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Interim safety and tolerability of TARA-002 in patients with BCG-naïve and unresponsive high-grade non-muscle invasive bladder cancer in ADVANCED-2.
776 Background: There continues to be a significant unmet need for safe, effective, and bladder sparing treatment options for patients with non-muscle invasive bladder cancer (NMIBC). TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger innate immunity, inflammation, and potential immunogenic cell death. ADVANCED-2 (NCT05951179) is an ongoing Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in adults ≥ 18 years with high-grade (HG)-NMIBC CIS (± Ta/T1). Preliminary results showed promising complete response (CR) rates and durable responses in patients with HG NMIBC treated with TARA-002 (Jayram et al. AUA 2025). This abstract presents pooled safety data of TARA-002 from the BCG-naïve cohort and BCG-unresponsive cohort of the ADVANCED-2 study. Methods: The ADVANCED-2 study includes 2 cohorts of BCG-naïve (Cohort A) and BCG-unresponsive (Cohort B) participants. Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; and concomitant prostatic or upper tract urothelial involvement. Each participant is treated with TARA-002 to receive induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. Results: As of 07-October-2025, 60 participants (median age: 74; range: 45 to 92), have been enrolled and exposed to TARA-002: 31 BCG-naïve (Cohort A) and 29 BCG-unresponsive (Cohort B). In both cohorts, 18/60 (30.0 %) participants reported drug-related treatment emergent adverse events (TEAEs). Related TEAEs were Grade 1 (18/60; 30.0%) and Grade 2 (3/60; 5.0%), with no reported Grade 3-5 related TEAEs. Commonly reported related TEAEs (≥ 5%) included bladder spasm (10.0%), dysuria (13.3%), fatigue (6.7%), and micturition urgency (6.7%). Most TEAEs were mild and transient. In both cohorts, 10/60 (16.7%) experienced serious AEs (SAEs); 4/60 (6.7%) were Grade 2 and 9/60 (15.0%) were Grade 3. No participants experienced drug-related SAEs or drug-related TEAEs leading to withdrawal or death. Conclusions: TARA-002 monotherapy was well tolerated, thus demonstrating a favorable tolerability profile to date for the treatment of BCG-naïve and BCG-unresponsive HG NMIBC with CIS (±Ta/T1). TARA-002 has a promising safety profile as a bladder-sparing treatment in HG NMIBC across BCG exposure status. Updated safety data will be provided based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .
Efficacy and safety of avelumab + axitinib vs sunitinib in patients (pts) with very favorable-risk advanced renal cell carcinoma (aRCC): Subgroup analysis from the JAVELIN Renal 101 trial.
560 Background: In the JAVELIN Renal 101 phase 3 trial, first-line (1L) treatment with avelumab + axitinib in pts with aRCC significantly prolonged progression-free survival (PFS) and increased the objective response rate (ORR) vs sunitinib, irrespective of International Metastatic RCC Database Consortium (IMDC) risk group or number of IMDC risk factors. In the final analysis, overall survival (OS) results favored avelumab + axitinib vs sunitinib but did not reach statistical significance. A previous study in pts with favorable risk within the IMDC dataset identified a very favorable-risk subgroup, defined as pts with time from primary diagnosis to systemic therapy ≥3 years, Karnofsky performance status >80, and no brain, liver, or bone metastasis. We report post hoc analyses in pts with very favorable-risk aRCC. Methods: In JAVELIN Renal 101 (NCT02684006), eligible pts with untreated aRCC (any IMDC score) were randomized 1:1 to receive avelumab + axitinib or sunitinib. In this exploratory analysis, PFS and ORR per investigator assessment (RECIST 1.1), OS, and safety were assessed in the subgroup with very favorable risk. Results: In the avelumab + axitinib (n=442) and sunitinib (n=444) arms, respectively, 30 (6.8%) and 36 (8.1%) pts had very favorable risk disease. Within these subgroups, median age was 61.0 and 63.5 years, 96.7% and 94.4% pts had previous nephrectomy, and 60.0% and 61.1% had positive PD-L1 status, respectively. Follow-up was ≥68 months in all pts (data cutoff: Aug 31, 2023). OS, PFS, and ORR data are shown in the Table. Subsequent anticancer drug treatments were received by 70.0% pts after avelumab + axitinib vs 75.0% after sunitinib, including a PD-(L)1 inhibitor in 33.3% vs 63.9%, respectively. In the avelumab + axitinib vs sunitinib arms, respectively, treatment-related adverse events of any grade occurred in 100% vs 97.2% pts, including grade ≥3 events in 73.3% vs 61.1%, and led to permanent discontinuation of all study drugs in 0% vs 16.7%. Conclusions: In post hoc analyses from the JAVELIN Renal 101 phase 3 trial, long-term efficacy benefits were observed with avelumab + axitinib vs sunitinib in the subset of pts with very favorable-risk aRCC, consistent with results in the overall population and favorable IMDC risk subgroup. Safety findings were similar to those of previous analyses. These results support the use of 1L avelumab + axitinib treatment in pts with very favorable-risk aRCC and suggest that a tailored treatment strategy may improve aRCC management in this population. Clinical trial information: NCT02684006 . Outcomes data. Avelumab + axitinib (n=30) Sunitinib (n=36) Hazard ratio (95% CI) OS, median (95% CI), months Not reached (72.1-NE) 69.1 (51.4-NE) 0.48 (0.21-1.09) PFS, median (95% CI), months 26.3 (18.2-31.8) 12.5 (11.1-26.3) 0.57 (0.30-1.08) ORR (95% CI), % 83.3 (65.3-94.4) 44.4 (27.9-61.9) – NE, not estimable.
