Browse Articles

Comparative outcomes of RANKL inhibitors versus bisphosphonates in metastatic prostate cancer with bone metastases: A TriNetX real-world analysis.

113 Background: Skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, and the need for palliative bone interventions are major complications in metastatic prostate cancer with bone involvement. Bone-targeted agents like RANKL inhibitors and bisphosphonates mitigate these risks but raise safety concerns, particularly regarding atypical fractures. We conducted a study to assess fracture risk and overall survival outcomes in patients receiving either RANKL inhibitors or bisphosphonates. Methods: Using the TriNetX Research Network database, we identified adults (≥18 years) diagnosed with prostate cancer and bone metastases between 2000 and 2024. Patients were stratified into two cohorts: those receiving RANKL inhibitors only and those receiving bisphosphonates only. Propensity score matching (1:1) was performed to adjust for baseline confounders. Kaplan–Meier survival analysis with log-rank testing was used to compare outcomes between groups. The primary outcome was fracture risk, while secondary outcomes included overall survival and incidence of cardiovascular events. Results: A total of 15,520 prostate cancer patients with bone metastases were identified. After 1:1 propensity score matching, each cohort included 5,282 patients. The 1-year fracture risk was significantly lower in the RANKL inhibitor group compared to the bisphosphonate group (−0.81% [95% CI, −1.40% to −0.21%]; p = 0.0079), although this difference was not sustained at 5 years; however, Kaplan–Meier analysis continued to demonstrate a significant divergence (p = 0.023). Fracture sites for both groups were most frequently classified as “other specified sites” which includes the ribs, vertebrae, and skull (65% RANKL vs 69% bisphosphonates), followed by the pelvis and femur (26 vs 25%), then the humerus (both 5%), with the remaining few fractures in upper and lower limbs. Among patients who experienced fractures, 1-year overall survival favored RANKL inhibitors (59.2% vs 47.6%; HR 0.69 [95% CI, 0.50–0.94]; p = 0.0196), with a trend toward improved 5-year survival (p = 0.0585; median 15 months vs 10 months). There were no significant differences in the incidence of deep venous thrombosis or pulmonary embolism (1.85% [95% CI, −5.40% to 9.11%]; p = 0.616). However, cardiac events were significantly more frequent in the bisphosphonates group (21.9% vs 10.7%; difference −11.8% [95% CI, −19.80% to −2.57%]; p = 0.012). Conclusions: In prostate cancer patients with bone metastases, RANKL inhibitors were associated with a lower short-term fracture risk and improved early survival compared with bisphosphonates, without an increase in thromboembolic events. Cardiac events were more frequent with bisphosphonates, suggesting that RANKL inhibitors may offer a safer skeletal and cardiovascular profile in metastatic prostate cancer.

Homologous recombination deficiency signature (HRDsig) status in <i>BRCA1/2</i> wild type ( <i>BRCA1/2</i> wt) clinically advanced prostate cancer (CAPC).

219 Background: The HRDsig biomarker has emerged as a putative predictor of PARP inhibitor (PARPi) efficacy in multiple tumor types including CAPC. Previous studies of HRDsig+ CAPC focused on BRCA1/2 genomic alterations (GA); while non-BRCA ( BRCA1/2 wt) GA have not been widely considered as drivers of HRDsig+ CAPC PARPi response. Methods: Using the FoundationOne CDx assay, 23,336 BRCA1/2 wt CAPC cases underwent hybrid capture based CGP to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI), tumor mutation burden (TMB), HRD signature (professional services assay), genomic ancestry and genomic signature were determined from the sequencing data. PD-L1 expression was determined by IHC using Dako TPS score (≥1%: positive). Comparisons were evaluated by χ2 2-tailed using the Yates correction. Results: In this analysis of BRCA1/2 wt CAPC only, 1,107 (4.7%) were HRDsig+. Men with BRCA1/2 wt HRDsig+ CAPC were slightly older (median age 71 vs 69; p&lt;.0001) and featured a slightly higher median number of GA per tumor (4 vs 3; p&lt;.0001). Genomic ancestry distribution revealed just slightly higher African ancestry in the BRCA1/2 wt HRDsig- CAPC (15.2% vs 12.5%; p&lt;.0001) and just slightly higher European ancestry in the BRCA1/2 wtHRDsig+ cases (77.9% vs 74.7%; p=.020). Putative biomarkers of anti-PD1/L1 response including TMB ≥ 10 mut/Mb (range 3.0% to 2.2%; NS) and PD-L1 expression ≥1% (range 10.8% to 11.2%; NS) were similar, although the highly infrequent MSI-high status was more frequent in the BRCA1/2 wt HRDsig- CAPC group (2.2% vs 0.6%; p&lt;.0001). Individual GA more frequent in the BRCA1/2 wt HRDsig+ CAPC involved AR (23.4% vs 10.1%; p&lt;.0001), ATM (8.3% vs 5.7%; p=.0004), FANCA (1.7% vs 0.9%; p=.01), MYC (17.1% vs 8.8%; p&lt;.0001), PTEN (36.1% vs 32.5%; p=.013), RAD21 (12.6% vs 6.1%; p&lt;.0001), RB1 (8.7% vs 4.6%; p&lt;.0001) and TP53 (48.8% vs 38.5%; p&lt;.0001). GA more frequent in the BRCA1/2 wt HRDsig- CAPC included CDK12 (5.3% vs 2.2%; p&lt;.0001), SPOP (11.6% vs 7.2%; p&lt;.0001) and TMPRSS2 (32.4% vs 29.9%; NS). Although relatively uncommon, chromosome 9p loss including CDKN2A / B and MTAP were more frequent in the BRCA1/2 wt HRDsig+ CAPC (MTAP 3.1% vs 1.6%; p=.003). Conclusions: The genomic landscape of BRCA1/2 wt CAPC with HRDsig+ status seems relatively distinct from HRDsig- BRCA1/2 wt cases, involving HRD pathway-associated and other genes that may impact prognosis and help guide clinical trial designs. Limitations include retrospective nature and lack of clinical outcomes data annotation. CAPC HRDsig- (22,229 cases) CAPC HRDsig+ (1,107 cases) P Value AR 10.1% 23.4% &lt;.0001 ATM 5.7% 8.3% 0.0004 CDK12 5.3% 2.2% &lt;.0001 FANCA 0.9% 1.7% 0.01 RAD21 6.1% 12.6% &lt;.0001 RB1 4.6% 8.7% &lt;.0001 SPOP 11.6% 7.2% &lt;.0001 TMPRSS2 32.4% 29.9% NS TP53 38.5% 48.8% &lt;.0001

