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PiP‐Plex: A Particle‐in‐Particle System for Multiplexed Quantification of Proteins Secreted by Single Cells

Abstract Cell signaling is modulated by the secretion of various proteins, which can be used to infer a cell's phenotype. However, these proteins cannot be readily detected in multiplex by commonly used methods at the single‐cell level. Here we present PiP‐plex a particles‐in‐particle (PiPs) system for multiplex protein secretion analysis by confocal microscopy. PiP‐plex‐comprises (i) fluorescence intensity barcoded microparticles (BMPs) co‐entrapped with (ii) a single cell inside an alginate hydrogel particle. We found that PiPs maintained >90% cellular viability and allowed live cells retrieval. A seven‐plex fluorescent barcoding and concomitant sandwich immunoassay in PiPs was developed with limits of detection ranging from 0.8 pg mL −1 to 2 ng mL −1 depending on the protein. PiP‐plex assays were benchmarked with bulk immunoassays and found to rival or outperform them. Proteins secreted by single THP‐1 cells upon exposure to lipopolysaccharide were measured by PiP‐plex and varying cell responses detected, including a significant increase in MIP‐1α, TNF‐α, and IL‐17A; MIP‐1α and IL‐17A were the most frequently secreted cytokines, while other cytokines were typically co‐secreted. Using PiP‐plex, we analyzed ≈750 THP‐1 cells, showcasing its potential for characterizing cells and cell‐based therapeutics for e.g. cancer immunotherapies.

GPR39-mediated molecular signaling by bile acids

Clinical and demographic disparities in prostate cancer patients undergoing radical prostatectomy: A 20-year retrospective cohort study from the United States.

205 Background: Radical prostatectomy remains a cornerstone treatment for localized prostate cancer. Understanding factors influencing surgical management is critical for addressing disparities in care delivery. This study examined demographic, clinical, and socioeconomic predictors of radical prostatectomy utilization using the national population-based cohort. Methods: We analyzed 1,259,662 male patients with a diagnosis of prostate cancer from SEERs database spanning 2000-2022. The primary outcome was receipt of radical prostatectomy (28.7% of cohort). Multivariable logistic regression was used to examine associations between surgical treatment and patient demographics (age, race/ethnicity, marital status), tumor characteristics (stage), socioeconomic factors (median household income), and treatment year. Missing data (1.2%) were excluded from analysis. Results: Among 1,244,064 patients with complete data, mean age was 67.1 years (SD 9.1). The cohort was 68.9% Non-Hispanic White, 14.1% Non-Hispanic Black, 9.6% Hispanic, and 5.1% Asian/Pacific Islander. Most had localized disease (62.5%), with 8.6% regional extension, 5.5% distant metastases, and 16.7% unstaged. In multivariable analysis, factors strongly associated with decreased surgical utilization included: 1. Advanced age (OR 0.89 per year, 95% CI 0.89-0.89, p<0.001). 2. Distant metastases (OR 0.10, 95% CI 0.09-0.11, p<0.001). 3. Unmarried status (OR 0.51, 95% CI 0.49-0.53, p<0.001). 4. More recent diagnosis year (OR 0.95 per year, 95% CI 0.95-0.95, p<0.001). Regional disease strongly predicted surgical management (OR 11.58, 95% CI 11.14-12.05, p<0.001). Married patients had 81% higher odds of surgery (OR 1.81, 95% CI 1.76-1.85, p<0.001). Higher income showed modest positive associations, with households earning >$100,000 having 14-28% higher odds compared to <$40,000. Racial disparities persisted after adjustment, with Non-Hispanic patients having lower surgical rates than Hispanic patients (OR 0.90, 95% CI 0.88-0.91, p<0.001). Conclusions: This large population-based study reveals significant disparities in radical prostatectomy utilization. The decline in surgical rates over time (5% decrease annually) may reflect evolving treatment paradigms and active surveillance adoption. Persistent disparities by race, marital status, and socioeconomic factors highlight the need for targeted interventions to ensure equitable access to surgical care. The strong influence of marital status suggests the importance of social support in treatment decision-making. Future research should examine whether these disparities impact oncologic outcomes and explore strategies to address modifiable barriers to surgical care.

Perioperative outcomes of open versus robot-assisted radical nephrectomy with IVC thrombectomy.