Intercalating Bulk Gold Crystal Into Ordered Single Atoms
ABSTRACT Gold single atoms (GSAs) have attracted considerable attentions due to their potential in electrocatalytic and photocatalytic reactions. However, achieving high gold density in conventional wet‐solution or mechanical approaches remains currently challenging, apart from uncontrolled spatial on‐support distributions, undesired bi‐products and wastes. Here we show that single gold atoms can be synthesized and patterned via a top‐down intercalation method, in which the topmost layer of gold (100) crystal evolves into isolated single atoms (conversion rate up to 25%) chiseled by a phosphorus monolayer. Scanning tunneling microscopy, X‐ray photoemission spectroscopy, and density functional theory calculations reveal that GSAs assemble into well‐ordered (2 × 2) arrays without thermodynamic tendency for coalescence and weakly couple with the underlying non‐planar phosphorus layer toward efficient hydrogen evolution reaction and oxygen evolution reaction catalysis. The on‐surface formation of GSAs can be readily tailored by varying the post‐annealing temperature and durations. This protocol is defect‐free, solvent‐free, eco‐friendly, scalable, and could regenerate a batch‐to‐batch of fresh GSAs arrays via a simple sputtering and intercalation process in case of catalyst deactivation. This work opens a green and sustainable way for the facile preparation of high‐density GSAs for efficient on‐surface electro‐/photo‐catalytic applications.
Polysaccharide Engineered Nanozymes Target Inflammation for Alleviating Colitis‐Associated Mental Disorders via Microbiome‐Gut–Brain Axis
ABSTRACT Molecular therapies for colitis‐associated mental disorders show limited efficacy because they usually focus on a single pathway and exhibit substantial off‐target toxicity toward healthy tissues. To tackle this limitation, bioinformatic approaches are employed to predict that inflammation and metabolism may be potential targets for Fucoidan. Guided by this prediction, we develop oral polysaccharide engineered nanozymes, Fucoidan‐cerium nanocomplexes (FucCeNCs), which are capable of targeting the inflamed colon through electrostatic interactions, exerting anti‐inflammatory effects, and concurrently regulating gut microbiota‐derived metabolism. In a murine model of ulcerative colitis‐associated mental disorders, FucCeNCs show anti‐inflammatory and gut barrier‐protective effects, thereby suppressing microglial/astrocytic overactivation and preserving neuronal integrity through the transmission of anti‐inflammatory cytokines via gut–brain axis. Importantly, FucCeNCs restore gut microbial homeostasis through increasing the relative abundance of probiotics and reducing proportions of pathogens. This shift results in a marked attenuation of abnormal amino acid biosynthesis and metabolism in fecal metabolites, which in turn leads to elevated levels of bioactive metabolites such as homovanillic acid and γ‐aminobutyric acid. These metabolites ultimately attenuate neuroinflammation via the microbiome‐gut–brain axis, ameliorating depression‐ and anxiety‐like behaviors. These results identify microbiome‐gut–brain axis as pivotal therapeutic target for colitis‐associated mental disorders therapy, which can be addressed by polysaccharide engineered nanozymes.
Pattern of disease recurrence and outcomes of localized high-risk renal cell carcinoma (RCC) patients treated with adjuvant (adj) immunotherapy: A single center experience.
510 Background: Standard treatment for high-risk localized RCC is radical or partial nephrectomy followed by adjuvant pembrolizumab. However, about 40% of patients progress within 5 years despite adjuvant immunotherapy. We sought to investigate the pattern of disease recurrence and the clinical management of RCC patients treated with adjuvant immunotherapy. Methods: We collected patients with high-risk RCC who received adjuvant immunotherapy after radical surgery in our Institution. The primary endpoint was the rate and pattern of disease recurrence. Secondary endpoints were patients’ outcomes in terms of disease-free survival (DFS) and overall survival (OS). Results: From March 2018 to September 2025, 70 patients were included in the analysis. 15 patients (21%) had disease recurrence, 7 of which (10%) during adjuvant treatment; in 10 cases (67%) the absolute number of metastases was ≤3, with a number of diverse metastatic sites ranging from 1 (n = 9, 60%) to maximum 3 (n = 1, 7%). The most frequent sites of metastasis were lung (60%), lymph node (33%) and renal bed (13%). In case of disease recurrence, 9 patients (60%) started systemic first-line therapy (60%), while 5 patients (33%) received loco-regional treatment (1 patient radiotherapy and 4 patients metastasectomy, all alive without subsequent progression disease). After a median follow-up of 30.2 months (26.8-33.6 months), the 30-months DFS rate was 74% in the overall population and 72% for patients treated with adjuvant pembrolizumab. The 30-months OS rate was 94% in the overall population and 92% after adjuvant pembrolizumab. For patients with a DFS event, after a median follow-up of 24.5 months, the 30-months OS rate was 100% for patients who received a local treatment and 88% for patients who received systemic treatment (p = 0.56). Conclusions: Patients with RCC treated with adjuvant immunotherapy are confirmed to be at high risk of recurrence (26% at 30 months), reinforcing the need of more efforts to further improve therapeutic strategies in the adjuvant setting. Patients treated with a loco-regional approach after recurrence showed excellent survival outcomes without requiring systemic therapy. These findings support the consideration of loco-regional approach as a valid option for the management of these patients.
New prostate cancer risk groups by PSMA-PET (PPP3).
