoma.
463 Background: Unclassified or not otherwise specified (NOS) renal cell carcinoma (RCC) is a rare and heterogeneous subtype, representing 2-6% of RCC cases [PMID: 30510921]. It is associated with poor prognosis, and prospective clinical trial data to guide treatment (Rx) decisions are limited. Herein, we aimed to assess Rx patterns and survival outcomes in pts with metastatic NOS RCC in a large real-world database. Methods: We utilized the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Eligibility: diagnosis of NOS RCC with metastasis and receipt of first-line (1L) systemic Rx. Rx types from 1L to 5L are summarized using frequency and percentages. Real-world time to next therapy (rwTTNT) was defined as time from each line initiation to the next line of Rx or death and censored at the lost to follow-up. Real-world overall survival (rwOS) was defined as time from each line initiation to death and censored at the lost to follow-up. Kaplan-Meier method was used to estimate median rwTTNT and rwOS, and their 95% confidence intervals (CIs). Results: Among 13,909 pts diagnosed with metastatic RCC in the dataset, 2,589 had metastatic NOS RCC, of whom 1,718 received 1L Rx and were eligible and included in our analysis. Pts initiated 1L Rx between 2/4/2011 - 10/25/2024. Median age was 68 years (IQR 60 – 76), 69% were male, and 60% were White non-Hispanic. Of these, 43% received 2L Rx and 19% received 3L. In 1L, tyrosine kinase inhibitors (TKIs) were most commonly used (48%), followed by PD-1 inhibitor (PD-1i)-based regimens (CTLA-4i + PD-1i, 18%; PD-1i + TKI, 13%) and single-agent PD-1i (9%). In 2L, TKIs remained the most common (35%), followed by single-agent PD-1i (24%) and PD-1i-based combinations (CTLA-4i + PD-1i, 4%; PD-1i + TKI, 13%). In 3L, TKIs were again most commonly used (46%), followed by single-agent PD-1i (16%). Median rwTTNT and rwOS by Rx and line of Rx are summarized in Table. Conclusions: In this large real-world study, significant attrition with each line of Rx was observed. TKIs were the most common Rx across all lines. Survival outcomes remained poor across all regimens. These data highlight the urgent need for more effective therapeutic strategies to guide Rx in pts with metastatic NOS RCC. Median rwTTNT (mo, 95% CI) and rwOS (mo, 95% CI) by Rx and line of Rx in pts with metastatic NOS RCC. Rx 1LMedian rwTTNTn = 1718 1LMedian rwOSn = 1718 2LMedian rwTTNTn = 745 2LMedian rwOSn = 745 3LMedian rwTTNTn = 325 3LMedian rwOSn = 325 TKI 6.1 (5.3–6.8) 14 (12–16) 5.1 (4.5–6.8) 10 (7.9–14) 4.8 (3.6–5.7) 9.7 (7.5–13) CTLA-4i + PD-1i 5.5 (4.7–7) 14 (12–19) 4.2 (3.5–NR) 8.8 (7.1–NR) 4.7 (3.7–NR) 12 (8.8–NR) PD-1i + TKI 8.5 (6.7–10) 12 (11–17) 9.7 (7.2–13) 16 (13–20) 4.3 (3.4–12) 11 (6.2–16) PD-1i 3.9 (2.9–5.5) 9.8 (7.9–13) 5.3 (4.3–7.1) 12 (9.2–18) 7.7 (4.2–17) 11 (4.9–30) Everolimus 3.4 (1.9–9.7) 11 (5.9–20) 4.4 (3.7–6.1) 10 (6.2–18) 5.6 (4–NR) 16 (4.1–NR) i: inhibitor, NR: not reached.