468 Background: Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus presents complex surgical challenges and significant perioperative morbidity. Traditionally managed with open radical nephrectomy and IVC thrombectomy, robotic-assisted approaches have emerged as a promising alternative. Due to the rarity of these procedures and the novelty of robotic techniques, comparative data are limited, often derived from small cohorts. This study compares perioperative outcomes of open versus robotic radical nephrectomy with IVC thrombectomy for level II-III thrombi using a large, multi-institutional database. Methods: We analyzed patients undergoing radical nephrectomy with IVC thrombectomy for AJCC T3b RCC from 2019 to 2023, identified through the ACS-NSQIP database using relevant CPT codes and pathologic staging. Patients were stratified by surgical approach (open vs. robotic). Baseline demographics, comorbidities, and 30-day perioperative outcomes were compared using chi-square tests and Student’s t-tests. Primary outcomes included major and minor complications, operative time, hospital length of stay (LOS), readmission, and mortality rates. Results: Of 321 patients, 256 (79.8%) underwent open and 65 (20.2%) underwent robotic IVC thrombectomy. Both groups were comparable in age, sex, BMI, and comorbidities, though robotic patients had lower ASA scores (p<0.0001). Robotic surgery was associated with significantly lower minor complication rates (33.8% vs. 64.7%, p<0.001), driven by reduced bleeding complications (30.8% vs. 56.3%, p=0.002). Hospital LOS was shorter in the robotic group (3.9 ± 3.8 vs. 7.5 ± 5.0 days, p<0.001). No significant differences were observed in 30-day major complication rates (10.8% vs. 21.1%, p=0.058), reoperation (3.1% vs. 1.6%, p=0.42), readmission (6.2% vs. 10.9%, p=0.25), or mortality rates (3.1% vs. 2.0%, p=0.58). Conclusions: This study, the largest to date, demonstrates that both open and robotic IVC thrombectomy for RCC with level II-III thrombi carry substantial perioperative morbidity. There was no difference in 30-day rates of major complications or mortality. Robotic surgery offered reduced blood loss and a shorter hospital stay, findings that have been demonstrated across various robotic operations. These findings suggest robotic IVC thrombectomy represents a viable alternative to open surgery in appropriately selected patients at experienced centers, without compromising perioperative safety outcomes. Open vs robotic IVC thrombectomy patient outcomes. Open N = 256 RoboticN = 65 P-value Minor Complications 167 (64.73%) 22 (33.85%) <0.0001* Major Complications 54 (21.09%) 7 (10.77%) 0.0581 Length of Total Hospital Stay (days) 7.53 ± 5.04 3.91 ± 3.79 <0.0001* Return to operating room 4 (1.56%) 2 (3.08%) 0.4208 Readmission 28 (10.94%) 4 (6.15%) 0.2503 Death 5 (1.95%) 2 (3.08%) 0.5796 *Statistically significant.

Cost-effectiveness analysis of new perioperative treatment regimens for muscle-invasive bladder cancer in Germany.

648 Background: The NIAGARA trial investigated the efficacy of adding perioperative durvalumab to standard gemcitabine/cisplatin chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Given the increasing economic burden of urothelial carcinoma management and the favorable clinical outcomes reported in the NIAGARA trial, this study aimed to evaluate the cost-effectiveness of incorporating durvalumab into perioperative therapy from a German healthcare perspective. Methods: A Markov model was developed from the payer’s perspective using clinical outcomes from the NIAGARA trial. A Monte Carlo simulation was applied to identify the most cost-effective treatment strategy within the German healthcare context. Incremental cost-effectiveness ratios (ICERs) were calculated for each treatment approach across varying willingness-to-pay (WTP) thresholds. Results: The average cost of the standard-of-care (SoC) regimen was €113,224, compared with €126,386 for the durvalumab plus gemcitabine/cisplatin combination, resulting in an incremental cost of €13,162. The quality-adjusted life years (QALYs) were 3.16 for SoC and 3.37 for the combination therapy, corresponding to an incremental gain of 0.21 QALYs. The resulting ICER for the durvalumab-based regimen was €61,006 per QALY. At a WTP threshold of €100,000, the combination therapy was cost-effective in 76.5% of simulations. A substantial portion of total costs was attributed to expenses related to subsequent therapies in the metastatic disease setting. Conclusions: The addition of durvalumab to perioperative chemotherapy represents a cost-effective strategy for MIBC in Germany, primarily due to its potential to reduce the need for costly subsequent treatments. These findings suggest that intensified perioperative therapy may provide not only clinical benefits but also meaningful socioeconomic value within the German healthcare system. Base case analysis. Strategy Costs(€) Incremental costs (€) Effectiveness (QALY)/estimated life years Incremental effectiveness/estimated incremental life years ICER (€) SoC 113 224 3.16 Gemcitabine/Cisplatin + Durvalumab 126 386 13 162 3.37 0.21 61 006 The table summarizes the cost-effectiveness outcomes evaluated over a lifetime horizon. It outlines the mean cost and effectiveness per patient for each treatment strategy, along with the incremental cost and effectiveness relative to the Standard of Care. Furthermore, the table reports the corresponding Incremental Cost-Effectiveness Ratios (ICERs).

A phase 2 study of cabozantinib and nivolumab in metastatic castration resistant prostate cancer (CANOPY): Interim analysis.