20 Background: PSMA-PET usage in prostate cancer patients is growing rapidly. Thus, novel risk group definitions based on PSMA-PET are urgently needed for guidelines, clinical use and study design. Here, we present improved risk classification based on PSMA-PET PROMISE nomograms (PPP3) to prognosticate 3-, 5- and 7-year overall survival (OS) for the first time. Methods: We included male patients with histologically proven prostate cancer at any disease stage, who underwent PSMA-PET for any indication in the PROMISE registry (NCT06320223). 35 investigator sites from Europe, Asia, Australia, North- and South America were split approximately 2:1 into development and validation cohorts considering equal distribution of site characteristics. Updated PPP3 nomograms were created based on Cox regression models with LASSO penalty for overall survival from the development cohort. We applied calibration curves and Harrell´s C-indices to assess the performance of both PPP3 nomograms. Based on the visual PPP3 nomogram, a simplified risk stratification table was created. Head-to-head comparison of PPP3 nomograms with clinical risk scores separated for each disease subgroup was conducted using area under the receiver operating characteristics curve. Results: We analyzed 11154 patients (n=7253 development and n=3901 validation cohorts) with a median OS follow-up of 4.9 (interquartile range 3.5-6.6) years and 3109 (27.9%) recorded deaths. Clinical disease group and PROMISE metrics (presence of distant metastases, PSMA expression score and total tumor load) were combined into visual and quantitative PPP3 nomograms, respectively. In the validation cohort we reached C-indices of 0.83 (95% confidence interval [CI] 0.82-0.84) for the visual nomogram and 0.84 (95% CI 0.82-0.85) for the quantitative nomogram, respectively. Both PPP3 nomograms and the simplified risk stratification table (Table 1) were accurate and equal or superior compared to established clinical risk scores (STARCAP, EAU, Gafita, NCCN). Conclusions: We created new risk nomograms by PROMISE along with a simple risk stratification table to prognosticate 3-, 5- and 7-year OS in prostate cancer. PROMISE and PPP3 assessments are available online free of charge (promise-pet.org) for global implementation. Visual PSMA-PET and PROMISE metrics for risk stratification in prostate cancer patients. 1 point 2 points 3 points Disease Group nmCRPC, mHSPC, mCRPC miM1a yes miM1b oligo diss or dmi miM1c yes Total lesion count 6-20 >20 PSMA expression score (highest) 3 Sum of the points results in the following risk groups: i) low risk: 0 points, ii) intermediate risk: 1-4 points, iii) high risk: ≥5 points. nmCRPC=non-metastatic castration resistant prostate cancer. mHSPC=metastatic hormone-sensitive prostate cancer. mCRPC=metastatic castration-resistant prostate cancer. diss=disseminated. dmi=diffuse marrow involvement. PSMA =Prostate Specific Membrane Antigen.
ARTO trial (NCT03449719): Long-term overall survival analysis from a randomized phase II trial testing the benefit of stereotactic body radiotherapy addition to abiraterone acetate in oligometastatic castrate resistant prostate cancer patients.
151 Background: ARTO (NCT03449719) is a multicentre, randomized phase II trial testing the benefit of stereotactic body radiation therapy (SBRT) addition on top of abiraterone acetate (AA) and androgen deprivation therapy (ADT) in first line Oligometastatic Castrate Resistant Prostate Cancer (omCRPC) patients. Results already showed significant benefit in favour of the experimental arm in terms of biochemical progression free survival (bPFS) and radiological PFS (rPFS) after a median follow up of 24.9 months. Here we present an updated analysis comprehensive of long-term overall survival (OS) and prostate cancer specific survival (PCSS) data. Methods: Patients affected by omCRPC (≤ 3 non-visceral metastatic lesions) were randomized 1:1 to receive either AA+ADT alone (control arm) or the same systemic treatment associated with SBRT on all sites of disease (treatment arm). No previous treatment for mCRPC was allowed. Cox regression analysis was performed to compare bPFS, rPFS, OS and pCSS in the different arms of treatment. Results: One hundred fifty-seven patients were enrolled in ARTO trial. After a median follow up of 53 months (IQR 43-60), 103 bPFS events were recorded (41 vs 62 in the experimental vs control arm, respectively), 100 rPFS events occurred (40 vs 60 in the experimental vs control arm, respectively) and 65 patients died (24 vs 41 in the experimental vs control arm, respectively). Significant benefit in terms of bPFS and rPFS in favour of the experimental arm was confirmed (43 vs 17 months, HR 0.49, 95% CI 0.33-0.73, p<0.001 and 44 vs 17 months, HR 0.48, 95% CI 0.32-0.72, p<0.001, respectively). In terms of OS and PCSS, significant benefit was detected in favour of the experimental arm (Not reached vs 50 months, HR 0.55, 95%CI 0.33-0.92, p=0.02 and not reached, HR 0.37, 95%CI 0.18-0.78, p=0.008, respectively). Results were confirmed after adjusting for stratification variables (performance status 0 vs 1; 1 vs > 2 lesions) (HR 0.54, 95%CI 0.36-0.81, p=0.003, HR 0.53, 95%CI 0.35-0.81, p=0.003, HR 0.6, 95%CI 0.36-0.99, p=0.04, HR 0.43, 95%CI 0.2-0.9, p=0.02 for bPFS, rPFS, OS and PCSS, respectively). No safety concerns emerged, with 64 vs 71 grade 1/2 and 13 vs 22 grade >2 adverse events in the experimental vs control arm, respectively. Conclusions: After more than doubling the median follow up in this updated analysis, a significant OS and PCSS benefit were detected in patients undergoing concomitant SBRT with AA and ADT treatment compared to AA and ADT alone. These results warrant for confirmation in phase III trials. Clinical trial information: NCT03449719 .
