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Radium 223 without androgen deprivation therapy (ADT) in patients (Pts) with biochemically recurrent prostate cancer (BCR) and PET findings in the bones.
192 Background: BCR pts have a rising PSA after definitive surgery or radiation, but negative CT/Tc-99m bone scans. While ADT-based strategies are commonly used, they can be associated with life-altering toxicities. Radium-223 is an alpha-emitting radiopharmaceutical that accumulates in areas of high bone turnover and has demonstrated a survival benefit in metastatic prostate cancer but its benefits as a monotherapy in BCR without ADT have not been explored prior to this study. This strategy may be important as bone metastasis drives morbidity/mortality in prostate cancer. Methods: Eligible pts in this study (NCT04206319) have BCR following definitive therapy, testosterone (T) >100ng/dL, normal organ and marrow function, and negative CT/Tc-99m bone imaging. Pts must have findings on NaF or PSMA PET suspicious for metastatic bone disease not seen on Tc-99m bone scan. Pts are treated with Radium-223 at the approved dosing of 55 kBq/kg for 6 cycles. PSA declines were defined as 2 or more confirmed declines from an intra-study apex PSA (ISAP; Madan ASCO GU 2018). All pts have pre- and post-treatment PSMA and NaF imaging. Immune responses (primary endpoint) are to be evaluated at study completion. Results: 25 pts have enrolled with 24 currently evaluable for response, with a median age of 69 yrs (57-80) and PSA of 1.75 ng/ml (0.2-49.5). 21/24 pts had PSMA+ scans. 21/24 pts had NaF+ scans. Grade 2 toxicities have been rare and no grade 2 changes in hemoglobin or platelets have occurred. There have been no grade 3/4 toxicities and no cycles missed for toxicity. Two pts with rapid PSA doubling times came off study early for progression and were not evaluable for follow up imaging. 8/24 pts (33%) had confirmed ISAP PSA declines of 12% to 80% lasting from 84 to 682 days, with two ongoing PSA responses. Delayed PSA responses following completion of treatment were observed. 13/21 evaluable pts had evidence of decreased maximum standardized uptake value (SUVmax) on NaF PET imaging after treatment. 5/19 evaluable patients with PSMA PET+ lesions had a radiographic response; two pts had resolution of multiple PSMA+ bone findings, one of whom remains with negative bone findings on PET after 2+ years and with a stable PSA. Conclusions: Radium-223 in BCR is safe and associated with minimal grade 1/2 toxicities. Decreases in SUVmax seen on most NaF scans suggest Radium-223 targeting of suspicious lesions. Improvements in PSMA imaging have been observed. Delayed but confirmed PSA declines have been seen in 33% of pts. Radium-223 monotherapy may have therapeutic activity in BCR and further studies are needed to define its potential role in BCR in patients with PET+ bone findings. Clinical trial information: NCT04206319 .
Realization of Iodinene with Tunable Topological Edge States and Flat Bands
ABSTRACT Halogens, known for their diatomic molecular structures, typically do not form extended covalent materials. The development of 2D elemental materials from halogens is therefore significant for both fundamental research and practical applications. Here, we report the realization of a monolayer iodine sheet, namely iodinene, with multiple exotic properties. Using angle‐resolved photoemission spectroscopy, scanning tunneling microscopy, and first‐principles calculations, we show that iodinene hosts 2D topological crystalline insulator states, a long‐sought topological state previously observed only in 3D materials. Moreover, iodinene is exceptionally stable under ambient conditions. By applying a tensile strain of 48%, we realize two nearly flat bands with robust topological edge states in between, paving the way for the design and fabrication of tunable topological and spintronic devices.
Directional Catalysis of Sulfur at Highly Ordered Triple‐Phase Interfaces in All‐Solid‐State Lithium‐Sulfur Batteries
ABSTRACT Sluggish sulfur reaction kinetics present a critical barrier to the practical application of sulfide‐electrolyte (SE) based all‐solid‐state lithium‐sulfur batteries (ASSLSBs). Achieving high performance requires both lowering the intrinsic energy barrier for sulfur conversion and engineering efficient transport pathways. Herein, we address these challenges by designing atomically dispersed cobalt sites on carbon nanotubes to directionally catalyze sulfur conversion at the triple phase interface. Strong orbital hybridization between Co 3d and S 3p states strengthens chemical bonding, effectively accelerating both sulfur reduction and lithium sulfide oxidation. The interfaces tailored for directional catalysis maximize highly ordered C/S/SE triple‐phase interfaces and minimize SE/C interfaces, establishing hierarchical ionic/electronic transport networks while mitigating side reactions. Consequently, the engineered cathode delivers a high reversible capacity of 1108 mAh g − 1 at 0.5 C, retaining 97 % capacity over 500 cycles. The resulting batteries also demonstrate remarkable robustness under demanding conditions. This work offers a powerful catalysis‐driven strategy for high‐performance ASSLSBs.
Real world outcomes comparing the use of GLP-1 agonists in patients with bladder cancer and comorbid obesity: A propensity score matched analysis from the Global Federated Health Research Network.