From Plating‐Centric to Full‐Cycle Design: A Perspective on the Critical Role of Zinc Anode Stripping

ABSTRACT The quest for stable aqueous zinc metal batteries has rightly focused on taming the unruly nature of zinc deposition. Pioneering research has produced a wealth of strategies to achieve uniform zinc plating. While these methods have significantly improved performance in laboratory half‐cells, a stubborn performance gap persists when moving to practical full‐cells. This chasm points to a fundamental oversight: the critical impact of the anode's initial stripping in a full‐cell configuration with zinc‐free cathodes. In this perspective, we highlight the pivotal yet underappreciated role of the initial zinc stripping process. We first decipher the operational protocols of zinc‐free cathode systems to illustrate how the initial stripping dynamically reshapes the anode and interface. By analyzing the multi‐step complexity of stripping, we contrast its mechanistic disparities with plating and assess the limitations of deposition‐centric strategies. We then evaluate current approaches that enhance full‐cell performance through optimized dissolution. Finally, looking toward future multi‐scenario applications, we argue that research must address the intricate coupling among stripping dynamics, chemo‐mechano‐thermal responses, and the crystallographic properties of zinc anodes. This paradigm shift from a plating‐centric view to a full‐cycle‐oriented is paramount to unlocking the full potential of the zinc metal anode for grid‐scale energy storage and beyond.

Integrating genomic profiling and circulating tumor DNA monitoring to optimize surveillance strategies in muscle-invasive bladder cancer.

797 Background: Up to 50% of patients with muscle-invasive bladder cancer (MIBC) relapse following curative-intent therapy, underscoring limitations of current surveillance with imaging and cystoscopy. Circulating tumor DNA (ctDNA) enables detection of molecular residual disease and early recurrence, however the genomic factors associated with ctDNA detection and their prognostic relevance remain poorly defined. Integrating ctDNA monitoring with tumor genomic profiling may refine surveillance strategies and improve biologic risk stratification in MIBC. Methods: Patients with histologically confirmed urothelial carcinoma who underwent curative-intent treatment (radical cystectomy [RC], neoadjuvant chemotherapy plus RC [NAC+RC], or trimodality therapy [TMT]) between 09/2022–08/2025 were retrospectively identified. ctDNA testing (Signatera assay, Natera) was performed before treatment initiation and every 3 months thereafter. Tumor genomic profiling was conducted using the Altera comprehensive genomic panel (&gt; 400 genes). Associations between genomic alterations and ctDNA positivity were assesed using Fisher’s exact test. Recurrence-free survival (RFS) was estimated by Kaplan-Meier analysis, and hazard ratios (HR) were calculated using Cox regression. Results: A total of 66 patients were included (median age 69.5 years; 83% male). Treatment modalities included NAC+RC in 53%, RC alone in 29%, and TMT in 18%. At diagnosis, clinical stage was T1 5%, T2 53%, T3 32%, and T4 10%, with pure urothelial carcinoma histology in 55%. Pre-treatment ctDNA was positive in 44%. Over a median follow-up of 9.6 months, radiographic recurrence occurred in 20%, 77% of whom were ctDNA-positive at baseline. Among initially ctDNA-negative cases, 8% converted to positive and 92% remained negative during surveillance. Across all patients, the most frequently altered genes were TERT (74%), TP53 (61%), ARID1A (23%), KMT2D (23%), and RB1 (23%). ctDNA positivity was significantly associated with ERBB3 (OR 0.06; p = 0.024) and TP53 (OR 3.2; p = 0.044). Patients with baseline ctDNA positivity had inferior RFS (HR 5.15; 95% CI 1.41–18.78; p = 0.006). Conclusions: ctDNA positivity was associated with specific genomic alterations in MIBC, suggesting a biologic basis for molecular disease detection. Integration of ctDNA monitoring with tumor genomic profiling may enhance surveillance and risk stratification. Initial ctDNA negativity remained undetectable in the majority of cases following curative-intent therapy, supporting further investigation of treatment de-escalation strategies in this subgroup.

FAP+FN1+CAV1+ cancer-associated fibroblast subtype and its association with aggressive behavior in localized prostate cancer.

