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Molecular mechanisms of mitochondrial AAA+ proteases

Comparing concordance of prostate cancer clinical trials and disease incidence in the United States in 2021 and 2022.

335 Background: Prostate cancer is the second-leading cause of cancer-related death in men in the United States. However, only about 5% of cancer patients in the United States are enrolled in a clinical trial. As of January 2022, clinical trial costs were mandated to be covered by Medicaid. We investigated whether or not this change in policy might have improved access to care by comparing the clinical trial and prostate cancer incidence from 2021 and 2022. Methods: Incidence data was obtained from the 2021-2022 Center for Disease Control U.S. Cancer Statistics database. Clinical trial enrolment was obtained from ClinicalTrials.gov, accounting for recruited persons from January 1 to December 31 of each year. Trial availability rates were normalized to per 100,000 persons per state. The incidence of prostate cancer and number of clinical trials per state were correlated with linear regression. Results: The average age-adjusted incidence per 100,000 for the nation in 2021 was 115.176 (±15.668), which increased to 120.616 (±16.992) in 2022. The states with the highest incidence being New Jersey (147.4) in 2021 and Maine (157.0) in 2022. Arizona stayed the state with the lowest incidence with 80 in 2021 and 81.5 in 2022. The average unique prostate cancer clinical trials per state per 100,000 was .808 (±1.379) in 2021 and .321 (±.2085). In 2021, we found that there was no significant correlation (coefficient of 0.0435, r2=.00001) between the incidence of disease and clinical trial access when normalized to the population. However, in 2022, we found that there was a significant correlation (coefficient of 3.316 r2 =0.0017) between disease incidence and clinical trials. We found that New Jersey and Maine which had the highest incidence each year, were ranked 39th (.109 trials) and 37th ( .1337 trials) out of the 50 states. As of January 2022, costs of clinical trials are mandated to be covered by Medicaid, which may affect both trial enrollment and medical center participation, shifting the research landscape towards greater inclusivity for all patients. Further directions would include comparing this data to more recent data as it becomes available each year, as well as comparing Medicaid enrollment data for the same time frame. Conclusions: We hope to elucidate how this policy change provides access and can lead to new clinical trials, especially in states with large increases in incidence, such as New Mexico and Maine.

The nature of progression on active surveillance for grade group 2 prostate cancer.

330 Background: Active surveillance (AS) is included in guidelines as a management option for men with Gleason Grade Group 2 (GG2; Gleason 3+4) prostate cancer (PCa), but uptake has been limited and variable between providers. We sought to describe progression of confirmed GG2 disease in a well-annotated AS cohort. Methods: The Urologic Outcomes Database (UODB) at the University of California San Francisco (UCSF) was queried for men with cT1-2N0/xM0/x, PSA <20 ng/mL, core positivity ≤50%, GG2 PCa, and ≥2 biopsies on AS. Outcomes were upgrade (≥GG3), increase in positive cores to >50%, disease progression (either upgrade or increase in core positivity to >50%), active treatment, metastasis, and prostate cancer–specific mortality (PCSM). Life-table estimates described outcomes, and Cox regression identified factors associated with risk of progression. Results: 319 men met inclusion criteria. Median (IQR) follow-up was 70 (42–104) months. CAPRA score was low risk in 159 (50%) and intermediate risk in 160 (50%). Median (IQR) PSA was 5.4 (4.1–7.4) ng/mL. 184 (57%) men had genomic testing (Decipher or GPS), and 221 (69%) had multiparametric prostate MRI (mpMRI). At 5 and 10 years, upgrade rate was 34% and 67%, increase in core positivity >50% was 16% and 19%, disease progression 44% and 76%, active treatment 45% and 65%, and metastasis 0.9% and 3.4%, respectively. No PCSM events were recorded. Initial core positivity and PSA density were associated with volume increase >50%, and PSA density (≥0.15) and positive mpMRI (PIRADS 4–5 vs 1–3) were significantly associated with disease progression and active treatment (Table 1). Genomic testing was not significantly associated with outcomes. Conclusions: Men with confirmed GG2 PCa on AS have moderate rates of progression requiring treatment at 10 years, but low metastasis and mortality rates suggest safety in well-selected patients. Positive mpMRI and increased PSA density may help tailor AS intensity. Multivariable Cox proportional hazards regression models for risk factors for progression and active treatment in 319 patients with GG2 prostate cancer. Disease progression (≥GG3 or increased core positivity >50%) Progression to Active treatment Parameter HR (95% CI) p-value HR (95% CI) p-value Year of diagnosis (per year) 1.03 (0.98-1.19) 0.24 1.03 (0.98-1.08) 0.26 Age at diagnosis (per 10 years) 1.09 (0.86-1.39) 0.47 0.96 (0.80-1.16) 0.70 Percent Positive Biopsy Cores (log-adjusted) 1.22 (0.90-1.67) 0.20 1.22 (0.94-1.58) 0.14 PSA density (≥0.15 vs <0.15) 2.08 (1.41-3.06) 0.03 1.47 (1.07-2.01) 0.02 Positive MRI (PIRADS 4-5 vs 1-3) 2.17 (1.16-4.06) 0.02 2.03 (1.22-3.38) 0.01 Genomic testing (GPS or Decipher, High vs Low) 0.70 (0.35-1.39) 0.32 0.98 (0.58-1.64) 0.93

Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, 2026.3.0

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases, or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more . PURPOSE To provide evidence-based recommendations for patients with stage IV non–small cell lung cancer (NSCLC) without driver alterations. METHODS This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials (RCTs), with the latest time frame spanning March-October 2025. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts was convened. The literature search included systematic reviews, meta-analyses, and RCTs. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Six new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients without driver alterations. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