End-of-life treatment patterns in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
92 Background: mCRPC remains the lethal form of metastatic prostate cancer with limited treatment options following disease progression on traditional therapies such as androgen receptor pathway inhibitors (ARPIs) and chemotherapy. The receipt of intensive therapies during the last three months of life may not improve survival outcomes and may instead increase toxicity and negatively affect quality of life. Therefore, in this analysis we sought to understand real-world end-of-life practice patterns in pts with mCRPC. Methods: This retrospective study utilized the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Inclusion criteria: pts diagnosed with mCRPC from 1/1/2013 to 4/10/2025, information of receipt of systemic therapy and recorded date of death. Pts were categorized into two groups: treatment-free, if no systemic therapy was administered during the last three months of life, or on-treatment, if systemic therapy was received within three months preceding death. Demographic and clinical variables at their last line of therapy (LOT) initiation, including age, race, region, socioeconomic status, practice type, and insurance were summarized using medians (IQR) or proportions. Comparisons were performed using Wilcoxon rank-sum or chi-squared tests. Results: Among 27,979 pts in the enhanced cohort, 14,793 had a recorded date of death, and 9,667 of these with available first-line treatment information were eligible and included in the analysis. Of these, 5,762 pts (59.6%) were classified as on-treatment, while 3,905 pts (40.4%) were treatment-free. At the time of last LOT initiation, treatment-free and on-treatment pts had similar age, race/ethnicity distribution and socioeconomic status. Significant differences in practice type and insurance were observed. In the on-treatment group, the most common end-of-life treatments were ARPIs in 43.3% (n = 2,497) of pts, followed by taxanes in 26.1% (n = 1,503). Further baseline characteristics, and treatment patterns will be presented at the meeting. Conclusions: The majority of pts with mCRPC continued to receive systemic therapy near the end of life. These findings highlight the need for further patient-centered decision-making to balance treatment benefit and quality of life in the final months of life, earlier goals of care discussion and integration of palliative care. Limitations include retrospective nature of study and possible data missingness.
Strengthening Substrate Anchoring of Polymeric Self‐Assembled Monolayers for Efficient and Stable Inverted Perovskite Solar Cells
ABSTRACT Small‐molecule‐based self‐assembled monolayers (SAMs) used as hole‐transporting layers have achieved exceptional efficiencies in inverted perovskite solar cells (PSCs). However, inadequate substrate coverage and insufficient operational stability of small molecules have led to the development of polymeric SAMs as an alternative. Nevertheless, the molecular configuration of polymeric SAMs remains underexplored, resulting in lower performance compared to small‐molecule SAMs. Here, our results show that the previously reported Poly‐4PACz contains linkage sites generating significant steric repulsion between monomers, forcing phosphate groups into an alternative alignment and reducing substrate anchoring capability. Inspired by this, we designed a new polymeric SAM, Poly‐4PADCB, by selecting specific monomer linkage sites to reduce steric hindrance. Consequently, the alignment of phosphate groups in Poly‐4PADCB becomes unidirectional after polymerization, resulting in higher coverage and improved molecular ordering. This ordered template facilitates high‐quality perovskite growth and optimizes energy level alignment at the buried interface via a synergistic dipole superposition effect. Ultimately, PSCs based on Poly‐4PADCB achieve a power conversion efficiency (PCE) of 26.90% (certified 26.50%) and a large‐area (1 cm 2 ) PCE of 25.54% (certified 25.19%). This robust interfacial architecture inhibits SAM desorption and diffusion, with 96% of initial performance retained after 2000 h of continuous maximum power point tracking under the ISOS‐L‐2 protocol.
Efficacy of selective renal tumor embolization combined with axitinib and reduced-dose toripalimab in oligometastatic clear cell renal carcinoma: An updated analysis with patient-derived organoid and immune co-culture insights.
495 Background: Oligometastatic clear cell renal cell carcinoma (ccRCC) presents an opportunity for aggressive local and systemic therapy. Combining selective renal tumor embolization with targeted therapy and immunotherapy is a promising strategy. We further established a patient-derived organoid (PDO) platform co-culturing ccRCC cells with immune cells to investigate its predictive value and the mechanism underlying treatment efficacy. Methods: This study included oligometastatic ccRCC patients treated since March 2023. Patients were propensity-score matched into two groups: the experimental group received selective renal tumor embolization, axitinib (5 mg BID), and reduced-dose toripalimab (160 mg Q3W); the control group received axitinib plus standard-dose toripalimab (240 mg Q3W). Primary outcomes were DCR, ORR, and 1-year PFS. Secondary outcomes included grade 3-4 AEs. A novel PDO model co-culturing patient-derived ccRCC cells with autologous immune cells was established to simulate the tumor microenvironment. Results: After matching (29 patients per group), baseline characteristics were balanced. The experimental group showed significantly superior DCR (100% vs. 69.8%, P < 0.05), ORR (93.1% vs. 56.7%, P < 0.05), and 1-year PFS rate (92.8% vs. 67.9%). Grade 3-4 AEs were lower in the experimental group (10.1% vs. 38.4%, P < 0.05). In vitro , the PDO-immune co-culture model demonstrated that hypoxia – mimicking post-embolization conditions – effectively increased the infiltration ratio of CD8+ T cells within the organoid. This remodeled immune microenvironment significantly enhanced the tumor-killing efficacy of axitinib combined with toripalimab. Conclusions: The combination of selective renal tumor embolization with axitinib and reduced-dose toripalimab yields significantly improved clinical outcomes and reduced toxicity in oligometastatic ccRCC. Our pioneering PDO-immune co-culture platform reveals that hypoxia-induced CD8+ T cell infiltration may be a key mechanism, positioning this model as a promising predictive biomarker for treatment response. These findings warrant further validation in larger prospective studies.
A phase II study bolstering outcomes by optimizing immunotherapy strategies with evolocumab and nivolumab in patients with metastatic renal cell carcinoma (BOOST-RCC).