From Fiber Architecture to Functional Attachment: A Clinically Relevant, Mechanically Tunable Cardiac Patch
ABSTRACT Contractile engineered cardiac patches hold great potential for treating myocardial infarction, serving as biological ventricular assist devices (BioVADs). However, optimal design and attachment of cardiac patches remain insufficiently explored, although both are essential for the mechanical support of damaged hearts. This study presents a platform for personalized macroscale patches with a multi‐zonal microarchitecture combining a regenerative zone for cell alignment, a stiff force transmission zone for load transfer, and an elastic attachment zone enabling integration. Based on computational modeling, the design is implemented using a custom G‐code generator for melt electrowriting (MEW). Digital image correlation reveals up to a 2.6‐fold strain difference between scaffold zones under physiological deformation, confirming zonal interplay. Biaxial testing with preconditioning shows scaffold mechanics replicating native myocardium properties up to 10% strain. For epicardial suture attachment, a reinforced outline enables shape‐morphing and increases suture retention 2.16‐fold. Dynamic BioVAD cultivation with fibrin‐embedded cardiomyocytes significantly (p = 0.01) improves cell alignment versus controls. Finally, in a porcine myocardial infarction model, the BioVAD achieves complete epicardial attachment and vascular ingrowth within 7 days, compared to partial attachment in controls. This study highlights MEW as a versatile platform for tailoring cardiac scaffold mechanics to support tissue integration and cardiac function.
Intensified Accumulation of OH <sup>−</sup> and Improved Electron Transfer by Reactive Chlorine‐Resistant Layer Achieve High‐Durability Seawater Electrolysis
ABSTRACT The stability and efficiency of direct seawater electrolysis are constrained by competitive Cl − adsorption and corresponding chlorine oxidation reaction, which further restricts diffusion and accumulation of OH − , as well as transfer of electrons involved in counterpart oxygen evolution reaction (OER), leading to severe Cl − ‐corrosion. Herein, intensified popular‐OH − accumulation and electron transfer are achieved through Ag‐mediated reactive chlorine‐resistant AgCl layer integrated onto NiCo‐oxyhydroxide (AgCl/NiCo‐OOH). Specifically, under external electric field driving, Ag species on the NiCo‐OOH surface undergo electrochemical transformation and free Cl − ‐immobilization via in situ formation of robust AgCl layer, subsequently leveraging common‐ion repulsion effect to sieve and control composition of ions in Stern layer, and thereby preventing Cl − corrosion. Simultaneously, the AgCl with high‐curvature induces electric fields across scales, incorporating mesoscale proximal‐tip and microscale built‐in electric fields, which significantly accelerates OER kinetics by intensifying diffusion and accumulation of reactant OH − and transfer of electron. Resultantly, the AgCl/NiCo‐OOH achieves an ultralow overpotential of 331 mV in alkaline simulated seawater and sustains stable operation for over 2200 h at Ampere‐level current density in alkaline seawater without Cl − ‐related corrosion. Further, the corresponding anion‐exchange membrane electrolyzer demonstrates a low energy consumption (4.50 kWh m −3 H 2 ) and long‐term durability (over 1500 h) at 500 mA cm −2 .
Evaluating the relationship between vasculitis and metastasis in kidney-related urogenital cancers: A multicenter real-world propensity-matched cohort study.
561 Background: Vasculitis, a disorder with systemic inflammation and immune dysregulation, can create a pro-tumorigenic microenvironment. While its connection with higher cancer incidence is recognized, its specific role in cancer development and metastatic spread remains poorly characterized. This study aims to evaluate whether a pre-existing diagnosis of vasculitis is associated with an increased risk of metastasis in patients with urogenital cancer. Methods: Using the multinational TriNetX database, we conducted a propensity-matched cohort study. Patients with malignant kidney, upper tract, or bladder cancer and a diagnosis of vasculitis were compared to a matched cohort with the same cancers but without vasculitis. A 3-year lookback period was used for comorbidity assessment. The primary outcome was the development of metastasis following the initial cancer diagnosis. By restricting the cohort to non-metastatic cancers at baseline, metastasis was assessed as a subsequent outcome rather than a pre-existing condition. The secondary outcome was all-cause mortality, analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Results: After matching, 2,222 patients were distributed to both groups. Patients with vasculitis had a significantly higher risk of metastasis than those without vasculitis (Hazard Ratio [HR] 1.68, 95% CI 1.26-2.24, p = 0.032). Survival without metastasis was 81.7% in the vasculitis group compared to 93.9% in the control group. Conversely, the difference in all-cause mortality was not statistically significant (HR 1.04, 95% CI 0.93-1.17, p = 0.050), though survival probabilities at 5 years were much lower in the vasculitis group (27.1% compared to 41.9%). Conclusions: Vasculitis is associated with a significantly higher risk of metastasis in urogenital cancer patients. These findings position vasculitis as a potential marker for aggressive disease. Increased vigilance and targeted management may be warranted for those urogenital cancer patients with accompanying vasculitis to combat this increased risk of metastasis.