712 Background: Bladder cancer is one of the most common malignancies of the urinary tract. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Their pleiotropic benefits including improved insulin sensitivity, potential anti-proliferative and anti- inflammatory benefits may significantly benefit these patients by potentially influencing tumor biology. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with bladder carcinoma with comorbid obesity, exploring potential interactions between metabolic modulation and disease behaviour. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with bladder cancer and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and common comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, heart failure, chronic kidney disease (CKD), ischemic stroke, risk of metabolic dysfunction associated liver disease and need for hemodialysis. Results: We identified 1282 patients with bladder cancer and obesity who received GLP-1 receptor agonists, and 10238 patients with bladder cancer and obesity who did not receive GLP-1 therapy. The average age was 67.3 years in the first cohort and 69 years in the second cohort. After propensity matching, each cohort consisted of 1282 patients with similar baseline characteristics and ethnicity distribution. Our analysis found that over 5 years, patients with bladder cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.611, 95% CI: 0.515 to 0.725, p-value =0.04), myocardial infarction (Risk difference: -4.418%, 95% CI: -6.608% to -2.228%, p-value <0.001), heart failure (Risk difference: -5.226%, 95% CI: -8.883% to -1.569%, p-value =0.005), CKD (Risk difference: -7.193%, 95% CI: -10.675% to -3.711%, p-value <0.001). There was no statistically significant difference in the risk of metabolic dysfunction associated liver disease and need for hemodialysis between the two subgroups. Conclusions: Our study revealed that patients with bladder cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, heart failure and CKD. Further longitudinal cohort studies are imperative to better understand these associations and guide evidence-based clinical practice in this population.
Ivonescimab in metastatic clear cell renal cell carcinoma (mccRCC) after immune checkpoint inhibitor therapy: The phase II IVORY trial.
TPS573 Background: ICI-based combinations, as dual ICIs or ICI plus a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), constitute the first-line treatment for metastatic mccRCC. However, in the subsequent-line setting, adding ICIs to VEGF-TKIs did not demonstrate superior activity compared to VEGF-TKI monotherapy (CONTACT-03 Pal et al. Lancet 2023, TiNivo-2 Choueiri et al. Lancet 2024), highlighting the need for novel approaches to overcome ICI resistance. Ivonescimab is a first-in-class tetravalent bispecific antibody targeting PD1/PD-L1 and VEGF/VEGFR signaling, simultaneously inhibiting, two key mechanisms of mccRCC pathogenesis: immune escape and angiogenesis. In non-small cell lung cancer, ivonescimab has recently shown superiority over pembrolizumab (HARMONi-2). By spatially coordinated and simultaneous inhibition of PD-1 and VEGF pathways through a single molecule, we hypothesize that ivonescimab will enhance efficacy, address tumor heterogeneity, and reduce pharmacokinetic variability compared with separate agents. Methods: This phase II, single-arm, open-label, investigator-initiated study evaluates the activity of ivonescimab monotherapy in patients with mccRCC previously treated with ICIs. Cohort 1 (n=20) enrolls patients with no prior exposure to VEGF-directed agents, while Cohort 2 (n=20) enrolls patients had previously received VEGF-directed therapy. Ivonescimab is administered at 20 mg/kg IV dose every 3 weeks until disease progression or unacceptable toxicities. Each cohort follows a Time-to-event Bayesian Optimal Phase 2 (TOP) design, with simultaneous monitoring of two efficacy endpoints: objective response rate (ORR), defined as complete or partial response at any time, and disease control rate (DCR), defined as complete response, partial response or stable disease at 24 weeks, per RECIST 1.1. In cohort I, the null hypothesis is ORR= 10% or DCR= 30%, while the alternative hypothesis is ORR= 30% or DCR= 50%. The regimen will be deemed acceptable if more than 4 patients experience an objective response, or more than 9 patients experience disease control at 24 weeks, providing 96% power with 20% type I error rate. In cohort II, the null hypothesis is ORR= 5% or DCR= 20% and the alternative hypothesis is ORR= 20% or DCR= 40%. The regimen will be considered acceptable if more than 2 patients experience an objective response, or more than 6 patients experience disease control at 24 weeks, with 91% power and 12.5% type I error rate. Tissue, blood, and stool correlatives will be collected at baseline, during therapy and at the end of treatment to identify changes in specific immune-cell and gut microbiome subsets and elucidate the dynamic evolution of tumor and immune-cell compartments as well as their spatial relationships following ivonescimab. Clinical trial information: NCT06940518 .
Impact of intraoperative frozen section analysis (NeuroSAFE) on oncologic and functional outcomes after radical prostatectomy: A systematic review and meta-analysis.
373 Background: The NeuroSAFE technique, which provides intraoperative frozen section analysis of the neurovascular bundles, aims to maximize nerve preservation during radical prostatectomy while maintaining oncologic safety. Its efficacy in reducing positive surgical margins (PSM) and improving postoperative functional outcomes remains uncertain. Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines. PubMed, Scopus, and Embase were searched through January 2025. Eligible studies compared NeuroSAFE-assisted with conventional radical prostatectomy. The primary endpoint was PSM. Secondary endpoints included biochemical recurrence (BCR), urinary continence, and erectile function recovery. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity was assessed using I² statistics, and publication bias was evaluated with Egger’s and Begg’s tests. Results: Eleven studies involving 15,639 patients (7,244 NeuroSAFE; 8,395 control) were included. NeuroSAFE significantly reduced PSM (OR 0.73, 95% CI 0.59–0.88, p=0.001; I²=76%). No significant difference in BCR was observed (OR 0.82, 95% CI 0.43–1.56, p=0.53). NeuroSAFE improved functional recovery, with higher odds of urinary continence (OR 1.55, 95% CI 1.09–2.20, p=0.014; I²=0%) and erectile function (OR 2.26, 95% CI 1.50–3.41, p<0.001; I²=71%). No significant publication bias was detected. Conclusions: NeuroSAFE significantly decreases positive surgical margins and improves postoperative continence and erectile recovery without compromising biochemical control. These findings support its selective implementation as a quality-enhancing adjunct in nerve-sparing radical prostatectomy. Meta-analysis. Outcome Studies (n) Patients (NeuroSAFE / Control) Pooled OR (95% CI) p-value I² (%) Positive surgical margins 11 7,244 / 8,395 0.73 (0.59–0.88) 0.001 76 Biochemical recurrence 5 1,232 / 1,689 0.82 (0.43–1.56) 0.53 59 Urinary continence 4 599 / 1,803 1.55 (1.09–2.20) 0.014 0 Erectile function 4 630 / 1,791 2.26 (1.50–3.41) <0.001 71
HER2 expression and genomic alterations in plasmacytoid urothelial carcinoma: Results from a large real-world institutional cohort.