187 Background: Advanced metastatic castration-resistant prostate cancer (mCRPC) remains a largely lethal disease with limited treatment options. Cabozantinib is a tyrosine kinase inhibitor targeting VEGFR, MET, and AXL that has demonstrated activity in mCRPC patients, particularly those with bone and liver metastases. The CONTACT-02 trial showed efficacy of cabozantinib combined with the PD-L1 inhibitor atezolizumab in mCRPC. Building upon this background, we investigated the efficacy of cabozantinib plus nivolumab, a PD-1 inhibitor, in patients with mCRPC (NCT05502315). Methods: This prospective, multi-center, single-arm, two-stage open-label phase II study enrolled patients with progressive mCRPC per PCWG3 criteria and prior androgen receptor pathway inhibitor exposure. Prior taxane was permitted. Patients received cabozantinib 40 mg daily orally plus nivolumab 480 mg IV every 4 weeks. The primary endpoint was radiographic progression-free survival (rPFS) at 6 months by RECIST 1.1/PCWG3. A Simon two-stage MiniMax design was used with 80% power, hypothesizing 6-month rPFS >30%. Stage 1 required ≥7 of 24 patients to be progression-free at 6 months to continue to Stage 2, which will enroll an additional 23 patients. Results: Twenty-four patients were enrolled in Stage 1 (median age 71 years). Baseline characteristics: 50% (12/24) had de novo metastatic disease, 91.7% (n=22) had bone metastases, 29.2% (n=7) bone-only disease, 16.7% (n=4) visceral metastases, 66.7% (n=16) received prior chemotherapy, and 25% (n=6) prior ¹⁷⁷Lu-PSMA-617 therapy. Eight patients remained progression-free at 6 months, meeting continuation criteria for Stage 2. Median rPFS was 5.5 months (95% CI >3.6 months). Objective response rate was 17.6% (3/17 evaluable patients). Median baseline PSA was 28.05 ng/mL and median time to PSA progression was 1.87 (95% CI 1.81-3.78) months. One patient experienced PSA 50 . Grade ≥3 treatment-related adverse events occurred in 52% (n=12) of patients, with 5 treatment-related serious adverse events. Most common adverse events were anorexia 58% (n=14), diarrhea 58% (n=14), fatigue 54% (n=13), nausea 46% (n=11), anemia 38% (n=9), AST increase 38% (n=9), ALT increase 33% (n=8), constipation 33% (n=8), and hypothyroidism 29% (n=7). Conclusions: The CANOPY trial met its interim efficacy threshold, demonstrating activity of cabozantinib plus nivolumab in mCRPC patients. The combination showed manageable toxicity. The study continues to Stage 2 enrollment to further evaluate this promising combination therapy. Clinical trial information: NCT05502315 .

Asymmetric Bi and S Single Atoms Over Porous Single‐Crystal TiO ₂ for Efficient CO ₂ Photoreduction to Acetic Acid

ABSTRACT Regulating multi‐step photocatalytic conversion of molecules remains challenging, primarily due to the complex interplays among light absorption, reactant binding, and charge separation and transfer processes. Here, the photocatalytic conversion of CO 2 to acetic acid is effectively achieved via the triadic synergy of asymmetric Bi (Bi–O 4 ), S (S–O 2 ), and 3D porous single‐crystal TiO 2 , which is realized through a selective extraction process. Specifically, Bi active sites lower the energy barrier for CHO * generation and C─C coupling; meanwhile, the S─O structure modulates Bi─O and Ti─O configurations to form strong Lewis base site ((SO 2– BiO 4 ) δ− ) by constructing a surface sulfate species, thereby accelerating the hydrogenation step in CO 2 reduction. The specifically designed photocatalytic system achieves a high acetic acid production rate of 66.7 µmol g −1 h −1 with over 89% selectivity. This design underscores the significance of engineering synergistic active sites and charge transfer to enhance photocatalytic conversion efficiency, offering valuable insight into the structure‐activity relationship for developing high‐performance photocatalysts.

Holographic Whole‐Object Photopolymerization Preserving Director Alignment in Liquid Crystalline Actuators

ABSTRACT Liquid crystalline (LC) crosslinked polymeric structures are promising for soft robotic applications, as their actuation profile is intrinsically encoded and results from the structure's shape and the LC molecular orientation (director). However, it remains challenging to fabricate 3D objects and at the same time control the director orientation within the 3D structure. Liquid crystalline molecules are commonly aligned using modified surfaces or electric/magnetic fields. However, additive manufacturing methods may locally distort the director, when fabricating 3D objects. Here, holographic microlithography is employed to form entire connected 3D objects in a single exposure by cross‐linking the LC, while allowing the director orientation within the object to be freely controlled. This enables us to independently choose a global director orientation and then realize complex 3D geometries in a single fabrication step. This approach avoids the director distortion present in sequential 3D printing and lithography methods, and allows for complex actuation profiles that are directly linked to the 3D director orientation. The method presented herein permits the rapid fabrication of complex 3D connected LC structures while preserving the molecular order, and thereby enables the fabrication of more complex 3D soft actuators.

More insights from Abca4 mouse models of recessive Stargardt disease

Patient-reported outcomes (PRO) from a dose-escalation and expansion trial of fractionated and multiple-cycle PSMA-targeted alpha radionuclide ²²⁵ Ac-J591.