392 Background: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, exerting both tumor-promoting and tumor-restrictive effects, and in some cases, dual roles. CAFs are heterogeneous and have been implicated in tumor progression, metastasis, and therapeutic resistance. Recent translational evidence suggests the existence of at least two CAF subtypes: CAV1+ CAFs and FAP+FN1+ CAFs. The clinical utility of subclassifying CAFs in prostate cancer remains undefined. In this study, we aimed to examine the correlation of CAF subtypes in localized prostate cancer with Decipher genomic classifier (GC) scores, Grade Group (GG), and the presence of adverse pathological features (APF). Methods: We retrieved de-identified transcriptomic and pathological data from 55,329 radical prostatectomy (RP) samples tested with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) between 2016 and 2024, available through the GRID registry (NCT02609269). A subset of 855 patients (META855 cohort) treated with RP was utilized for outcomes analyses. CAF subtypes were defined based on the expression of key biomarkers (FN1, FAP, and CAV1), normalized to total CAF estimates. Correlation analyses and multivariable Cox regression models were performed to evaluate the association of CAF subtypes with GC scores, GG, APF. Metastasis-free survival (MFS) estimates were generated using Kaplan–Meier methodology. Results: FAP and FN1 normalized expressions were highly correlated (r=0.61) and weakly correlated with CAV1 suggesting that they represent two distinct subtypes of CAF. Samples with high expression (top 25%) of FN1 (FN1+) and FAP (FAP+) were enriched with very high Decipher (&gt; 0.85, VHD) and GG4-5. As such, 37% and 32% of FAP+ were VHD and GG4-5 respectively compared to ~18% for low FAP(low 25%). While for FN+ 33.9% were VHD, and 31.5% GG4-5. Patients with FAP+FN1+, 42.5% and 37.1% were VHD, and had GG4-5. Samples with high CAV1 (CAV1+) were associated with lower rate of VHD (15.5%) or GG4-5 (20.8%) compared to low CAV1 (35.4% for VHD and 24.5% for GG4-5). When evaluating VHD in FAP+FN1+CAV1- subgroup, 58% were VHD compared to 6.4% in FAP-FN1-CAV1+. The 5-year MFS was 78% in FAP+FN1+CAV- compared to 96% in FAP-FN1-CAV1+ (p&lt;0.01). When evaluating the biological implications of FAP+FN1+, we found that FAP and FN1 expression is highly correlated to angiogenesis and EMT pathways, radiation sensitivity signature (PORTOS). Conclusions: FAP+FN1+CAV- is a unique subset of CAFs that is associated with aggressive prostate cancer behavior. Our findings may lay the foundation for future efforts to modulate CAFs in localized prostate cancer with existing therapeutics targeting FAP or FN1.

Effect of loss of KDM6A-mediated genomic instability and metabolic reprogramming on response to therapeutic perturbations in bladder cancer.

816 Background: Mutations in genes encoding critical epigenetic regulators are frequently observed in advanced bladder cancer; however, the mechanisms by which these alterations shape therapeutic responses remain incompletely understood. Through retrospective analyses of multiple bladder cancer patient cohorts, we identified that loss-of-function mutations in KDM6A , a histone demethylase, are found in approximately 26% of patients with advanced bladder cancer. Notably, inactivating mutations in KDM6A are associated with reduced overall survival following cisplatin-based chemotherapy whereas they correlate with improved outcomes after anti–PD-1/anti–PD-L1 therapy. Methods: To investigate the divergent therapeutic outcomes, we generated KDM6A -deficient murine and human bladder cancer cell lines using CRISPR-Cas9 and evaluated their phenotypes both in vitro and in syngeneic mouse models of bladder cancer. Whole-genome sequencing, ChIP-sequencing, and RNA-sequencing were performed to define the genomic and epigenomic alterations associated with KDM6A loss. In addition, mass cytometry (CyTOF) and metabolic profiling were conducted to characterize Kdm6a -dependent metabolic reprogramming and tumor microenvironment remodeling. Results: Whole-genome sequencing revealed increased generation of extrachromosomal circular DNA (eccDNA) encompassing gene loci linked to chemoresistance in KDM6A -deficient human bladder cancer cells, establishing a mechanistic connection between KDM6A loss and cisplatin resistance. In parallel, KDM6A loss impaired DNA repair pathways and reprogrammed tumor metabolism, reducing glycolysis and lactate production. This metabolic shift diminished histone lactylation (H3K9la, H3K18la) in regulatory T cells (Tregs), suppressing key immunoregulatory genes ( Foxp3, Tgfβ, Pdcd1 ) and limiting the expansion of PD-1 hi Tregs. Functionally, this enhanced the cytotoxic T cell-to-Treg ratio and improved response to anti–PD-1 therapy in Kdm6a-deficient tumor-bearing mice. Conclusions: Our findings establish KDM6A as a key epigenetic regulator that links eccDNA biogenesis, maintenance of genomic stability, and remodeling of the tumor immune microenvironment thus providing a unifying mechanistic basis for its role as a predictive biomarker to guide precision therapy in advanced bladder cancer.

A novel large language model framework for automated extraction of pathology data in radical cystectomy.

876 Background: Manual chart review has long been the standard for data collection in clinical research; however, this approach is time-intensive, costly, and prone to human error. Large Language Models (LLMs) are neural networks that are trained on large amounts of data, enabling them to perform natural language processing tasks. Our group has previously developed a framework for branching logic prompt design to leverage LLMs to handle complex reasoning queries and adapt to varied inputs. We sought to evaluate the feasibility and accuracy of this LLM framework using Llama-3b for automated, local extraction of pathologic variables from pathology reports in bladder cancer. Methods: Patients undergoing radical cystectomy from 2001 to 2025 were included in retrospective analysis. Prompts were designed to evaluate nine variables from surgical pathology notes, to include pT stage, pN stage, number of lymph nodes examined/positive, margin status, variant histology, and lymphovascular invasion (LVI). A manually extracted database was used as a reference. Patients with missing manual data were excluded on a variable-by-variable basis. Comparison between LLM and manual extracted data was assessed via % agreement and Cohen’s Kappa statistic. Results: 1898 radical cystectomy patients were included for analysis with matched manual data. The LLM generated 16046 datapoints across 9 variables with an overall agreement of 85.8% compared to manually abstracted data. There were no missing LLM generated datapoints across variables. Agreement and statistical comparisons by variable are demonstrated in Table 1, with (LVI) demonstrating the highest statistical agreement (n = 1734, kappa = 0.78, agreement 91.5%). Urethral margin status demonstrated the lowest statistical agreement with kappa = 0.136. Conclusions: We demonstrated the ability of branch logic prompting with an open-source LLM to accurately review, interpret, and extract pathology data for patients undergoing radical cystectomy. Future iterative improvements to improve variable agreement for tumor stage and margin status are nearing completion. Further refinement of prompt design and manual arbitration is needed to improve LLM accuracy for the eventual utilization of LLMs as the primary means for clinical data extraction. Pathology agreement of LLM and manual data extraction. Variable n Agreement (%) κ Lymphovascular Invasion 1734 91.5 0.7795 # Positive Nodes 1723 92.3 0.7633 # Nodes 1729 74.6 0.7377 pN Stage 1883 86.6 0.6922 Margin Status 1741 93.28 0.6716 pT stage 1883 66.8 0.6317 Variant Histology 1872 79.9 0.4141 Ureteral Margin Status 1741 90.9 0.3588 Urethral Margin Status 1740 98.6 0.136 Cohen's Kappa statistic denoted by κ.