803 Background: Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive histologic subtype of urothelial carcinoma (UC), characterized by discohesive growth, frequent peritoneal dissemination, and poor response to conventional systemic therapies. Despite its distinct clinical behavior, the molecular features of PUC remain poorly characterized. The prevalence and clinical significance of HER2 expression and ERBB2 alterations in PUC are unclear. Given the availability of FGFR3- and HER2-directed systemic therapies in UC, characterizing the molecular landscape of PUC may provide biological insight into its aggressive behavior and reveal novel therapeutic targets. We hypothesized that HER2 overexpression and other genomic alterations underlie the aggressive phenotype of PUC. Methods: This retrospective cohort study included patients diagnosed with histologically confirmed plasmacytoid urothelial carcinoma (PUC) at our institution between 2019 and 2025. Clinicopathologic data, HER2 immunohistochemistry (IHC; Ventana 4B5 assay, Roche), and comprehensive genomic profiling (CGP; Altera, Caris, FoundationOne, or other platforms) were collected. Tumor mutational burden (TMB) was categorized as low (≤5 mut/Mb), intermediate (6–19 mut/Mb), or high (≥20 mut/Mb). Overall survival (OS) was estimated using the Kaplan-Meier method, and all other data were summarized descriptively. Results: A total of 125 patients with plasmacytoid urothelial carcinoma (PUC) were identified (median age 72 y [IQR 65–79]; 78% male). Median follow-up was 19.8 months (95% CI 15.0–30.4, and median overall survival across all stages was 23.6 months (95% CI 17.6–NR). Clinical T-stage distribution at diagnosis was 33% ≤T1, 32% T2, 22% T3, and 12% T4. HER2 IHC and CGP findings are summarized in Table 1, highlighting frequent HER2 overexpression, ERBB2 alterations, and common co-mutations in TERT , TP53 , and RB1 . Conclusions: HER2 positivity (IHC 3+) and ERBB2 were frequently present in pts with PUC. These findings suggest a potential role for systematic HER2 IHC assessment and warrant exploration of HER2-directed therapies in pts with PUC. Molecular and genomic characteristics of plasmacytoid urothelial carcinoma (PUC). Feature n (%)/Description HER2 IHC (n = 62) HER2 3+ (positive) 13 (21%) HER2 2+ (equivocal) 25 (40%) CGP (n = 24) ERBB2 alterations 4 (17%) CDH1 alterations 3 (13%) TMB High in 25%, intermediate in 4% Frequent pathogenic alterations TERT (71%), TP53 (54%), RB1 (33%), ARID1A (29%), KDM6A (25%)
A‐Site High‐Entropy Engineering of Oxygen Electrode: A Promising Route to Durable and Active Reversible Solid Oxide Cells
ABSTRACT Reversible solid oxide cells (RSOCs) are promising for their highly efficient power‐fuel interconversion and serve as a critical technology for building a carbon‐neutral energy ecosystem. However, their widespread implementation is impeded by insufficient electrocatalytic activity and stability of conventional oxygen electrodes. Here, we design a high‐entropy single‐phase perovskite, Pr 0.2 Nd 0.2 Sm 0.2 Ba 0.2 Sr 0.2 CoO 3‐δ (PNSBSC), engineered from Sm 0.6 Sr 0.4 CoO 3‐δ (SSC), to overcome the classic activity‐stability trade‐off in perovskite oxides. A PNSBSC‐based button cell delivers a peak power density of 2.06 W cm −2 in fuel cell mode and a high current density of 2.54 A cm −2 at 1.3 V in electrolysis mode (50% H 2 O) at 800 °C. The cell also demonstrates exceptional stability, sustaining 120 h of continuous operation in both modes and three reversible cycles at 700 °C without performance degradation. Its scalability and robustness are further verified using a large‐area cell (30 W output, >80 h stability) and by sustaining a notable 40 A electrolysis current at 1.3 V (80% H 2 O, 750 °C). First‐principles calculations corroborate the enhanced activity and stability, which are attributed to the high‐configurational‐entropy design. This work establishes entropy engineering as a viable paradigm for developing high‐performance and durable electrodes for advanced RSOCs.
Efficacy of rezvilutamide in preventing the flare phenomenon induced by GnRH agonists in newly diagnosed metastatic hormone-sensitive prostate cancer: An exploratory multicenter randomized controlled trial.