208 Background: A prior phase I dose-escalation study demonstrated encouraging safety and efficacy of single administration of anti-PSMA antibody J591 linked to α-emitter 225 Ac, with or without prior 177Lu-PSMA exposure. We subsequently performed a dose-escalation/expansion trial (NCT04886986) in two parallel cohorts: fractionated (dose-dense) and multiple-cycle (q6 weeks). Here, we report protocol-specified secondary endpoint of health-related quality of life (HRQoL). Methods: Patients with metastatic, hormone-resistant PC received escalating doses of 225 Ac-J591 in either a fractionated (D1 and D15) or multiple-cycle (q6 weeks × up to 4) regimen. HRQoL was assessed using the validated FACT-P (39-item, 5-domain instrument for prostate cancer) and, in an amended protocol, the FACT-RNT (novel, 15-item questionnaire evaluating symptoms and toxicities specific to targeted RNT). Both instruments were administered at baseline and at multiple follow-up time points. Descriptive statistics and mixed-effects modeling evaluated longitudinal HRQoL changes and dose–time interactions. Results: 60 patients were enrolled (fractionated n=42; multiple-cycle n=18), median age 73 years. Prior therapies: ≥2 ARPI in 32 (53%), chemotherapy in 43 (72%), radium-223 in 7 (12%), sipuleucel-T in 17 (34%), and 177Lu-PSMA in 11 (18%). Metastatic sites: bone (88%), lymph nodes (62%), and viscera (26%); 53% were Halabi high-risk. A ≥50% PSA decline was achieved in 68% (fractionated) and 28% (multiple-cycle). The RP2D was 60 KBq/kg ×2 for fractionated dosing; multiple-cycle dosing was not advanced due to thrombocytopenia-related delays. At cutoff, 95% (fractionated) and 100% (multiple-cycle) completed ≥1 FACT-P, and 31% (13/42) completed ≥1 FACT-RNT. In the multiple-cycle arm, median FACT-P declined from 106 to 74 at Day 85, with most pronounced decreases in physical (–13) and functional (–8) well-being. In contrast, the fractionated cohort showed stable or improved HRQoL: median FACT-P rose from 116 to 123 (+14; p=0.2), with no significant dose–time interaction. FACT-RNT total scores remained stable (median 49), showing no meaningful deterioration across timepoints or dose levels. Conclusions: 225Ac-J591 was well tolerated with preserved HRQoL, particularly in the fractionated regimen. FACT-P demonstrated maintained or modest improvement in QoL, while FACT-RNT confirmed stability of treatment-related symptom burden across dose levels. Together, these results suggest that 225 Ac-J591 preserves quality of life during therapy without significant physical or emotional decline. On-going follow up with larger sample size is needed to clarify long-term HRQoL trends. Clinical trial information: NCT04506567 .

Treatment (Rx) patterns and attrition rates in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated between 2021-2025.

94 Background: The Rx landscape for mCRPC has shifted significantly in recent years with the introduction of poly(ADP-ribose) polymerase inhibitors (PARPi) alone, PARPi in combination with androgen receptor pathway inhibitors (ARPIs), and 177 Lu-PSMA-617 (Lu). This expansion in the Rx armamentarium increased the complexity of Rx sequencing decisions. In this analysis, we sought to assess recent Rx patterns and attrition rates in pts with mCRPC. Methods: This retrospective cohort study utilized the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Eligibility: diagnosis of mCRPC and receipt of first-line (1L) Rx. The data cut-off date was 6/30/2025. The types of Rx from 1L to 5L were summarized using frequency and percentages. Subgroup analysis by the year of 1L initiation was performed. Rx was categorized into: ARPIs, taxane based therapies, PARPi-based therapies, platinum-based therapies, Lu-based therapies, radium-223, sipuleucel-T, immunotherapy, and other. Results: Overall 5,008 pts with mCRPC who received 1L Rx between 1/1/2021 and 6/30/2025 were included in the analysis. Median age was 75 years (IQR 68 – 82), 55% were White non-Hispanic, and 76% were treated in community practice. Among these, 54% received 2L Rx, and 26% received 3L. Rx trends are summarized in Table. ARPIs were the most commonly used Rx in 1L (80%) and 2L (43%), with decreasing use in subsequent lines. Taxane use increased from 12% in 1L to 34% in 2L and remained common in later lines. Use of Lu and PARPi rose in later lines. From 2021 to 2025, ARPI use in 1L decreased from 80% to 67%. Further results stratified by year will be presented at the meeting. Conclusions: In this large real-world mCRPC cohort, only about half of pts received 2L Rx, with attrition rising significantly across subsequent lines. ARPIs and taxanes remained the most common 1L Rx including 2025, with increased utilization of Lu and PARPi in later lines. These findings highlight the evolving complexity of mCRPC management and significant drop-off with later lines, underscoring the need for optimized sequencing strategies, more efficacious frontline therapies, and interventions to improve access. Rx patterns across 5 lines of therapy in pts with mCRPC. Rx, n (%) 1LN = 5,008 2LN = 2,695 3LN = 1,325 4LN = 589 5LN = 228 ARPIs 4000 (79.8) 1152 (42.6) 319 (24.1) 74 (12.6) 18 (7.9) Taxane 606 (12.1) 918 (34.1) 486 (36.6) 212 (36) 62 (27.2) Lu 108 (2.2) 178 (6.6) 203 (15.3) 138 (23.4) 69 (30.3) PARPi 100 (2) 146 (5.4) 100 (7.5) 42 (7.1) 12 (5.2) Sipuleucel-T 69 (1.4) 31 (1.2) 10 (0.8) 1 (0.2) 2 (0.9) Platinum-based Rx 50 (1) 89 (3.3) 86 (6.5) 47 (8) 25 (11) Radium-223 50 (1) 64 (2.4) 22 (1.7) 12 (2) 5 (2.2) Immunotherapy 22 (0.4) 24 (0.9) 18 (1.4) 19 (3.2) 11 (4.8) Other 3 (0.1) 93 (3.5) 81 (6.1) 44 (7.5) 24 (10.5)