The efficacy and safety of <sup>177</sup> Lu-PSMA-617 in Chinese patients with post-taxane metastatic castration-resistant prostate cancer: From a multicenter phase II study.
181 Background: The global phase III VISION trial established the efficacy of 177 Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who had been previously treated with ≥1 androgen receptor pathway inhibitor (ARPI) and one or two taxane regimens. 177 Lu-PSMA-617, along with Best Standard of Care (BSoC), demonstrated a median radiographic progression-free survival (rPFS) of 8.7 months. Methods: This open-label, multicenter single-arm phase II study (NCT05670106) evaluated 177 Lu-PSMA-617 in Chinese pts with prostate-specific membrane antigen (PSMA)-positive mCRPC who progressed after ≥1 ARPI and 1-2 taxane regimens. The trial employed a two-part design: the Main part enrolled only pts with ≥1 measurable soft tissue lesion at baseline, while the Extension part enrolled additional pts with or without measurable lesions. Pts received 177 Lu-PSMA-617 (7.4 GBq ±10%) every 6 weeks for up to 6 cycles, in addition to BSoC. The primary endpoint was soft tissue overall response rate (ORR) assessed by blinded independent central review (BICR) per PCWG3-modified RECIST v1.1 in the Main part. Secondary endpoints included duration of response (DOR), rPFS, overall survival (OS), prostate-specific antigen (PSA50) response rate, ORR in all pts with measurable lesions, the safety profile and tolerability, health-related quality of life (HRQoL) and the pharmacokinetics (PK) and dosimetry. Results: From June 1, 2023 to January 17, 2024, a total of 62 pts (median age 68.5 years; 72.6% with ≥3 prior ARPI treatments) were enrolled, and 59 received treatment (Main part, n=29; Extension part, n=30). With a median follow-up of 14.29 months, the ORR in the Main part was 41.4% (95% CI: 23.5–61.1%), comparable to VISION trial (AAA617+BSoC arm: 51.1%; BSoC arm: 3.1%). The ORR based on all pts with measurable lesions was 39.2% (95% CI: 25.8-53.9%; n=51). Secondary endpoints in the Main part included a median DOR of 7.69 months (9.8 months in VISION), median rPFS of 6.05 months, median OS of 11.89 months, and PSA50 response rate of 44.8%, confirming the clinically meaningful efficacy in this population. In the safety analysis set (n=59), grade ≥3 treatment-related adverse events (TRAEs) were observed in 44.1% of pts. Treatment-related serious adverse events were reported in 23.7% of pts, and TRAEs leading to treatment discontinuation occurred in 18.6% of pts. The most common grade ≥3 safety topics of interest (≥2%) included myelosuppression (42.4%), hepatotoxicity (8.5%) and renal toxicity (3.4%). No grade 3 dry mouth were observed. These safety findings align with the established safety profile of 177 Lu-PSMA-617. Conclusions: This is the first trial showing the efficacy and safety of 177 Lu-PSMA-617 in Chinese mCRPC pts, supporting its favorable benefit-risk profile when administered with BSoC. Clinical trial information: NCT05670106 .