191 Background: Current guidelines recommend first-generation antiandrogens ≥7 days before or concomitant with gonadotropin-releasing hormone (GnRH) agonists to prevent transient surges in luteinizing hormone (LH), testosterone, prostate-specific antigen (PSA) and clinical symptoms, known as the flare phenomenon. Data on next-generation androgen receptor inhibitors in this context are limited. This study evaluated the efficacy of rezvilutamide combined with a GnRH agonist in preventing the flare phenomenon in metastatic hormone-sensitive prostate cancer (mHSPC) (Clinical Trial Registration: ChiCTR2300076106). Methods: In this exploratory multicenter randomized trial, 60 patients aged > 18 years with newly diagnosed, histologically confirmed prostate adenocarcinoma and ≥1 distant metastasis, baseline PSA > 2 ng/mL and testosterone > 1.5 ng/mL, were enrolled. Participants were randomized 1:1 to: (1) control, rezvilutamide administered 1 day before GnRH agonist (“1-day regimen”), or (2) experimental, rezvilutamide administered with 1-hour interval relative to GnRH agonist (“1-hour regimen”). Treatment continued until disease progression or intolerable toxicity. PSA, LH, and testosterone were assessed on Days −1 (control only), 0, 1, 3, 7, 14, and 28 post-GnRH administration, with follow-up every 28 days thereafter. Results: Between October 2023 and October 2025, 54 patients from eight centers met eligibility criteria and completed treatment (n = 27 per group). Groups were comparable in age at baseline and in PSA, testosterone, and LH levels on day 0. Median PSA declined rapidly in both groups, with significant reductions from Day 7 (experimental P < 0.05; control P < 0.01) and sustained suppression through Day 84 (experimental: 376.3→0.2 ng/mL, P < 0.01; control: 366.7→0.3 ng/mL, P < 0.01); The experimental group showed greater relative PSA reduction on Days 0, 1, and 3 (P < 0.01). LH peaked on Day 1 (experimental: 34.7 ng/mL; control: 26.6 ng/mL) and testosterone peaked on Day 3 (experimental: 6.3 ng/mL; control: 6.6 ng/mL), declining below baseline by Day 14 (P < 0.01). Relative changes in LH and testosterone were similar between groups at all early time points (Days 0–15). Conclusions: In treatment-naïve mHSPC patients, rezvilutamide, administered either one day before or with a 1-hour interval relative to GnRH agonists, rapidly and durably suppressed PSA and clinical symptoms, effectively preventing the flare phenomenon. Clinical trial information: ChiCTR2300076106 .
Association of coexisting amyloidosis with survival outcomes in bladder cancer: A real-world cohort study.
650 Background: Bladder cancer (BC) is one of the most prevalent urologic malignancies. Amyloidosis, characterized by extracellular deposition of amyloid fibrils, may coexist with cancer but remains underexplored as a comorbidity affecting cancer outcomes. This study compares clinical outcomes, including mortality and urinary incontinence, between patients with BC alone and those with concurrent BC and amyloidosis. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, comprising data from 157 healthcare organizations worldwide. Two cohorts were defined: (1) patients with a diagnosis of malignant neoplasm of the bladder (ICD-10-CM: C67) and (2) patients with both bladder cancer and amyloidosis (ICD-10-CM: E85). Propensity score matching (PSM) was performed 1:1 to balance demographics and comorbidities. Outcomes were assessed over a 12-month follow-up window using risk analysis and Kaplan-Meier survival methods. Results: Before matching, 412,823 patients had BC alone, and 1,488 had BC with amyloidosis. After PSM, each cohort included 1,375 patients. Mean age was 76.9 years in both groups, and 80.5% were male. Mortality: The 1-year mortality risk was 12.4% for BC alone vs 17.2% for BC+amyloidosis (Risk Difference: −0.048; p < 0.001). Kaplan-Meier analysis showed reduced survival in the BC+amyloidosis group (log-rank p = 0.000; HR = 0.701, 95% CI 0.576–0.854). Urinary Incontinence: Incidence was similar between groups (1.5% vs 1.7%, p = 0.652), with no significant differences in mean instance frequency or time-to-event analysis ( p = 0.623). Conclusions: Coexistent amyloidosis in patients with bladder cancer is associated with significantly higher short-term mortality, independent of age, sex, and comorbidities like hypertension, and diabetes. However, urinary incontinence outcomes did not differ significantly suggesting that amyloidosis does not directly exacerbate lower urinary tract dysfunction in the short term.. Amyloidosis may represent a marker of systemic frailty influencing survival in bladder cancer populations. To our knowledge, this is the first large-scale comparative study evaluating the clinical characteristics and outcomes of bladder cancer patients with coexisting amyloidosis. Our findings reveal that this rare comorbidity is associated with inferior survival outcomes, underscoring the need for multidisciplinary management and tailored therapeutic strategies. Keywords: Bladder cancer, Amyloidosis, TriNetX, Propensity score matching, Mortality, Survival analysis.
Neoadjuvant (Neoadj) gemcitabine intravesical system (Gem-iDRS) plus cetrelimab (CET) or CET alone in patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for/refusing neoadj cisplatin-based chemotherapy (NAC): Updated perioperative outcomes from SunRISe-4.