Twenty-five years of bladder cancer mortality in the U.S. (1999–2024).

658 Background: Bladder cancer is the sixth most common malignancy in the United States and remains a significant contributor to cancer-related mortality. Despite diagnostic and therapeutic advances, comprehensive evaluation of long-term mortality trends by demographic and geographic factors remains limited. This study assessed national bladder cancer mortality patterns over a 25-year period. Methods: Age-adjusted mortality rates (AAMRs) for bladder cancer from 1999 to 2024 were obtained from the CDC WONDER database. Rates were calculated per 100,000 population using the U.S. standard population. Temporal trends were analyzed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CI). Trends were examined by race/ethnicity, sex, age group, U.S. Census region, and urbanization level. Results: Overall bladder cancer mortality demonstrated a modest decline over the study period (AAPC: –0.26%; 95% CI: –0.34 to –0.18; p < 0.001). Mortality decreased among Hispanic (APC: –0.47%; 95% CI: –0.71 to –0.23) and Asian/Pacific Islander populations (APC: –0.57%; 95% CI: –0.86 to –0.28), while American Indian/Alaska Native populations showed a slight increase (APC: +0.19%). Black/African American populations demonstrated declining mortality until 2019 (APC: –0.98%) followed by a plateau. In 2024, Whites had the highest AAMR (17.90 per 100,000), followed by Black/African American (12.00), American Indian/Alaska Native (8.55), Hispanic (7.92), and Asian/Pacific Islander groups (5.95). Males exhibited an AAMR nearly four times higher than females in 2024 (27.63 vs. 7.04 per 100,000). Mortality increased with age, peaking among adults aged ≥85 years (63.80 per 100,000), followed by those aged 75–84 (24.82) and 65–74 years (6.73). Regionally, the Northeast experienced the greatest decline after 2012 (APC: –1.14%), whereas the South showed increasing mortality after 2019 (APC: +1.55%). Based on available urbanization data, non-metropolitan areas consistently had higher mortality compared to metropolitan regions. Conclusions: Bladder cancer mortality in the United States has declined modestly over the past two decades, though trends vary across race, sex, geography, age, and urbanization categories. Continued monitoring and targeted resource allocation may support improved outcomes in populations with persistently elevated mortality trends.

Features of early and late recurrence versus de novo metastatic ccRCC: Findings from JAVELIN Renal 101.

544 Background: Many patients with clear cell renal cell carcinoma (ccRCC) recur after nephrectomy, yet how these recurrences differ clinically and biologically from de novo metastatic (DNM) disease is not well understood. In this post-hoc analysis, we sought to characterize DNM versus early, intermediate, and late recurrent (ER, IR, and LR) ccRCC. Methods: JAVELIN Renal 101 was a Ph 3 trial comparing avelumab + axitinib (Av+Ax) to sunitinib (Su). Patients were categorized as DNM if presenting with metastatic disease (n=267) or recurrent after nephrectomy: ER (<12 months, n=137), IR (1-5 years, n=144), and LR (>5 years, n=139). Groups were compared across key clinical and RNA features. The prognostic impact of recurrence type was assessed using Cox models – adjusting for age, IMDC, and treatment arm. To assess whether treatment efficacy differed by recurrence type, subgroup analyses were performed on Av+Ax versus Su, with an interaction term to test for effect modification. Results: DNM and ER shared aggressive features (≥T3 in 63% and 66%; grade 4 in 42% and 43%), in contrast to features of LR (29% ≥T3+ and 13% grade 4). Biologically, LR also differed, including higher angiogenic scores (Table 1). In adjusted analyses, all recurrence groups had improved survival compared to de novo metastatic disease; (LR: PFS & OS HR 0.64 & 0.49, p < 0.001). Median OS for DNM, ER, IR, and LR was 24, 44, 58, and 61 months, respectively. In subgroup analyses, Av + Ax versus Su was associated with better PFS in ER and DNM (HR= 0.49 & 0.67, p<0.01) in contrast to IR and LR (HR= 0.84 & 0.84, p>0.3) with interaction suggesting differing treatment effect (p=0.015). Conclusions: ER and LR ccRCC are biologically and clinically distinct, with ER resembling DNM ccRCC while LR exhibit more indolent features and angiogenic profiles. Recurrence is associated with better survival than DNM. ER and DNM disease may uniquely benefit from the addition of immune checkpoint inhibition. Select Features De Novo Metastatic (DNM) N = 267 Early Recurrence (ER: <12 months) N = 137 Intermediate Recurrence(IR: 1-5 years) N = 144 Late Recurrence (LR: >5 year) N = 139 p-value Initial ≥T3 168 (63%) 90 (66%) 76 (53%) 41 (29%) <0.0001 Grade 4 89 (42%) 56 (43%) 38 (27%) 16 (13%) <0.0001 Sarcomatoid 37 (14%) 20 (15%) 16 (11%) 3 (2.2%) 0.0015 PD-L1+ 169 (70%) 101 (76%) 83 (63%) 77 (63%) 0.058 No IMDC Risk Factors* 85 (32%) 63 (46%) 79 (55%) 82 (59%) <0.0001 RNA Data(n=583) Angio Signature -0.09(-0.19, 0.02) -0.10-0.23, 0.03 0.08-0.05, 0.22 0.220.07, 0.37) 0.0006 15-Gene Prognostic Score 0.1(-0.62, 0.90) 0.7(-0.15,1.6) 0.2(-0.68,1.0) -1.9(-3.0,-0.86) 0.0036 *Excluding time to diagnosis <12 months.