TPS581 Background: Metastatic clear cell renal cell carcinoma (mccRCC) progressing on prior immune checkpoint inhibitors (ICIs) poses significant challenges, with less effective treatment options in refractory disease. More therapies to overcome ICI resistance are needed. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) directs MHC-I molecules to the lysozyme, and inhibition of PCSK9 improves MHC-I expression and tumor antigen presentation. Evolocumab is a PCSK9 inhibitor shown in preclinical studies to improve tumor antigen expression, intratumoral CD8 T-cell infiltration and activation, and tumor control. We launched BOOST-RCC, a phase 2 trial with safety lead in to give combination evolocumab and nivolumab in mccRCC refractory to ICIs. Methods: BOOST-RCC is an investigator-initiated, phase 2, multicenter, single cohort study investigating the efficacy of evolocumab and nivolumab as treatment for ICI refractory mccRCC (NCT06284564). A Simon 2-stage design will be used, with 10 patients treated in the first cohort. If at least 1 objective response is observed among the first 10 patients, enrollment will continue with 19 more patients, for a total of 29 patients. Primary endpoints are objective response rates based on RECIST v1.1 as well as trial limiting toxicities for the safety profiling of the combination of treatment. Patients will be treated until progression of disease, unacceptable toxicity, or up to 2 years if ongoing response. The first stage of enrollment was completed in 2025, and the study is ongoing. The study is funded by CPRIT and open within the DOD-supported Kidney Cancer Research Consortium at UT Southwestern Simmons Comprehensive Cancer Center and MD Anderson Cancer Center. Clinical trial information: NCT06284564 .
Utilization of bone modifying agents in metastatic hormone resistant prostate cancer: A retrospective study of real world patients.
127 Background: Bone metastases affect up to 90 % of patients with metastatic hormone-resistant prostate cancer (mHRPC) and cause substantial morbidity from skeletal-related events (SREs) such as fracture, spinal-cord compression, and palliative interventions. Bone-modifying agents (BMAs) including bisphosphonates and denosumab reduce SRE risk and are NCCN-recommended, however, real-world use remains inconsistent. Methods: Patients with mHRPC treated from January 2017-September 2024 across Mayo Clinic sites were identified using SQL-based EHR queries confirmed by manual chart review. Bone Metastases were detected through keyword searchers of radiology reports and confirmed through manual chart review. SRE-prevention dosing was defined as zoledronic acid 4mg IV or denosumab 120mg SC; osteoporosis dosing was excluded. SREs were identified using diagnosis codes and text-pattern searches for radiotherapy, surgery, fracture, and spinal-cord compression. Descriptive statistics summarized BMA utilization and SRE incidence. Categorical variables were compared using Chi-square tests, and a risk ratio (RR) with 95% confidence intervals was calculated to evaluate association between early BMA initiation and SRE risk. Results: Among 778 patients with mHRPC, 685 (88 %) had bone metastases (mean age 70.5 years). Of these, 169 (24.7 %) had an SRE, and 261 (38.1 %) received BMAs at SRE-prevention doses (denosumab n = 157 [60 %]; zoledronic acid n = 104 [40 %]). Based on a chi-square test, combined SRE incidence did not differ significantly (No BMA 23 %, denosumab 23 %, zoledronic 33 %; p = 0.069). Bone pain at baseline was more common in patients who later received a BMA (136 [68 %]) than in those who did not (82 [41 %]; p < 0.001). Among 200 randomly sampled non-BMA patients, 83 had no recorded BMA discussion (66 also lacked bone pain), 38 lacked dental clearance, 32 had uncompleted plans and 18 declined therapy. Early BMA initiation (before first bone metastases) was associated with fewer SREs (16 % vs 29 %; RR 0.56, 95 % CI 0.33–0.96). Conclusions: Less than half of bone-metastatic mHRPC patients received BMAs. Non-initiation was often linked to modifiable factors such as delayed dental clearance or lack of treatment discussions, highlighting the need for system-level strategies to improve timely bone-directed care. SREs were common, affecting one quarter of patients. Small sample size precluded meaningful comparison of the impact of BMAs on SRE incidence however early BMA initiation may lower SREs. Incidence of SREs stratified by no BMA vs BMA treatment. SRE No BMA BMA Overall Pathological Fracture 6.4% (27/424) 4.9% (13/261) 5.8% (40/685) Radiotherapy to Bone 13.9% (59/424) 18.8% (49/261) 15.7% (108/685) Spinal Cord Compression 0.7% (3/424) 3.1% (8/261) 1.6% (11/685) Surgery to Bone 2.1% (9/424) 0.3% (1/261) 1.5% (10/685) Combined 23% (98/424) 27.2% (71/261) 24.7% (169/685)
Combining PSMA-PET metrics and circulating tumor cell RNA sequencing to predict LuPSMA response.
261 Background: Metastatic castrate-resistant prostate cancer (mCRPC) is a deadly and incurable disease. Targeted radioligand therapies such as 177 Lu-PSMA-617 (LuPSMA) are a promising new class of treatment for men with mCRPC progressing after standard therapy. There remain challenges in patient selection and predictive biomarkers for clinical response. Circulating tumor cells (CTCs) are a minimally invasive source of tumor material to explore biomarkers. We previously reported the largest CTC RNA sequencing cohort of patients with mPC to date and defined four CTC transcriptional phenotype associated with prognosis in mCRPC, and found that the poor prognosis Luminal-B like (LumB) CTC phenotype was associated with early progression on LuPSMA. Here we evaluate the intersection between CTC and imaging biomarkers for LuPSMA to elucidate a biomarker-driven framework for stratifying mCRPC patients most likely to benefit from LuPSMA therapy. Methods: Pretreatment CTCs were isolated from a prospective cohort of 37 patients with mCRPC undergoing LuPSMA therapy using automated microfluidic technology. CTCs were captured via immune-magnetics and analyzed via RNA-seq, followed by CTC transcriptional phenotype classification and quantification of FOLH1 gene expression. The following features were extracted from pretreatment PSMA PET scans available for 25/37 patients: whole-body PSMA-positive disease volume, tumor mean and tumor maximum SUV. Association between CTC phenotypes and PSMA PET metrics and impact on clinical response was evaluated. Results: CTC FOLH1 expression was significantly higher in patients with PSMA-positive disease volume above median (p = 0.0324). CTC FOLH1 expression and pretreatment PSMA PET metrics were not different between patients with LumB versus non-LumB CTC phenotypes. Patients with early progression within the first 3 cycles (18 weeks) of treatment had higher PSMA-positive disease volume compared to patients who did not (p = 0.04). 5/8 patients with early progression had a LumB CTC phenotype compared to 2/16 patients without early progression (p=0.0207). 0/6 patients with a pretreatment tumor PSMA SUVmax above the median and a non-LumB CTC phenotype experienced early progression, while 2/2 patients with pretreatment tumor PSMA SUVmax below the median and a LumB CTC phenotype experienced early progression (p=0.0196). Conclusions: Combining functional imaging with CTC transcriptional phenotype shows potential for refining the selection of patients for LuPSMA therapy to maximize likelihood of response.