748 Background: There is a high unmet need for effective neoadj treatments (tx) for MIBC that maintain overall health and do not delay or complicate planned radical cystectomy (RC). Gem-iDRS, previously TAR-200, is a novel intravesical drug-releasing system designed to provide sustained delivery of gemcitabine in the bladder. SunRISe-4 (NCT04919512) is a randomized phase 2 study evaluating neoadj Gem-iDRS and CET in pts with MIBC who are ineligible for or refuse NAC. This analysis from SunRISe-4 evaluated if neoadj Gem-iDRS plus CET (Cohort 1 [C1]) or CET alone (C2) impacted pre- and post-RC surgical, laboratory, or safety outcomes, including clinical declines, delay to RC, or increased perioperative complications. Methods: Pts (≥18 yr; ECOG PS 0-1) had histologically confirmed cT2-T4a N0M0 MIBC, were ineligible for or refused NAC, and planned for RC. Pts were randomized 5:3 to receive Gem-iDRS plus CET or CET alone Q3W for 12 wks, followed by RC (protocol-specified RC window: 11-15 wks). Perioperative outcomes included time to RC, 30- and 90-d post-RC morbidity and mortality, and changes on tx in ECOG PS, BMI, albumin, creatinine, and hemoglobin. ECOG PS was recorded on site at baseline and wks 6 and 36. Results: As of the May 9, 2025, data cutoff, 134 pts underwent RC (C1: 88; C2: 46). Median time to RC was 13.6 wks in C1 and 13.3 wks in C2. Most pts had RC within the window (C1: 85.2%; C2: 84.8%). 5/88 (5.7%) pts in C1 and 6/46 (13.0%) in C2 underwent RC after 15 wks (1 pt had a delay due to grade 2 hematuria,1%, during neoadj tx). 79.3% of C1 and 69.6% of C2 pts received ileal conduit. No clinically significant changes in ECOG, BMI, albumin, creatinine, and hemoglobin were noted on tx. At 30 and 90 d post RC, no significant increase in morbidity or mortality was observed (Table). Conclusions: In pts with MIBC ineligible for or refused NAC, neoadj Gem-iDRS plus CET and CET alone were not associated with declines in overall health, delays to RC, or significant increase in 30- and 90-d post-RC morbidity or mortality. Addition of Gem-iDRS to the checkpoint inhibitor CET did not worsen safety and post-RC morbidity compared with CET alone. Clinical trial information: NCT04919512 . Safety outcomes within 30 and 90 d post RC. Pts, n (%) ≤30 d post RC ≤90 d post RC Overall(N=118) Gem-iDRS + CET (n=76) CET alone (n=42) Overall (N=100) Gem-iDRS + CET (n=68) CET alone (n=32) Morbidity Serious AEs 46 (39.0) 32 (42.1) 14 (33.3) 49 (49.0) 37 (54.4) 12 (37.5) Grade ≥3 AEs 54 (45.8) 38 (50.0) 16 (38.1) 55 (55.0) 40 (58.8) 15 (46.9) Mortality a Any cause 3 (2.5) 1 (1.3) b 2 (4.8) c 4 (4.0) 2 (2.9) d 2 (6.3) c AE, adverse event. a No deaths that occurred ≤30 and 90 d post RC were related to neoadj tx with Gem-iDRS or CET. b Due to hypoxia. c Due to peritonitis and cardiac arrest in 1 pt each. d Due to hypoxia and cardio-respiratory arrest in 1 pt each.
Baseline biochemical and clinical predictors of castration resistance and survival in metastatic hormone-sensitive prostate cancer treated with first-line androgen receptor pathway inhibitors: A multicenter real-world study.
108 Background: Androgen receptor pathway inhibitors (ARPIs) plus androgen deprivation therapy (ADT), with or without docetaxel, are standard for metastatic hormone-sensitive prostate cancer (mHSPC). Predictors of progression and survival in real-world populations remain limited. We evaluated baseline biochemical and clinical factors associated with time to castration resistance (tCRPC) and overall survival (OS). Methods: We retrospectively analyzed 333 patients treated Jan 2020–Apr 2025 with abiraterone (ABI), apalutamide (APA), enzalutamide (ENZ), or darolutamide (DARO) plus ADT, with or without docetaxel. Baseline variables included age, ECOG PS, disease volume (CHAARTED), risk (LATITUDE), ISUP grade, visceral/liver metastases, LDH and ALP. Endpoints were tCRPC and OS; PSA response was assessed, with undetectable PSA ≤0.2 ng/mL. Kaplan–Meier and multivariable Cox regression analyses were performed. Results: Median age was 70; 142 received ABI, 157 APA, 28 DARO, 6 ENZ; 258 received doublet, 75 triplet therapy. Synchronous metastases were present in 229, high-volume disease in 186, high-risk features in 246. At 3 months, PSA50/PSA90 responses were 79%/64%, undetectable PSA in 30%. Median follow-up was 48 months. At 24 months, overall castration-resistance rate was 76%. High-volume rates: 68% doublets (67% APA, 70% ABI), 65% triplets (12m: 88% ABI, 86% DARO); low-volume: 88% doublets (86% APA, 92% ABI), 60% triplets (ABI). OS rates at 24 months: high-volume 61% doublets (56% ABI, 65% APA), 59% triplets (12m: 75% ABI, 84% DARO); low-volume 90% doublets (84% ABI, 94% APA), 72% triplets (80% ABI). After multivariable Cox analysis, high-volume predicted shorter tCRPC (HR 3.25, 95% CI 1.67–6.32, p<0.001) and worse OS (HR 2.58, 95% CI 1.44–4.62, p=0.001). LDH >220 U/L associated with shorter tCRPC (HR 2.79, 95% CI 1.35-5.80, p=0.06) and worse OS (HR 2.20, 95% CI 1.11-4.37, p=0.024). ALP >350 U/L, ISUP grade, and visceral metastases were not significant. In high-volume patients, LDH >220 U/L strongly predicted tCRPC in triplets (HR 20.0, p=0.006) but not in doublets. Conclusions: In this large real-world dataset, ARPI-based therapy achieved high PSA responses and durable disease control. High-volume disease and elevated LDH were the strongest predictors of earlier castration resistance and shorter OS, while ALP, ISUP grade, and visceral metastases were not prognostic. High LDH was a predictive factor for treatment outcomes in high-volume. This clinical parameter might be integrated with genomic markers to guide treatment intensification in mHSPC, specially in high-volume disease.