Multi‐functional Phase‐Changeable Salt for Inverted Perovskite Solar Cells

ABSTRACT Non‐radiative recombination and uncontrolled crystallization at the buried perovskite interface remain key barriers to achieving highly efficient and stable perovskite solar cells (PSCs). Herein, we introduce a multi‐functional phase‐changeable salt, 2‐(diphenylphosphino)ethanaminium tetrafluoroborate (DPPEABF 4 ), as a functional interfacial modulator. DPPEA + interacts with perovskite precursors (FAI and PbI 2 ) through coordination and hydrogen bonding, suppressing excessive nucleation and reducing nucleation density. During annealing, DPPEABF 4 undergoes a reversible solid‐to‐liquid phase transition that buffers heat transfer, ensuring more uniform heating and slower, more controlled crystallization across the substrate. These effects collectively yield perovskite films with enlarged grains, reduced defect densities, and improved crystallinity. Concurrently, π–π stacking between DPPEA + and Me‐4PACz establishes an interfacial dipole that increases the work function and tunes the energy‐level alignment at the buried interface, facilitating efficient hole transport. As a result, the optimized devices achieve a champion power conversion efficiency of 26.52% (certified 26.46%) and retain over 90% of their initial efficiency after more than 2000 h of storage under 30–40% relative humidity. This work provides a new paradigm for designing dynamic interfacial materials for high‐performance optoelectronic devices.

Relapsed/refractory clinically advanced (CA) testicular non-seminomatous germ cell tumors (NSGCT): A genomic landscape study.

618 Background: The successful outcome for most men with NSGCT of testis after surgery and, in some cases, chemotherapy is a milestone in oncology. However, a minority of patients may become platinum-refractory with relapse or progression after chemotherapy. Comprehensive genomic profiling (CGP) has the potential to uncover new therapy targets for these patients. Methods: Hybrid capture based CGP was performed using the FoundationOne CDx assay on 182 CANSGCT to identify all classes of genomic alterations (GA). The site of the analyzed sample was available in 161/182 patients: 12.4% locoregional lymph nodes, 16.8% testis, 70.8% distant metastases. Microsatellite instability status (MSI), tumor mutational burden (TMB) and Homologous Recombination Deficiency (HRDsig) were determined from the sequencing data. Genomic ancestry and Cosmic trinucleotide signatures were also identified. PD-L1 expression was determined by IHC using Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). Most cases had relapsed after surgery and chemotherapy, either loco-regionally or with metastatic disease at the time of CGP. Results: 182 men with CANSGCT had median age of 33. Genomic ancestry revealed that 65.4% of patients were European, 29.1% were admixed American, 3.3% were African, 1.6% were East Asian and 0.5% were South Asian. There was a median of 3 GA per sequenced tumor. At 2.2% frequency, MSI-high status was rare and TMB was relatively low with 95% of cases having TMB &lt; 10 mut/Mb. A positive HRD signature was identified in 4.7% of cases. Identification of specific genomic signatures was uncommon with 2.7% having MMR signature and 1.1% having a tobacco exposure signature. PD-L1 expression was low level in 18.1% and high level in 15.3% of cases. KRAS mutations were the most frequent individual GA with &lt;1% KRAS G12C. Inactivation of PTEN (6.6%) and activation of KIT (4.9%) were GA with potentially associated targeted therapies. Conclusions: CGP of CANSGCT cases revealed potential therapy targets with opportunities for clinical trials, e.g. focused on PTEN/MTOR pathway and KIT. Although initial clinical experience with targeted agents and anti-PD1/L1 have yielded limited benefit in unselected patients with these tumors, further CGP-based study of refractory NSGCT is warranted to enable the development of biomarker-driven clinical trials designed to rescue men who exhibit platinum refractory disease. Study limitations include the retrospective nature, lack of comparison with the genomic landscape of platinum-sensitive tumors, lack of clinical outcomes data annotation, selection and confounding biases.

Gaps in BRCA mutation testing among mCRPC patients: Insights from US cancer practices (2018–2024).

102 Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has advanced with the approval of poly(ADP-ribose) polymerase inhibitor monotherapy and in combination with androgen receptor pathway inhibitor for patients (pts) with specific homologous recombination repair gene mutations, including BRCA mutations (BRCAm). Access to biomarker targeted therapy requires timely identification of BRCAm through genetic testing. This real-world study aims to characterize BRCAm testing patterns among pts with an mCRPC diagnosis (dx) in US cancer practices. Methods: This retrospective cohort study analyzed electronic health record-derived data from the Flatiron Health Research Database, identifying pts with an mCRPC dx from Jan 1, 2018 to Mar 31, 2024. Pts who participated in a clinical trial were excluded. For eligible pts, records of BRCAm testing during the study period (Jan 1, 2013–Jun 30, 2024) were evaluated. BRCAm testing (yes/no) was assessed by year of mCRPC dx. Multivariable logistic regression was used to estimate differences in the odds of BRCAm testing between pts with different characteristics, selected a-priori (age/year of mCRPC dx, insurance status, care setting, socioeconomic status [SES], race/ethnicity, Gleason score at initial dx, ECOG performance status [ECOG PS] at mCRPC dx, prostate specific antigen [PSA] at mPC dx, and de novo metastatic presentation). Results: This study included 6761 pts with a mCRPC dx in 2018–2024 (median age 75y; 60% White; 80% treated in community settings only; 61% had commercial health insurance). Overall, 3438 (51%) underwent BRCAm testing (1372 [40%] somatic; 804 [23%] germline; 1253 [36%] somatic + germline; 9 [0.3%] unknown). The proportion tested increased by year of mCRPC dx (37% in 2018 to 57% in 2023) but plateaued near 55% in 2020–2024. Regression analyses showed that, among pts who were otherwise similar, the likelihood of BRCAm testing was significantly lower for pts with mCRPC dx at older age (≥65y), whose race/ethnicity was classified as Hispanic/Latino (ethnicity) or other (ie not White, Black/African-American or Asian), with ECOG PS ≥1 or unknown at time of mCRPC dx, had a Gleason score ≤7, or a mCRPC dx before 2020. Differences in the odds of BRCAm testing were too small to estimate with confidence (ie not/borderline significantly different) across insurance status, care setting, SES, PSA at mPC dx, and de novo metastatic presentation. Conclusions: Using data from community oncology centers and academic medical centers in the US, this real-world study found that nearly half of pts diagnosed with mCRPC in 2018–2024 had not undergone BRCAm testing within the review period, which likely limited their access to biomarker-driven therapies. This persistent gap highlights the need to improve BRCAm testing in mCRPC.