Correction to “Living Artificial Skin: Photosensitizer and Cell Sandwiched Bacterial Cellulose for Chronic Wound Healing”

Machine Learning‐Assisted Ultraelastic and Vibration‐Resolvable Microwebs

ABSTRACT Bioinspired structural designs have introduced a new paradigm in material science and mechanical engineering. Among them, the emerging spiderweb‐inspired structures have shown potential for creating artificial microstructures with enhanced tunability and functionality. However, the restricted structural elasticity of current spiderweb‐like designs causes limited mechanical performances, especially at the micro/nanoscale. Here, we employ machine learning and kirigami micro/nanofabrication to develop an ultraelastic microweb. Data‐driven optimizations enable efficient transformation of the natural configuration with limited elasticity into an artificial design with ultrahigh elasticity, achieving a remarkably low stiffness of ∼0.188 nN/nm. Both mechanical simulations and experimental characterizations confirm the superior mechanical properties of the optimized microweb, conclusively validating the optimization model with the combination of genetic algorithm and deep learning. Further dynamic vibration analyses reveal ultrasensitive low‐frequency mechanical resonances of the microweb, benefited from the greatly enhanced structural elasticity. For proof‐of‐concept demonstrations, the mass sensing of micro‐objects with a high sensitivity of −0.801 kHz/pg and diversified vibration‐resolvable information encryption are realized, respectively. This work establishes a generalizable strategy for creating highly elastic microstructures, with broad implications in the areas of mechanical micro‐/nano‐sensors, micro‐/nano‐electro‐mechanical systems (MEMS/NEMS), mechanical metamaterials, biological manipulations, information encryptions, and beyond.

The RNA-binding protein MSI2 controls blood-tumor barrier permeability via LINC00667-Mediated IRF6 mRNA decay

A novel method of analysis that uses standard of care PSA values to help guide optimal treatment decisions in the management of metastatic prostate cancer.

61 Background: Metastatic prostate cancer is commonly treated with androgen deprivation therapy (ADT) combined with abiraterone, enzalutamide or chemotherapy. However, these regimens have not been directly compared in head-to-head trials. This retrospective study leverages data from Kaiser Permanente Northern California (KPNC) to compare these treatment regimens and introduces a novel analysis of a tumor’s growth rate as a metric that can be leveraged to guide optimal treatment decisions in the management of patients with metastatic prostate cancer. Methods: We identified 2,327 patients with a diagnosis of prostate cancer in the KPNC Health Connect database (1/1/2011–12/31/2021) who were prescribed abiraterone, enzalutamide, or docetaxel across different lines of treatment. Serial prostate-specific antigen (PSA) values were collected during each treatment line. Using these PSA values, we applied a tumor growth equation to calculate tumor growth rates (g-rates) for each treatment regimen and correlated these rates with overall survival (OS). Results: Tumor growth rates were calculated using PSA values. As has been shown in multiple diseases the rates tumor growth is inversely correlated with overall survival (OS), an endpoint as important in real-world practice as it is in clinical trials. Kaplan-Meier (K-M) curves for all-cause mortality by tumor growth rate quartiles demonstrated that OS was consistent with tumor growth rates. Survival was significantly inversely corelated with the log of growth rates. This correlation was apparent both overall and across all lines of treatment analyzed. As expected, the rate of tumor growth while receiving first-line abiraterone was slower compared to second-line abiraterone. Similar trends were observed for enzalutamide and docetaxel in both first- and second-line settings. However, first-line abiraterone treatment achieved a greater reduction in tumor growth rate than did first-line enzalutamide treatment. Box plots comparing tumor growth rates among patients on abiraterone, enzalutamide, and docetaxel found statistically indistinguishable rates across racial/ethnic groups, age, and quintiles of Neighborhood Deprivation Indices (NDI). Conclusions: This study demonstrates that tumor growth rates can be estimated using a novel analytical approach in a real-world setting. While both abiraterone and enzalutamide show excellent real-world outcomes as effective and tolerable therapies, our findings suggest that enzalutamide should follow abiraterone in treatment sequencing. Estimates of tumor growth rates using real-world data can help evaluate the efficacy of therapies in prolonging survival and inform optimal treatment selection for patients with metastatic prostate cancer.