Robust Adsorption of Self‐Assembled Monolayer on NiOx via Multiple Hydrogen Bonds for Stable Inverted Perovskite Solar Cells
ABSTRACT In inverted perovskite solar cells, self‐assembled molecules (SAMs) employed as hole‐transport layers can significantly improve device performance, with power conversion efficiencies currently exceeding 27%. However, the non‐uniform and weak adsorption of SAMs on metal oxide substrates leads to severe non‐radiative recombination at the buried interface, which remains a critical bottleneck for long‐term operational and thermal stability. In this study, heptafluorobutyramide (HA) or heptafluorobutylimidamide (HM) is introduced into MeO‑4PACz to tailor its adsorption on the NiO x surface. Leveraging multiple hydrogen‑bonding interactions between HM and MeO‑4PACz, the resulting SAMs adopt an inclined orientation of approximately 60° relative to the NiO x surface. This configuration increases the proportion of Ni 3 + on the substrate and raises the surface coverage from 0.912 to 1.236. It also effectively passivates undercoordinated Pb defects at the buried interface, enhances interfacial uniformity, and suppresses non‑radiative recombination. Using a vacuum‑flash processing method, HM‑optimized devices achieve a champion efficiency of 26.99% (certified steady‑state efficiency 26.62%) and reach 20.36% on a large‑area module with an active area of 809.69 cm 2 . Moreover, small‐area devices retained 92% and 87% of their initial efficiency after 1500 h of maximum power point tracking at 25°C and 60°C, respectively.
Emerging Biomaterials Blocking PD‐1/PD‐L1 Pathway for Cancer Therapy
ABSTRACT Conventional monoclonal antibodies targeting either PD‐1 or PD‐L1, despite the clinical significance as immune checkpoint inhibitors (ICIs), exhibit limited effect in the majority of cancer patients. The persistent challenges in ICIs have prompted extensive research into next‐generation biomaterial‐based immunotherapeutic strategies to inhibit PD‐1/PD‐L1 pathway. Herein, this review started with the retrospect of recent insights into the dynamic regulation of PD‐L1 expression patterns and its multifaceted functional mechanisms within the tumor microenvironment. Subsequently, the emerging alternatives to PD‐1/PD‐L1 inhibitors are summarized by their categories, including peptides, nucleic acids, small molecule inhibitors, and natural compounds, which could function by reducing PD‐L1 expression, degrading PD‐L1, or inhibiting PD‐1/PD‐L1 interactions. Furthermore, recent efforts on combination therapy based on these biomaterials are discussed, especially those with chemotherapy, radiotherapy, phototherapy, and sonodynamic therapy. This paradigm shift in PD‐1/PD‐L1 immune checkpoint blockade therapy underscores the prospects of emerging biomaterials in orchestrating anticancer immune responses, which would provide insights for developing next‐generation immunotherapeutic strategies for clinical oncology to improve patient outcomes.
Low-coverage whole-genome sequencing of urinary tumor DNA to characterize genomic correlates of lymphovascular invasion in bladder cancer.
804 Background: Lymphovascular invasion (LVI) is a key pathological feature linked to tumor dissemination and poor outcomes in bladder cancer, yet no reliable preoperative predictor exists. Low-coverage whole-genome sequencing (lcWGS) of urinary tumor DNA (utDNA) has emerged as a noninvasive method for detecting genome-wide copy number variations (CNVs) and chromosomal instability (CIN) from urine samples, with proven value in disease diagnosis and recurrence monitoring. Typical CNV patterns in bladder cancer include recurrent gains (e.g., 1q, 8q) and losses (e.g., 5q, 9p/q), reflecting genomic instability related to tumor invasion and progression. High CIN is also recognized as an indicator of unfavorable prognosis. However, the association between specific chromosomal alterations detected in preoperative urine and LVI status remains unclear. This study aimed to evaluate the relationship between chromosomal alterations detected by urine-based lcWGS and the presence of LVI in bladder cancer. Methods: A total of 71 patients with histologically confirmed urothelial carcinoma of the bladder who underwent transurethral resection of bladder tumor (TURBT) were prospectively analyzed. Preoperative urine samples were subjected to low-coverage (~0.1×) whole-genome sequencing for CNV profiling. Z-scores were calculated for each chromosomal arm, and arms with |Z|>3 were defined as abnormal. Genome-wide CIN status was categorized as high when ≥1 arm showed |Z|>3. LVI was assessed on TURBT pathology. Associations between chromosomal alterations and LVI were tested using Fisher’s exact test, with multiple testing adjusted by the Benjamini–Hochberg (BH) procedure. Standardized mean differences (SMD) were calculated to evaluate genome-wide CNV balance between LVI groups. Results: Among 71 patients, 58 (81.7%) were classified as CIN-high and 20 (28.2%) exhibited LVI. Deletion of chromosome 5q (5q−) was detected in 17 patients, including 12 with LVI and 5 without, whereas among 54 patients without 5q−, 8 had LVI and 46 did not. Fisher’s exact test revealed a strong association between 5q− and LVI (OR = 13.8, 95% CI 3.59–43.0, p < 0.001). After BH correction across all chromosomal arms, no other arm reached statistical significance (q < 0.05), and most demonstrated |SMD| < 0.20, indicating comparable genome-wide CNV patterns between groups aside from 5q. These findings support a specific and independent link between 5q loss and the presence of LVI in bladder cancer. Conclusions: Urine-based lcWGS revealed a significant association between chromosome 5q deletion and LVI, independent of global CIN pattern differences. These findings suggest that 5q loss may serve as a potential noninvasive biomarker reflecting invasive tumor behavior in bladder cancer. Further studies are needed to elucidate the biological mechanisms underlying this association.