Spatial and molecular determinants of response in penile squamous cell carcinoma.

12 Background: Penile squamous cell carcinoma (PSCC) is a rare, aggressive malignancy with limited treatment options and poor outcomes. The tumor microenvironment (TME) plays a key role in disease behavior and response to immunotherapy, but its immune composition and spatial organization in PSCC remain poorly defined. Methods: We conducted the first and largest longitudinal, multi-omics study of PSCC, integrating spatial transcriptomics (NanoString CosMx 6K panel) and single-cell RNA sequencing across 81 patients spanning all disease stages. Tissue Microarray 1 (TMA1) included 35 primary tumor samples from 31 patients, yielding &gt; 390,000 spatially resolved cells. Patients were stratified by progression status, HPV, stage, and chemotherapy response (n = 12) per RECIST 1.1. Spatial cell–cell proximity and immune neighborhood analyses were used to define TME architecture linked to outcomes. Results: Spatial transcriptomic profiling of 35 primary PSCC samples identified two major TME patterns linked to outcomes. Progressors (n = 18) showed perivascular immunosuppressive hubs enriched with Tregs, SPP1⁺/M2-like macrophages, and CD14⁺ monocytes, along with reduced immune–endothelial cell distances (CD8, CD4, B, macrophages; p &lt; 0.05). This vascular–myeloid suppressive axis was most evident in HPV-negative tumors (n = 17) and chemotherapy non-responders (n = 4). Conversely, patients that never progressed and chemotherapy responders displayed antigen-presenting, cytotoxic hubs enriched with CD8 effector and ISG⁺ T cells, cDC1s, and B/TLS features, with closer CD8–neutrophil interactions (p &lt; 0.05), a pattern favoring HPV-positive disease. Early-stage (I–II) progressors showed higher Treg and fibroblast levels, suggesting stromal constraint while advanced-stage (III–IV) tumors demonstrated monocyte and CD4⁺ T-cell accumulation, indicating a shift toward myeloid-driven inflammation with interferon and exhaustion features. Across samples, reduced immune-endothelial proximity was linked to progression and non-response, whereas stronger CD8-neutrophil and cDC1-CD8 interactions correlated with treatment response (p &lt; 0.05). Conclusions: This study establishes the first spatially resolved atlas of PSCC, integrating spatial and single-cell multi-omics to uncover distinct immune and stromal architectures linked to progression and therapy resistance. The discovery of vascular–myeloid immunosuppressive hubs versus cytotoxic immune neighborhoods provides a framework for precision immunotherapy development and biomarker stratification in this rare cancer.

Baseline and longitudinal body composition profile association with immune-checkpoint inhibitor (ICI) outcomes in metastatic clear-cell renal cell carcinoma (mccRCC).

553 Background: Body composition parameters, including skeletal muscle and fat distribution, have been associated with outcomes in mccRCC. However, limited data exist on dynamic body composition changes during ICI therapy and their relationship to treatment outcomes. Methods: We retrospectively analyzed 287 patients with mccRCC treated with ICI +/- tyrosine kinase inhibitors (TKIs) at Johns Hopkins University (2012–2023). Eligible patients received ≥4 weeks of ICI and had baseline CT imaging. Automated body composition metrics were extracted from CT scans at baseline and 3 months using the Data Analysis Facilitation Suite (DAFS). Quantified indices included body mass index (BMI), skeletal muscle index (SMI), subcutaneous (SATI), visceral (VATI), and intramuscular adipose tissue index (IMATI). Obesity was defined as BMI ≥25 kg/m². High vs. low VATI and SATI were categorized by sex-specific medians; sarcopenia (low SMI) was defined as SMI &lt;35 cm²/m² in females or &lt;55 cm²/m² in males. An optimized IMATI cutoff of 7.0 was applied, as no validated standard exists. Overall survival (OS) and progression-free survival (PFS) from the start of ICI were assessed using Kaplan-Meier and Cox regression models. Results: A total of 155 patients met inclusion criteria; 75% were male, median age was 63 years, and 82% were White. 97 patients (63%) received ICI monotherapy or dual ICI, and 58 (37%) received ICI + TKI. On multivariable analysis, higher baseline IMATI (&gt;7.0) was independently associated with worse OS (HR 1.95, 95% CI 1.05–3.60, p=0.03). In the 3-month landmark analysis, an increase in VATI correlated with improved OS (HR 0.78 per SD, 95% CI 0.62–0.98, p=0.04), while an increase in IMATI showed a favorable trend (HR 0.82 per SD, 95% CI 0.66–1.02, p=0.07). When evaluating the 3-month IMATI value (cutoff &gt;7.0) in a univariate model, higher IMATI remained directionally associated with worse OS (HR 1.76, 95 % CI 0.92–3.34, p = 0.09) but did not reach statistical significance. No significant differences were observed for PFS. Other parameters, including BMI, SMI, and SATI, were not significantly associated with survival or radiologic response. Conclusions: An optimized IMATI cutoff of 7.0, for which no validated standard currently exists, identified patients with poorer survival when above this threshold. Baseline IMATI was independently associated with inferior OS, and higher IMATI at 3 months remained directionally adverse but nonsignificant. Although early increases in VATI and IMATI correlated with improved OS, these effects attenuated after adjustment, likely reflecting selection among patients who remained on therapy. These findings suggest that baseline body composition, particularly intramuscular adiposity may carry stronger prognostic value than short-term compositional changes during ICI therapy in mccRCC.