Self‐Powered Phototriggered Memristor Array with pW‐Level Computing for Monolithic in‐Sensor Vision
ABSTRACT 2D Ruddlesden–Popper (RP) hybrid perovskites are widely used in the field of optoelectronic devices due to their high carrier mobility and absorption coefficient. Herein, BA 2 MAPb 2 Br 7 (BMPB) single crystals were synthesized via the quasi‐static cooling method, with a thorough investigation of the nucleation mechanism and the intrinsic relationship between rectangular and hexagonal morphologies. Remarkably, BMPB exhibits outstanding memristive performance, featuring an ultrahigh on/off ratio (∼10 5 ), ultralow power consumption of ∼82.8 pW, and a long retention time (>22 000 s). Leveraging its inherent ferroelectric polarization and optoelectronic properties, we demonstrate a monolithic 5×5 optoelectronic memristor array that unifies sensing, memory, and computing functions. The array device exhibits self‐powered performance under 410 nm illumination, with responsivity of 0.96 A/W and detectivity of 2.89×10 8 Jones. Through digital logic circuit design and Vivado verification, we successfully implement solar‐tracking time prediction and sunflower growth‐stage monitoring. Critically, this integrated architecture enables hardware‐level in‐sensor computing for real‐time applications. Our work provides valuable insights for next‐generation in‐sensor computing devices, providing a material‐level solution based on 2D RP perovskites for energy‐efficient AI and IoT systems.
The therapeutic efficacy of radical prostatectomy and external beam radiation therapy in patients with histologic variants of prostate cancer.
366 Background: To evaluate the prognostic value of histologic variants of prostate cancer (PCa) in men treated with radical prostatectomy (RP) and external beam radiation therapy (EBRT). Methods: We identified patients with localized PCa treated with EBRT (n=221) or RP (n=2,039) at West China Hospital between 2011 and 2023. 1:3 propensity score matching was performed to adjust the patients’ backgrounds. Histologic variants of PCa included intraductal carcinoma of the prostate (IDCP), ductal adenocarcinoma of the prostate (DA), and neuroendocrine differentiation (NED), all biopsy-confirmed. We compared the biochemical recurrence (BCR)-free survival using the Phoenix definition (prostate-specific antigen [PSA] nadir plus 2 ng/mL) for EBRT and the surgical definition (PSA cut-off value of 0.2 ng/mL) for RP. We also directly compared the BCR-free survival using the same PSA cut-off value of 0.2 ng/mL for both EBRT and RP. Results: Totally, 884 patients were included. Patients with histologic variants of PCa harbored the worst prognosis compared with adenocarcinoma of the prostate (PAC) in both RP and EBRT cohort (RP: 23-Mo vs 138-Mo, p < 0.001; EBRT: neither reached the median BCR-free survival, p < 0.001). Subsequent multivariate cox regression analysis further established histologic variants of PCa as an independent risk factor in RP and EBRT cohort (RP: HR: 2.00, 95%CI: 1.55-2.60, p < 0.001; EBRT: HR: 2.19, 95%CI: 1.03-4.66, p = 0.042;). Comparing the BCR-free survival using the above definitions for RP and EBRT showed that EBRT yielded a significantly better BCR-free survival than did RP whether in PAC or histologic variants of PCa (PAC: RP vs EBRT: 138-Mo vs not reached, p < 0.001; Histologic variants of PCa: RP vs EBRT: 23.3-Mo vs not reached, p < 0.001;). When the surgical definition was applied to both treatments, there was no significant difference between EBRT and RP in PAC (138 months vs not reached, p=0.062), whereas EBRT remained superior in histologic variants of PCa (23.3 months vs not reached, p=0.001). Conclusions: Histologic variants of PCa is associated with inferior prognosis after both RP and EBRT. EBRT was linked to longer BCR-free survival than RP, including under a uniform surgical definition, among patients with histologic variants of PCa. EBRT should be strongly considered when selecting definitive therapy for localized histologic variants of PCa.
Frequency and determinants of reproductive organ involvement in female patients undergoing radical cystectomy for bladder cancer.