CYTOSHRINK: A randomized phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with ipilimumab/nivolumab for metastatic kidney cancer.
416 Background: Patients (pts) presenting with de novo metastatic renal cell carcinoma (mRCC) have a poor prognosis. The role of cytoreductive nephrectomy (CN) is uncertain in these pts. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. The efficacy and safety of primary SBRT in combination with ipilimumab and nivolumab (I/N) in pts with previously untreated mRCC are unknown. Methods: A randomized phase II trial was conducted at sites in Canada (6) and Australia (1). Inclusion criteria were: previously untreated, biopsy-proven, IMDC intermediate or poor risk de novo clear cell mRCC. Pts with a primary kidney lesion > 20cm, previous abdominal radiation precluding SBRT, or with a contraindication to I/N were excluded. Randomization was 2:1 to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm), versus I/N alone. The primary endpoint was progression free survival (PFS). Target sample size was 78 pts. Secondary objectives included safety, overall survival (OS), objective response rate (ORR), health-related quality of life (QOL), and correlative biomarker analyses. Results: Pts were recruited between February 2020 and July 2024, with accrual paused for 8 months during COVID-19 pandemic. Median follow-up is 23.5 months. A total of 67 pts were randomized: 43 pts to I/N+SBRT, 24 to I/N alone. Median age was 65 years, 73% were male, IMDC risk groups were 58% intermediate and 42% poor. Pts in the experimental arm had larger renal tumours (T3/T4 stage 70% vs 46%), primary target lesion (95 mm vs 87.5 mm), and more likely to have liver sites of metastasis (23% vs 8%) compared to the I/N alone arm. Three pts died prior to any SBRT. PFS rate at 12-months was 35% (95% CI 21-49%) for I/N+SBRT vs 48% (27-66%) for I/N alone (HR 1.29, 0.69-2.40). The ORR was 33% vs 42% and 18-month OS was 59% vs 70%, for I/N+SBRT vs I/N alone. In per protocol analysis of pts who received 4 cycles of I/N +/- SBRT, 12-month PFS was 46% vs 56%, ORR was 50% vs 44%, and 18-month OS was 74% vs 79%, for I/N+SBRT (n = 24) vs I/N alone (n = 16). Grade 3/4 treatment related adverse events were 23% vs 29%, respectively, with no new safety signals related to I/N or SBRT toxicity noted. Conclusions: CYTOSHRINK is the first randomized trial testing the addition of early cytoreductive SBRT to first-line immune checkpoint blockade for patients with de novo mRCC. While 12-month PFS was not improved compared to I/N alone, there were notable baseline imbalances. The addition of SBRT to I/N was considered safe. Further follow up of OS, QOL and correlative biomarker analyses are ongoing. Clinical trial information: NCT04090710 .
Rethinking germline testing in localized prostate cancer: Prevalence of germline variants and association with Gleason score and NCCN risk grouping.
322 Background: Men with prostate cancer who harbor germ-line pathogenic variants have increased likelihood of a more aggressive cancer and/or an increased risk for second primary cancers. However, current National Comprehensive Cancer Network (NCCN) guidelines limit germline genetic testing recommendations to men with prostate cancer who have higher Gleason scores or NCCN Risk Groups, metastatic disease and/or a family history of cancer. We examined the prevalence of pathogenic variants in a real-world cohort of men with localized prostate cancer, stratified by Gleason score and NCCN Risk Group. Methods: Blood was drawn for germline genetic testing at the time of prostate cancer diagnostic biopsy. For patients who had biopsy-confirmed cancer, germline testing was initiated. Those with a benign biopsy were not included in this analysis. A positive result was defined as a pathogenic variant in at least one of the 49 genes tested. Relationships between a positive test result and Gleason score or NCCN Risk Group were assessed using logistic regression. Results: A total of 3995 men completed germline testing and 274 (6.9%) had a positive test result. Gleason scores and NCCN Risk Groups are summarized in Table 1. Positive test rates of 6.3%, 6.0%, 7.8%, and 8.4% were observed for Gleason scores 3+3, 3+4, 4+3, and greater than 7, respectively. Positive test rates by NCCN Risk Group were 6.7%, 5.7%, 5.6%, and 8.4% for low, favorable intermediate, unfavorable intermediate, and high risk NCCN Risk Groups, respectively. There was no statistically significant difference in positive testing rates across Gleason scores (p = 0.17) or NCCN Risk Groups (p = 0.14). Conclusions: A substantial proportion of men with localized prostate cancer harbor pathogenic germline variants. Neither Gleason scores nor NCCN Risk Groups were associated with positive germline test results. These results have the potential to impact the management of prostate cancer and/or screening for other cancers. Our findings suggest that limiting germline testing based on Gleason score or NCCN Risk Group may miss a significant number of patients harbor a pathogenic variant, supporting consideration for broader testing criteria for all men with localized prostate cancer. Distribution of Gleason Score and NCCN Risk Group (N=3995). N (%) Gleason score 3+3 1454 (36.4) 3+4 1056 (26.4) 4+3 640 (16.0) >7 (8, 9, 10) 620 (15.5) Unknown 225 (5.6) NCCN Risk Group Low 1031 (25.8) Favorable Intermediate 679 (17.0) Unfavorable Intermediate 663 (16.6) High 726 (18.2) Unknown 896 (22.4)
Impact of androgen receptor pathway inhibitor (ARPI) dose reduction on overall survival of metastatic castration-resistant prostate cancer: A multi-centre retrospective study.