Epigenetic editing: from concept to clinic

Self‐Oscillating Helix Showing Amplified Winding and Unwinding Motions

ABSTRACT Helical architectures in nature amplify motion via winding–unwinding. We report a simple, universal photopolymerization strategy to fabricate hydrogel helices with precisely controlled radial polymer gradients inside glass capillaries. A helically wrapped photomask and a chemical UV absorber (Ru(bpy) 3 ) jointly encode longitudinal and radial asymmetry. Their geometry is readily programmed by adjusting the photomask width and spacing, and our approach is polymer‐general, including thermoresponsive gels and organogels. As a representative example, lower critical solution temperature (LCST)‐type poly(NIPAAm) helices convert small, isotropic volume change into amplified uniaxial deformation, showing 1.6‐fold larger axial shrinkage than their total length shrinkage under heating. They respond to various stimuli, including temperature, acid, and near‐infrared (NIR) light. As a proof‐of‐concept soft robotic actuator, we fabricated a helix with a gradual axial variation in diameter and demonstrated stepwise, unidirectional locomotion along a string under cyclic heating and cooling. Integrating vinyl‑functionalized Ru(bpy) 3 as a covalent catalyst yields self‑oscillating helices driven by the Belousov–Zhabotinsky reaction, which autonomously repeat winding–unwinding accompanied by peristaltic waves. Compared with conventional rods, helices exhibit four‐fold larger amplitude and 3.4‐times faster deswelling kinetics. Our platform establishes a geometry‑driven design rule that harnesses helical coupling to amplify displacement in programmable and autonomous soft actuators.

A phase 2 trial of darolutamide to enhance prostate-specific membrane antigen expression in patients with localized prostate cancer (Daro-PET).

310 Background: PSMA PET/CT improves prostate cancer detection and guides PSMA-targeted therapies. Preclinical data suggest androgen receptor pathway inhibitors (ARPIs) may transiently upregulate PSMA expression in the metastatic setting, but prospective evidence in localized disease is lacking. Methods: Daro-PET (NCT05900973) was a single-arm, Simon’s two-stage phase 2 trial of men ≥18 years with localized prostate adenocarcinoma, no metastasis on CT/MRI or bone scan, and scheduled for prostatectomy. Patients had a baseline PSMA PET/CT, received darolutamide 600 mg twice daily for 7 days, then a second PSMA PET/CT. The primary endpoint was the proportion with ≥20% SUVmax increase in the intention-to-treat (ITT) set. Secondary endpoints were changes in tumor volume, SUVmean, total lesion PSMA, new metastases, and safety, plus per-protocol analyses (radiotracer dose 4.0 ± 1.0 mCi, ≤30% variation). Sample size assumed 80% power, one-sided α=0.05. If ≥3 patients met the primary endpoint, the regimen would be considered worthy of further study. Results: Between July 2023 and March 2025, 16 patients were enrolled (median age 61 [IQR 55–70]; 50% ISUP grade 4; 62.5% cT3; median PSA 10 ng/mL [IQR 6.4–11.2]). Baseline PSMA PET/CT showed nodal involvement in 4 patients and multifocal prostate uptake in 4 patients. No adverse events were reported, and all patients completed treatment. In ITT, 3 of 16 patients (18.8%; 90% CI 5.3–41.7) met the primary endpoint, with SUVmax increases of 36.5–62%. In per-protocol, 3 of 14 (21.4%; 90% confidence interval [CI] 6.1–46.6) achieved ≥20% SUVmax rise. Seven of 14 patients (50%; 90% CI 26.4–73.6) showed increased tumor volume (ranging from 6.2% to 98.6%). SUVmean and total lesion PSMA increased in 3 patients (21.4%). No new pelvic or extrapelvic metastases were detected. Two patients did not undergo prostatectomy due to shared decision-making unrelated to PET findings. Conclusions: A 7-day course of darolutamide increased PSMA expression in a subset of men with high-risk localized prostate cancer. These findings support further evaluation of ARPIs to improve the performance of PSMA PET/CT and PSMA-targeted therapies. Funding: Instituto D’Or de Pesquisa e Ensino, Bayer, RPH. Clinical trial information: NCT05900973 .

Predictive associations between serum oxo-androgens, race, and radiographic progression-free survival (rPFS) among patients treated with apalutamide (Apa), abiraterone acetate (AA) plus prednisone (P) in the PANTHER study.