Influence of body composition on the efficacy of chemotherapy in men with metastatic aggressive variant prostate cancer (AVPC).

200 Background: Higher levels of adiposity have been associated with an improved response to AR pathway inhibition (ARPI) among patients with mCPRC (PMID 39019979). However, it is unclear if the influence of adiposity was driven by disease setting (mCRPC) or was specific to ARPI. Further, it remains unclear which obesity-linked factors best predict response to therapy in this context. This study tested the hypothesis that elevated skeletal muscle will be associated with improved efficacy with cabazitaxel + carboplatin in patients with aggressive variant mCRPC, but elevated adiposity measures will not. We then explored differences in gene expression by body composition measures. Methods: This was a post-hoc analysis of NCT03263650 where patients with metastatic AVPC received 6 cycles of cabazitaxel + carboplatin before randomization 2:1 to olaparib vs observation at MD Anderson from 2017 to 2020. Body composition was measured using an AI segmentation tool at the L3 vertebra from a CT scan within 30 days prior to chemotherapy initiation. Gene set enrichment analyses (GSEA) of Hallmark pathways, stratified by skeletal muscle mass (SMMi) and subcutaneous adiposity (SATi), were performed using bulk RNA sequencing data from pre-treatment tumor biopsies of patients with AVPC enrolled in NCT02703623 to derive normalized enrichment scores (NES) for each pathway. Efficacy endpoints included progression-free survival (PFS) and overall-survival (OS). Flexible survival modeling was performed using multivariable Cox regression adjusting for ECOG and age, with body composition measures modeled as continuous variables using restricted cubic splines. Results: 95 patients were included in the efficacy analysis with a median age of 67 years (range 43-86) and most had ECOG PS ≤ 1 (88.4%). The association between SATi or visceral adiposity (VATi) and PFS or OS was inconclusive (Table 1). SMMi was associated with a trend towards improved PFS (HR 0.56, Table 1). Increased SMMi correlated with significant downregulation of the MYC (NES -2.56; adj. p-value 2.5E-09) and oxidative phosphorylation (NES -2.56; adj. p-value 2.5E-09) pathways, and to a lesser extent the DNA repair, E2F, mTORC1, and G2M checkpoint pathways. Conclusions: Among men with metastatic AVPC, adiposity was not associated with the efficacy of chemotherapy, whereas increasing skeletal muscle showed a favorable trend. These findings suggest that the impact of adiposity on outcomes in mCRPC may be specific to AR-directed therapies. Treatment response using body composition as continuous variables. Body Composition Measure PFS OS Hazard Ratio (HR) – 95% CI Body Mass Index (BMI) 0.97(0.57 – 1.67) 1.26(0.71 – 2.23) Subcutaneous Adipose Tissue Index (SATi) 0.91(0.50 – 1.66) 1.03(0.57 – 1.87) Visceral Adipose Tissue Index (VATi) 1.14(0.60 – 2.15) 0.99(0.53 – 1.84) Skeletal Muscle Mass Index (SMMi) 0.56 (0.31 – 1.02) 0.97(0.55 – 1.69)

Effect of digital Ki67-based risk modeling on prognostic precision in non–muscle-invasive bladder cancer and high-risk subsets in mixed-grade tumors.