115 Background: Androgen receptor pathway inhibitors (ARPIs) have been a cornerstone in the management of metastatic castration-resistant prostate cancer (mCRPC) but can be associated with increased risk of cardiovascular disease, fractures and falls, and toxic cognitive effects. Dose reductions are frequently implemented to manage toxicity or minimise drug interactions, but their impact on overall survival (OS) remains unclear. This is a multi-institutional study from 4 UK NHS Foundation Trusts to evaluate the effect of ARPI dose reduction on OS outcomes in patients with mCRPC. Methods: A retrospective cohort study of mCRPC patients treated with ARPIs in the period from 2016-2018. We collected patient demographics; ,Docetaxel in hormone sensitive setting, PSA nadir level after the start of ARPIs, dose reduction and reason for reduction, and date of death or last follow-up up. Median OS calculated from the date of the start of ARPI until the date of death or lost to follow-up. Survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional hazards models, adjusting for age, disease volume, docetaxel use, and PSA level at diagnosis and PSA Nadir. Results: The median age of the cohort was 69.7 years (range: 41–95). Of the 607 patients, 71% received enzalutamide and 29% received abiraterone. High-volume disease was present in 44.2% of patients, and 21.3% received docetaxel. Dose reduction of ARPI occurred in 14.3% of patients (n=87), with fatigue and cardiovascular comorbidities being the most common reasons. Median OS for the whole cohort was 22 months (95% CI: 19.9–24.01). Patients who underwent dose reduction had a significantly longer median OS of 31.0 months (95% CI: 25.2–36.9) compared to 21.0 months (95% CI: 19.0–23.0) in those without dose reduction. Cox regression analysis confirmed that dose reduction was independently associated with improved survival (HR = 0.714, 95% CI: 0.560–0.911, p = 0.007). Conclusions: Though the landscape for therapy options has now changed, with increasing use of ARPI at the time of initial diagnosis of hormone-sensitive metastatic prostate cancer, this retrospective review is hypothesis-generating. Further investigation is warranted as to whether dose reduction of ARPI can improve quality of life, reduce side effects and impacts on OS. These findings further support recruitment to the Cancer Research UK (CRUK) and Prostate Cancer UK (PCUK) -funded ENHANCE study. Multivariate Cox regression of different prognostic factors in relation to overall survival of metastatic castrate resistant prostate cancer. Parameter Sig. Exp(B) 95.0% CI for Exp(B) 95.0% CI for Exp(B) Lower Upper Dose reduction 0.007 0.714 0.560 0.911 Age 0.000 1.038 1.026 1.051 Volume of disease 0.026 1.106 1.012 1.209 Docetaxel in Hormone sensitive setting 0.000 0.814 0.732 0.904 PSA nadir level after start of ARPI 0.000 1.002 1.001 1.002
Broadband Nanocavity Imaging with Machine Vision for Multiplex miRNA Assays
ABSTRACT Sensitive and multiplexed quantification of microRNAs (miRNAs) remains challenging due to their short length, low abundance, and sequence homology, particularly in complex biological matrices. This paper presents an approach that combines a distributed Bragg reflector (DBR)‐coupled silver nanoparticle (AgNP) gap nanocavity with deep learning instance segmentation for automated image readout. Applied to A549 lung cancer cell extracts, the assay directly quantifies endogenous miR‐191, miR‐25, and miR‐130a without enrichment or amplification. The nanocavity concentrates fields and favors radiative decay, enhancing collection and suppressing quantum dot (QD) blinking, while Mask R‐CNN enables robust, high‐throughput counting and classification. The system achieves an attomolar LOD (∼10 −17 mol/L), a linear dynamic range spanning five orders of magnitude, and >99% correct identification across spectrally encoded channels. These results establish an AI‐enabled nanophotonic biosensing platform that is sensitive, specific, robust, and scalable for multiplexed miRNA analysis in research and clinically relevant matrices.
Self‐Amplified Nanomedicine Enables Lysosomal Blockade to Potentiate Starvation Therapy of Pancreatic Ductal Adenocarcinoma
ABSTRACT Starvation therapy targeting the metabolic vulnerability of pancreatic ductal adenocarcinoma (PDAC) holds great potential; however, analyses of clinical samples and orthotopic models reveal that its efficacy is undermined by lysosome‐mediated metabolic compensation. To disrupt this metabolic adaptability, we herein engineer a homotypic membrane‐camouflaged nanomedicine capable of hypoxia‐responsive cascade drug release and enhanced tumor accumulation. The resulting nanomedicine performs a hypoxia‐induced phase transition that first liberates glucose oxidase to intensify oxygen deprivation and subsequently triggers burst release of chloroquine. Such a design of self‐amplified relay drug release ensures effective starvation induction and precise lysosomal alkalization, thereby shutting down lysosome‐mediated nutrient recycling. In a xenograft orthotopic PDAC model, this nanomedicine achieves 9.75‐fold increase in tumor accumulation, robust tumor inhibition of 92.8%, and an elevated survival rate of 80% with favorable biosafety. Collectively, our findings highlight lysosomal disruption as a therapeutic lever to potentiate starvation therapy and provide a clinically actionable nanoplatform to enhance metabolic interventions for other metabolically vulnerable malignancies.