247 Background: Prior studies have demonstrated that the hormonal environment in which prostate cancer develops may predict for sensitivity to Androgen Receptor pathway inhibition (ARPI). We hypothesized that high levels of serum 11-oxygenated androgens, a group of potent adrenal-derived steroids, might predict for better AR pathway targeting . We analyzed baseline serum androgens, including the oxo-androgens 11-OH testosterone (11-OHT), and 11-ketotestosterone (11-KT) from patients in two studies: (1) PANTHER, a prospective trial of Black and White cohorts of metastatic castration-resistant prostate cancer (mCRPC) patients treated with dual ARPI Apa and AA + P and (2) Abi Race, a similar prospective study of mCRPC patients treated with AA + P. We explored baseline androgen levels and their association with radiographic progression-free survival (rPFS) in each study and by race. Methods: We measured levels of 12 steroid hormones using liquid chromatography-tandem mass spectrometry in serum samples obtained at baseline from 161 of the 193 patients enrolled in PANTHER or in Abi Race. Samples were batched and sera assessed contemporaneously. Median levels for each hormone were calculated combining both study populations and used as a cut point. Cox proportional hazard models were used to calculate the hazard ratio for rPFS associated with above or below median in the overall populations and stratified by race. Results: In the Abi Race study, baseline androgen levels did not associate with differences in rPFS for the group as a whole. In the PANTHER study, baseline levels of 11-OHT and 11-KT above the median were the only androgens significantly associated with longer rPFS for the entire group (Table). For both androgens, when stratified by androgen and race, Black men with baseline 11-OHT and 11-KT levels above the median had the best outcomes. (see Table). In the PANTHER study, in which treatment was stopped at two years, androgens were not predictive for overall survival. Conclusions: Elevated baseline serum levels of the adrenal androgens 11-OHT and 11-KT were associated with improved rPFS for patients treated with combination Apa and AA + P, particularly Black men. These results suggest the hypothesis that higher baseline 11-OHT and 11-KT may reflect a prostate cancer biology that is sensitive to combination ARPI. Larger prospective studies are needed to evaluate this hypothesis in mHSPC and mCRPC. Baseline 11-OHT and 11-KT levels, race and treatment outcome in PANTHER. 11-OHT 11-KT rPFS Cohort Level HR 95% CI Level HR 95% CI All pts &gt; Med 1 &gt; Med 1 All pts &lt; Med 2.6 1.5, 4.7 &lt; Med 2.0 1.1, 3.5 Black &gt; Med 1 &gt; Med 1 Black &lt; Med 2.6 0.9, 7.0 &lt; Med 2.31 0.9, 6.2 White &gt; Med 2.3 0.9, 5.8 &gt; Med 2.66 1.1, 6.7 White &lt; Med 5.9 2.5, 14.3 &lt; Med 4.27 1.8, 10.2

Pharmacokinetics and dosimetry of lutetium Lu 177 zadavotide guraxetan in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the ECLIPSE sub-study.

174 Background: ECLIPSE (NCT05204927) is an ongoing confirmatory, pivotal, randomized, open-label, multicenter Phase 3 trial, evaluating efficacy and safety of Lutetium Lu 177 zadavotide guraxetan (a proprietary formulation of 177Lu-PSMA-I&amp;T) compared with androgen receptor pathway inhibitors (ARPI) switch in patients with mCRPC who have not previously received taxane-based chemotherapy for mCRPC. The ECLIPSE sub-study evaluated PK and radiation dosimetry of Lutetium Lu 177 zadavotide guraxetan in a subset of patients. Methods: Biodistribution, PK and radiation dosimetry were assessed in a subset of 26 patients (not randomized to the main ECLIPSE trial). Eligible patients received a target of 7.4 ± 10% GBq of Lutetium Lu 177 zadavotide guraxetan at the beginning of each 6-week cycle for up to 6 doses. Single photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed 4, 24, 48, and 168h post-administration of Cycle 1. PK plasma samples were collected at the same time points and measured for activity. A subset of patients (16/26) also underwent SPECT/CT imaging and PK sampling at the same timepoints after Cycle 3. Organ Level Internal Dose Assessment (OLINDA 2.2.3) was used to compute organ and whole body absorbed radiation doses for each patient. Results: Physiologic uptake of Lutetium Lu 177 zadavotide guraxetan was predominantly observed in the kidneys (0.41 ± 0.15 Gy/GBq), bladder (0.41 ± 0.05 Gy/GBq), salivary glands and lacrimal glands (0.19 ± 0.16 and 0.40 ± 0.36 Gy/GBq, respectively) and some parts of the gastrointestinal (GI) tract (left colon, 0.47 ± 0.31 Gy/GBq and rectum, 0.44 ± 0.30 Gy/GBq). Extrapolated to a cumulative activity of 44.4 GBq over 6 cycles, the absorbed doses were estimated at 18.2 Gy for the kidneys, 8.44 Gy for the salivary glands, and 17.8 Gy for the lacrimal glands, allowing for an increase in the maximum number of cycles to 6 in the ECLIPSE trial. Plasma concentration decreased over time with a similar profile in all patients, initially with a faster decline (mean distribution t 1/2 was 1.89 ± 0.34 hours) followed by a slower, prolonged decrease. The mean elimination t 1/2 was 14.70 ±10.10 hours. The clearance values (13.06±16.50 L/h) indicate a rapid clearance of most of the injected dose from the body with renal excretion as the primary route. Conclusions: These results demonstrate that Lutetium Lu 177 zadavotide guraxetan exhibits predictable physiologic uptake patterns, with the highest absorbed doses observed in the kidneys. The PK profile indicates a biphasic clearance with a rapid initial distribution phase followed by slower elimination, supporting suitability of Lutetium Lu 177 zadavotide guraxetan for therapeutic use with acceptable organ-specific radiation exposure in patients with mCRPC not previously treated with taxane-based chemotherapy for mCRPC. Clinical trial information: NCT05204927 .

Comparison of docetaxel triplet therapy with androgen receptor pathway inhibitor (ARPI) doublet in US veterans with metastatic hormone sensitive prostate cancer (mHSPC).