699 Background: Traditionally, radical cystectomy (RC) in females includes removal of adjacent reproductive organs (RO) along with the bladder and regional lymph nodes. The growing adoption of reproductive organ-sparing RC underscores the need to better understand the frequency and preoperative predictors of reproductive organ involvement (ROI). Methods: We utilized our prospectively maintained, IRB-approved RC database to identify all female patients who underwent RC between 2003 and 2024. Patients with a history of prior surgery on ROs were excluded. Multivariate logistic regression model was applied to identify predictors of ROI. Results: A total of 324 female patients were included in the analysis, of whom 42 (13.0%) demonstrated ROI. Baseline characteristics are shown Table 1. The most involved RO was vagina (N=25, 7.7%), followed by the cervix (N=24, 7.4%), uterus (N=21, 6.5%), and fallopian tubes/ovaries (N=4, 1.2%). Among the 18 patients with involvement of a single RO, the vagina was the most frequently affected (N=10, 3.1%), followed by the uterus (N=5, 1.5%). The strongest correlations of ROI were observed between the cervix and uterus (r = 0.6) and between the vagina and cervix (r = 0.5; both p < .001). In multivariate analysis, extravesical disease (OR: 17.2, 95% CI: 6.8 – 43.1, p<.001) or lymph node positivity (OR: 17.5, 95% CI: 6.1 – 50.1, p=.001) in clinical staging, along with higher comorbidity burden (Charleson comorbidity index ≥ 2 vs. 0: OR: 3.7, 95% CI: 6.8 – 43.1, p= 0.020) were predictive of ROI. In patients with ROI, the median recurrence-free survival (RFS) and overall survival (OS) were 8.3 and 12.4 months, respectively. Predictably, log-rank analyses demonstrated significantly worse OS and RFS in patients with ROI compared to those without (both p<.001). Conclusions: ROI was identified in approximately 13% of female patients undergoing RC. Reproductive organ-sparing surgery should not be offered to patients presenting with extravesical or lymph node-positive disease, or those with a higher comorbidity burden. Demographics and perioperative characteristics stratified by reproductive organ involvement. Patient characteristics No ROI (N=282) ROI (N=42) P value Age (yrs.), mean ± SD 67.7 ± 11.0 67.9 ± 12.3 0.798 Charleson Comorbidity Index, n(%) 0.028 0 83 (29.4%) 5 (11.9%%) 1 84 (29.8%) 12 (28.6%) >=2 115 (40.8%) 25 (59.5%) Clinical Staging, n(%) <0.001 Organ confined (≤ cT2N0) 218 (77.3%) 7 (16.7%) Extravesical (> cT2N0) 39 (13.8%) 23 (54.8%) Lymph node positive (cN+) 25 (8.9%) 12 (28.6%) Positive Bimanual Examination, n(%) 25 (8.9%) 11 (26.2%) <0.001 Neoadjuvant chemotherapy, n(%) 78 (27.7%) 16 (38.1%) 0.164
Integration of genomic classification and clinical characteristics as a predictor of survival in de novo metastatic prostate cancer.
123 Background: Genomic assessment has revolutionized cancer care and individual gene alterations inform prognosis and predict benefit from specific therapies. No comprehensive DNA-based genomic classification of metastatic prostate cancer exists that accounts for both individual alterations and combinations of alterations that are frequently identified. Methods: Retrospective cross-sectional study of U.S. Veterans diagnosed with synchronous (de novo) metastatic hormone-sensitive prostate cancer (mHSPC) and DNA-based comprehensive genetic profiling (CGP) through the National Precision Oncology Program. Multivariable models with overall survival (OS) as the endpoint were used to develop a clinic-genomic prognostic risk classification. Validation was performed in metachronous mHSPC and patients in MSK-IMPACT. Results: In 2484 veterans with synchronous mHSPC and tissue (primary tumor or metastasis) CGP (median age; 72 years), baseline data including age, PSA, and Charlson comorbidity index (CCI) was collected. The cohort was divided into training and testing datasets, and 16 genes associated with survival were identified (TP53, PTEN, RB1, BRCA2, FGFR1, FGFR3-4, FGFR19, CDK12, RAD21, MYC, CCND1, LYN, AR, PRKCI, SPOP). DNA alterations associated with specific genes/gene combinations were assigned into favorable, intermediate, or unfavorable groups based upon mortality risk. In a multivariable model classification of alterations into intermediate (aHR 1.75, 95% CI 1.46-2.08) or unfavorable groups (aHR 2.71, 95% CI 2.15-3.42) was associated with increased mortality relative to the favorable/no alteration group, demonstrating a tAUC of 0.77 at 12 months. In 1236 Veterans with metachronous mHSPC intermediate (aHR 1.45, 95% CI 1.17-1.79) and an unfavorable classification (aHR 2.06, 95% CI 1.54-2.76) was associated with increased mortality with AUC of 0.69 at 12 months. In an external validation in non-veterans, intermediate (aHR 2.45, 95% CI 1.87-3.21) and unfavorable classifications (aHR 4.37, 95% CI 3.06-6.22) were associated with increased mortality with AUC of 0.75 at 12 months. Conclusions: Tumor genomic classification is prognostic for OS in patients with synchronous mHSPC. The genomic classification produced consistent, robust results in multiple validation datasets across additional clinical metastatic states, CGP analytes, and in a non-VA cohort. This prognostication approach has the potential to guide decision-making related to therapeutic intensity and duration.
Assessing the impact of cardiovascular disease and ADT on survival disparities in prostate cancer.