642 Background: Grade is a major determinant of progression in non–muscle-invasive bladder cancer (NMIBC), but tumor heterogeneity and subjective histologic grading complicate risk stratification. Ki67, a proliferation marker, provides an objective, reproducible measure of tumor biology. We evaluated whether digitally quantified Ki67 predicts recurrence, grade progression, and T1+ stage progression across low-grade (LG), mixed-grade (MG), and high-grade (HG) NMIBC. Methods: We retrospectively reviewed 472 patients with non-invasive papillary urothelial carcinoma (2012–2023). Exclusions included carcinoma in situ, BCG-unresponsive disease, lymphovascular invasion, prostatic urethral involvement, and re-staging specimens. Histology was reclassified per 2022 WHO criteria. Ki67 IHC was digitally quantified (Visiopharm) recording total and strong nuclear staining. Associations with recurrence, grade progression, and T1+ stage progression were evaluated using Kaplan–Meier, Fine–Gray competing risk, and multivariable Cox regression adjusting for tumor size, multifocality, prior bladder cancer, and intravesical therapy. Results: The cohort included 472 patients (LG 125, MG 192, HG 155) with a mean follow-up of 41.7 months. Ki67 expression increased significantly with tumor grade, both in total (LG 16.1%, MG 21.1%, HG 38.9%) and strong nuclear staining (LG 7.9%, MG 11.3%, HG 25.0%) (p < 0.001). In multivariable Cox models, strong nuclear Ki67 independently predicted recurrence (HR 1.01 per 1% increase, 95% CI 1.003–1.02, p = 0.007) and T1+ stage progression (HR 1.06, 95% CI 1.03–1.08, p < 0.001). Total Ki67 predicted T1+ progression (HR 1.04, 95% CI 1.02–1.06, p < 0.001) but not recurrence after adjustment. Threshold analyses: Ki67 ≥25.6% for recurrence (HR 1.43, p = 0.039) and ≥35% for T1+ progression (adjusted HR 3.1, p = 0.027). High Ki67 identified MG tumors with aggressive, high-grade–like behavior not apparent morphologically. Tumor size (HR 1.2, p = 0.03) and multifocality (HR 1.5, p = 0.02) also independently predicted progression. Conclusions: Digital Ki67 quantification provides an objective, reproducible proliferation measure that improves prognostic precision in NMIBC. High Ki67 (> 25–35%) identifies patients at increased risk for recurrence and T1+ progression, particularly within MG tumors. Incorporating digital Ki67 into risk models may enhance individualized management and surveillance.

Optimal hour of immune checkpoint inhibitors (ICIs) administration in metastatic renal cell carcinoma (mRCC): The “Tic-Tac” study.

452 Background: Recent studies suggest that early time-of-day (ToD) ICI-administration improves outcomes in metastatic cancer pts, likely due to circadian regulation of the immune response. Data in mRCC are limited, with no consensus on ToD cut-off or optimal number of morning-administered ICI cycles. Methods: This retrospective study included clear cell mRCC pts treated with ICIs (2015-2025). ToD was recorded for the first 4 treatment cycles. Pearson’s correlation tested ToD variation across the first 4 cycles. ToD was analyzed as a continuous predictor of cancer-specific survival (CSS) using Cox models. Kaplan-Meier analysis compared CSS between ToD cut-off groups. Results: Median follow-up of 223 pts was 28 months (mo): 100 received first-line ipilimumab–nivolumab and 123 later-line nivolumab. Median age at the start of ICIs was 67 years (range 54-69), 71% were men, and 25% had IMDC poor risk. The mean ToD for the first 4 ICI cycles was 13:09, 13:37, 13:39 and 13:31 respectively, with significant correlations between cycle 1 and subsequent cycles. Univariable analysis showed a linear negative association between ToD and CSS across the first 4 cycles, but on multivariable analysis (MVA) only ToD of cycle 1 was independently correlated to CSS (Table). Hence, focus was placed on cycle 1. Pts (n=36) receiving cycle 1 <11:00 had a CSS of 71 months versus 34 mo in pts (n=187) who received cycle 1 >11:00 [HR 0.53 (95%CI 0.3-0.8), p=0.01]. Pts (n=115) receiving cycle 1 <13:00 had a CSS of 62 mo versus 28 mo in pts (n=108) who received cycle 1 >13:00 [HR 0.55 (0.4-0.8), p=0.0006]. Pts (n=190) receiving cycle 1 <16:00 had a CSS of 49 mo versus 19 mo in pts (n=33) who received cycle 1 >16:00 [HR 0.40 (0.2-0.7), p<0.0001). The HR for CSS yielded 0.27 (0.1-0.5, p<0.0001) when comparing pts treated <11:00 with pts treated >16:00. On MVA including ToD at cycle 1, age, IMDC risk, ICI type, and the presence of liver, brain, or bone metastases, ToD at cycle 1 remained independently associated with CSS, with a linear negative effect [HR (+1 hour) 1.1 (1.03-1.2); p = 0.008]. Poor IMDC risk [HR 1.9 (1.1-3.6), p=0.04], older age [HR (+1 year) 1.03 (1.01-1.04); p=0.005], and liver metastases [HR 1.7 (1.1-2.5); p=0.03] were independently linked to worse CSS. Conclusions: Consistent with previous findings showing improved outcomes in mRCC patients who received ICIs in the morning, our study confirms that earlier ICI-administration (especially <11:00) is associated with better CSS. ToD of the first treatment cycle carries the greatest impact on CSS in mRCC. Univariable and multivariable analysis: ToD administration cycle 1-4. ToD Univariable analysisN=223 Multivariable analysisN=180 HR (+ 1 hour) (CI); p-value Cycle 1 1.2 (1.1-1.3); 0.0001 1.1 (1.05-1.3); 0.005 Cycle 2 1.1 (1.04-1.2); 0.003 1.0 (0.9-1.1); 0.9 Cycle 3 1.1 (1.03-1.2); 0.008 1.0 (0.9-1.2); 0.6 Cycle 4 1.1 (1.04-1.2); 0.007 1.1 (0.9-1.2); 0.2