185 Background: Combination therapy has improved survival in clinical trials of mHSPC, but there are no head-to-head studies comparing docetaxel triplet and ARPI doublet therapy. The ARASENS and PEACE-1 trials showed survival benefit with darolutamide or abiraterone added to ADT and docetaxel. This study compares overall survival (OS) between docetaxel triplet and ARPI doublet in a real-world veteran cohort based on disease presentation and ARPI used. Methods: A retrospective study of US veterans with mHSPC treated with an ARPI (abiraterone, enzalutamide, apalutamide, darolutamide) within 4 months of diagnosis after July 1, 2021. Docetaxel triplet therapy was defined as docetaxel given within 90 days of ARPI. Veterans were grouped by disease presentation (synchronous vs metachronous) and volume of disease (high vs low), using CHAARTED criteria. Propensity score matching (caliper 0.05) was performed by age, highest PSA within 6 months, and disease volume. OS was compared using Cox proportional hazard models, with subgroup analyses by presentation, volume, and by ARPI type (abiraterone vs. darolutamide). Results: After matching, 608 veterans were identified with no significant baseline differences. With a median follow-up of 24.1 months, median OS not reached in either group. Triplet therapy was associated with decreased risk of death vs doublet therapy (HR 0.60, 95% CI 0.43-0.82). Survival benefit was greatest in synchronous disease (n=508, HR 0.51, 95% CI 0.35-0.74) and high volume disease (n=428, HR 0.55, 95% CI 0.38-0.79), with no difference in metachronous (HR 1.00, 95% CI 0.49-2.03) or low volume cases (HR 0.77, 95% CI 0.38-1.54). Among triplet patients treated with abiraterone or darolutamide, darolutamide (n=190) showed improved OS vs abiraterone (n=101), (HR 0.52, 95% CI 0.30-0.91). Conclusions: In this real-world cohort, docetaxel triplet therapy was associated with lower mortality than ARPI doublet, particularly in de novo and high-volume mHSPC. Exploratory analysis suggested darolutamide triplet was associated with decreased mortality compared to abiraterone. These findings support the role of docetaxel triplet therapy in selected patients with high-volume, de novo mHSPC, though prospective validation is warranted. Baseline characteristics of matched cohort. Mean age High volume Synchronous Median PSA (highest, ng/mL) Docetaxel triplet n=305 69.0 70.5% 81.6% 107 ARPI doublet n=303 69.4 70.3% 85.5% 84.9

Stereochemically Active Lone Pair Effect of Cations Triggers Giant Rashba–Dresselhaus Spin Splitting in Ferroelectric Semiconductors for Circularly Polarized Light Detection

ABSTRACT Rashba–Dresselhaus (RD) spin splitting arising from spin‐orbit coupling in spatial inversion asymmetric semiconductors is critical for realizing numerous advanced spintronic applications. However, modulating the RD spin splitting coefficient ( α RD ) is challenging due to the unclear structural‐property relationship. Herein, inspired by highly distorted inorganic selenites containing stereochemically active lone pair (SCALP) electrons, we selected 4‐aminomorpholine cation (4AM) containing SCALP electrons to synthesize a new two‐dimensional (2D) ferroelectric semiconductor (4AM) 2 PbBr 4 , exhibiting a giant α RD of 2.377 eV Å with Δ E RD = 126 meV and Δ k 0 = 0.106 Å −1 that differentiates circularly polarized light‐excited carriers in the momentum space via spin‐dependent optical transition selection rules with an asymmetric factor of 0.65. A geometric structure‐property relationship study reveals that incorporating SCALP into the organic cations enhances their net polarity and induces substantial distortions within the inorganic sublattices that enhance the α RD . This work reveals the regulatory mechanism of organic cations on distortion of inorganic octahedron and provides a new approach for efficient synthesis and rapid screening of 2D ferroelectric semiconductors with large α RD .

Effects of 3β-HSD1 on back-conversion and androgen signaling in CRPC.

238 Background: Dihydrotestosterone (DHT), the principal androgen driving prostate cancer progression, is synthesized in the prostate from gonadal and adrenal precursors. It is then metabolized to downstream 5α-reduced androgens to be eliminated. 3β-Hydroxysteroid Dehydrogenase type 1 (3β-HSD1) catalyzes C3 oxidation in androgen synthesis. Inheritance of the adrenal-permissive HSD3B1 allele prolongs enzyme stability and increases DHT synthesis from adrenal precursors, contributing to castration resistance and prostate cancer mortality. Abiraterone acetate (AA) is a steroidal drug that may also be subject to 3β-HSD1 metabolism. We investigated whether 3β-HSD1 mediates the back-conversion of 3β-androstanediol (3β-diol) to DHT and 3β-OH-abiraterone (3β-OH-Abi) to 3-keto-abiraterone (3-keto-Abi), a weak androgen receptor agonist, thereby potentially promoting CRPC progression. Methods: Vector control and HSD3B1 -overexpressing 293T cells were treated with 3β-diol or 3β-OH-Abi. Genetic and pharmacologic blockade of 3β-HSD1 in C4-2 CRPC cells were used to assess DHT metabolism and back-conversion of 3β-diol to DHT via mass spectrometry. Expression of androgen-responsive genes (ARGs) was measured in parental and CRISPR-knockdown cells following 3β-diol treatment. In the clinical setting, serum 3β-OH-Abi levels were compared between adrenal-permissive and adrenal-restrictive HSD3B1 genotypes across treatment cycles in the PANTHER trial (mCRPC patients treated with apalutamide and AA + prednisone). Results: Overexpression of HSD3B1 in 293T cells enabled back-conversion of 3β-diol to DHT. These cells also back-converted 3β-OH-Abi to 3-keto-Abi. C4-2 cells metabolize DHT to both C3 stereoisomers of androstanediol. Pharmacologic inhibition with trilostane blocked 3β-HSD1-mediated conversion of 3β-diol to DHT. Similarly, back-conversion of 3β-diol was abolished in HSD3B1 -knockdown cells, as DHT was detected in both media and intracellularly in parental C4-2 cells following treatment with 3β-diol, but was absent in knockdown cells. Also, 3β-diol treatment upregulated ARGs in parental cells. Pharmacokinetic data from the PANTHER trial demonstrated higher serum 3β-OH-Abi levels in men with the adrenal-restrictive genotype at 4- and 8-hour timepoints during treatment cycles 1 and 2. Conclusions: 3β-HSD1 activity sustains intra-tumoral DHT by back-converting its downstream inactive metabolite, 3β-diol, thereby maintaining androgen signaling activity. This pathway also mediates back-conversion of 3β-OH-Abi to 3-keto-Abi, a weak androgen receptor agonist. These findings provide further mechanistic insight into the adverse outcomes associated with the adrenal-permissive HSD3B1 genotype and suggest new avenues for CRPC management.