268 Background: US Black men are on average diagnosed with more aggressive prostate cancer (PCa) and have higher mortality than White men. Studies in predominantly White populations show that PCa patients with pre-existing cardiovascular disease (CVD), metabolic syndrome (MetS), or prior CVD events face increased risk for further CVD and cardiotoxicity during/after androgen deprivation therapy (ADT). However, racial disparities in this context are underexplored. This study evaluates the impact of race, ADT use, and CVD on overall survival (OS) following radiation therapy (RT) for PCa, assessing disparities by stage and demographics. Methods: We conducted a retrospective review of a single institution prostate cancer database to identify patients with PCa who received IMRT or brachytherapy RT as their initial treatment between 2003 and 2023. Within each AJCC stage (I,II,III or IV), we compared OS curves by ADT use (any vs. none) and race, and by CVD (present vs. absent), and race using log-rank tests. Cox proportional hazards models were used to assess interactions and additionally adjust for age and substage (e.g. IIA vs IIB). Age was modeled as time-varying in stage II due to assumption violations. Descriptive statistics and chi-square tests compared baseline characteristics and CVD by race and ADT use. Results: Of 4,247 eligible patients (Black and White), 17% were Black, and 32% received ADT. Black patients were younger at diagnosis (mean 63.4 vs. 67.7 years, p<0.0001) and at more advance stage at diagnosis (Trend p=0.02). CVD affected 49% of patients, with no racial difference (p=0.48). ADT use increased by stage (5% to 85%), with no racial differences within stages (p>0.1). Median follow-up from end of RT to death or last follow-up was 85.4 months (IQR=43.5-139.8), with no difference by race (p=0.63). Among ADT patients, CVD was significantly associated with reduced OS in stage II (p = 0.02) and marginally in stage IV (p = 0.08). Age consistently predicted higher mortality across stages. CVD linked to increased mortality in stage I (HR 1.36, 95% CI 1.09–1.70, p=0.006), but not in later stages. Race was not independently associated with mortality. However, one significant interaction was found: In stage III only, ADT’s effect on survival differed by race. Among Black men, all deaths occurred in the ADT group (24/84) vs. none in the no-ADT group (0/9), HR was undefined; in contrast, among White men, OS was not associated with ADT, HR was 1.09 (95% CI 0.64–1.85). Conclusions: In this large, diverse cohort, CVD was common and linked to worse survival in early-stage PCa, especially in stage II ADT patients. Race did not independently predict mortality. ADT’s impact on survival did not differ significantly by race except in stage III, but interpretation was limited. CVD assessment in early stage PCa and larger studies to clarify ADT’s role in racial disparities in survival is needed.
Ultrasensitive Mesh‐Structured Position‐Sensitive Detectors Enabling Eye Tracking for Human‐Machine Interaction
ABSTRACT Eye tracking provides highly efficient, intuitive, and seamless human‐machine interaction by measuring eye movements and revealing user attention and intention. Currently, video‐based eye tracking systems, while achieving sub‐degree accuracy, suffer from high power consumption due to data acquisition and processing of redundant pixels. Here, we present an energy‐efficient eye‐tracking system employing a position‐sensitive detector (PSD) with a graphene photoconductive mesh, which operates with only four readout signals, reducing data volume by over three orders of magnitude compared to video‐based systems, while achieving superior accuracy. With the synergistic effects of lateral photoelectric and interfacial gating, the mesh‐structured PSD operates under eye‐safe ultra‐weak light (as low as 10 pW) without a detection dead zone. Leveraging the real‐time, precise tracking capability of the PSD, the eye‐tracking system determines gaze orientation by tracking the reflected trajectories of light beams from the cornea, achieving a 1 kHz tracking frequency and < 0.1° angular accuracy. Human‐machine interaction applications such as eye‐controlled typing and a Gluttonous Snake game are demonstrated using the PSD‐enabled eye tracker. The PSD‐based eye tracking holds significant promise for the application of human‐machine interaction in miniaturized systems.
Effect of upfront dose reductions on efficacy of enfortumab vedotin and pembrolizumab (EVP) in advanced urothelial carcinoma (aUC): A UNITE analysis.
696 Background: EVP is the preferred 1st-line therapy for patients (pts) with aUC. Upfront EV dose reductions may be utilized to enhance tolerance and minimize treatment-related toxicities when intolerance is anticipated. Prior studies of EV monotherapy suggest that starting dose 1.25 mg/kg resulted in exposure that maximized chance of response. We hypothesize that upfront EV dose reductions would not compromise EVP efficacy. Methods: Pts with aUC treated with EVP in the multi-site UNITE database were analyzed. Upfront dose reduction was defined as starting dose < 1.25 mg/kg. Correlation between clinical features and EV dose reduction were assessed using Fisher’s Exact test. Endpoints include progression-free survival (PFS) and overall survival (OS) from EVP initiation, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (< 75 vs ≥ 75), ECOG performance status (PS) (0-1 vs 2-3), hemoglobin level (< 10 vs ≥ 10), and liver metastases (present vs absent), chosen in accordance with Bellmunt criteria. Correlation with investigator-assessed observed response rate (ORR) was determined using logistic regressions. All tests were 2-sided with p < 0.05 considered significant. Results: A total of 456 pts across 17 sites were included (median age 72; 77% Caucasian; 75% male; 26% upper tract primary; 66% pure UC; 77% ECOG PS 0-1; 17% with liver metastasis; 89% 1 st line EVP). Upfront dose reduction occurred in 96 pts (21%); 76 pts (79%) started at 1.0 mg/kg and 20 pts (21%) at 0.75 mg/kg. Upfront dose reduction was significantly associated with age ≥ 75 (p = 0.002), ECOG PS 2/3 (p = 0.04), and hemoglobin < 10 (p = 0.01) but not with liver metastasis (p = 0.9). Lower starting EV dose correlated with shorter median PFS (5 vs 6 months) and OS (9 vs 10 months), and lower ORR (28% vs. 60%) when compared to full dose (Table). In MVA adjusting for prognostic factors for PFS and OS, these associations were no longer statistically significant. Conclusions: In this real-world analysis, upfront EV dose reductions were most frequently used in pts with factors associated with frailty and poor prognosis, e.g. older age and ECOG PS 2/3, and were associated with lower ORR. When adjusted for these factors, upfront EV dose reductions were not associated with shorter PFS/OS though a trend towards inferior outcomes persisted. These differences in outcomes may reflect baseline risk factors rather than dose intensity; however, prospective investigation is required to validate our hypothesis-generating results. Association of upfront EV dose reduction with outcomes. Outcome (Upfront dose reduction vs no upfront dose reduction) Univariable analysis Multivariable analysis PFS: HR (95% CI), p 1.50 (1.11 – 2.02), 0.008 1.33 (0.95-1.86), 0.09 OS: HR (95% CI), p 1.56 (1.11-2.20), 0.01 1.41 (0.96-2.06), 0.08 ORR: OR (95% CI), p 0.35 (0.21-0.60), 0.0001 0.38 (0.21-0.67), 0.0009