A Smart‐Perception Rare Earth MOF

ABSTRACT Smart responsive luminescent materials have attracted considerable scientific and technological interest owing to their broad optoelectronic applications. However, issues such as single responsive mode, inadequate spectral coverage, and poor environmental adaptability still hinder their diversified development. Herein, we propose the concept of smart multi‐stimuli responsive scintillator (SMRS) and fabricate a new series of rare earth metal–organic frameworks (RE‐MOFs) with active and passive perception capabilities. Such RE‐MOFs exhibit excellent scintillation performances, including high relative light yield (max ∼ 42,200 photons MeV −1 ), low dose rate detection limit (min ∼ 128.2 nGy air s −1 ), and great photostability. Systematic modulation of RE 3+ contents endows MOFs with tunable broadband luminescence, thereby ensuring the passive perception. The distinct photo‐ and radio‐luminescent mechanisms lead to significant spectral contrasts under UV and X‐ray irradiation. Furthermore, RE‐MOFs demonstrate thermal‐stimuli responsive luminescent variation since heat will influence the energy transfer processing among the organic and inorganic units. As a result, RE‐MOFs autonomously produce active luminescent perception toward both irradiation and thermal stimuli. These SMRSs exhibit great potential in in situ optical imaging and high‐security photonic barcodes (the widest spectral range among MOFs for photonic encoding). This study establishes a new paradigm for smart MOF‐based scintillators for an advanced intelligent perception system.

Loss of ATM causes R-loop–associated transcriptional dysregulation and attenuates the related response to DNA damage

Novel androgen receptor inhibitors for the treatment of metastatic castration-sensitive prostate cancer: A cost-effectiveness analysis.

196 Background: Management of metastatic castration-sensitive prostate cancer (mCSPC) continues to evolve. Pivotal trials of androgen deprivation therapy (ADT) intensification with androgen receptor pathway inhibitors established this approach as the preferred first-line treatment for mCSPC, showing meaningful survival benefits; however, unmet clinical needs and financial burden remain. Given high treatment costs and the importance of preferred formulary placement for payer coverage, conducting economic evaluations has become more relevant. We analyzed the cost-effectiveness of darolutamide plus ADT (DAR+ADT) compared with enzalutamide plus ADT (ENZ+ADT) and apalutamide plus ADT (APA+ADT) in progression-free mCSPC. Methods: We developed a partitioned survival model from a U.S. payer perspective over a lifetime horizon with monthly cycles and three health states: mCSPC; metastatic castration-resistant prostate cancer; and death. Patients entered in mCSPC, with transitions determined by progression-free survival and overall survival rates; in the absence of head-to-head trials, clinical outcomes were derived from a network meta-analysis. Parameters included direct costs (2025 USD) and quality-adjusted life years (QALYs) discounted at 3% annually. Outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefits (NMBs) at a $150,000/QALY willingness-to-pay (WTP) threshold. Red Book informed drug prices (acquisition, administration), while published literature provided costs for grade ≥3 adverse event management and end-of-life care. Results: Lifetime costs ranged from $1,042,666 (ENZ+ADT) to $1,059,522 (APA+ADT), while QALYs ranged from 3.990 (APA+ADT) to 4.182 (DAR+ADT). Compared with ENZ+ADT, DAR+ADT generated 0.148 additional QALYs at $12,564 higher costs per patient, resulting in an ICER of $85,108/QALY. DAR+ADT dominated APA + ADT, providing 0.192 QALYs with $4,293 in cost savings per patient. Conclusions: DAR+ADT is a cost-effective first-line therapy for patients with mCSPC from a U.S. payer perspective. Its favorable tolerability and lower adverse event burden reduce downstream costs and improve quality-of-life. Providing seamless open access to DAR expands availability to an evidence-based therapy that can provide favorable patient outcomes at lower overall costs, supporting formulary alignment with clinical value and economic efficiency. This supports providers in selecting optimal regimens without creating affordability barriers, ultimately accelerating time to treatment milestones and reducing long-term healthcare expenditures. Lifetime cost-effectiveness results. Intervention Cost ($) Δ Cost ($) QALYs Δ QALYs ICER($/QALYs) NMB($150K WTP) DAR + ADT 1,055,229 - 4.182 - - - ENZ + ADT 1,042,666 12,564 4.035 0.148 85,108 9,579 APA + ADT 1,059,522 (4,293) 3.990 0.192 Dominant 33,153

Impact of lutetium Lu 177 vipivotide tetraxetan on prostate cancer outcomes by race.

155 Background: Lutetium Lu-177 vipivotide tetraxetan (Pluvicto) is a PSMA-targeted radioligand therapy approved for men with metastatic castration-resistant prostate cancer (mCRPC) who progressed after novel hormonal and taxane based therapy. The VISION trial showed improved overall and radiographic progression-free survival versus standard care with good tolerability. However, real-world data remain limited, particularly among underrepresented groups. Only 34 Black men were included in VISION, and the TheraP trial occurred in Australia. This study evaluates real-world outcomes and safety of patients treated with lutetium Lu 177 vipivotide tetraxetan at Ochsner Medical Center (OMC), focusing on racial differences. Methods: We conducted a retrospective, IRB-approved cohort study of patients with mCRPC treated with lutetium Lu 177 vipivotide tetraxetan at OMC after October 10, 2023, with up to one year of follow-up. Demographic and treatment data were collected from institutional databases. Descriptive statistics summarized patient characteristics. Group comparisons were performed using chi-square or Fisher’s exact tests, and relative risk estimates were calculated to assess associations. Results: Among 62 patients, 27 (43.6%) were Black or African American and 35 (56.5%) were White (Table). A ≥50% decline in prostate-specific antigen (PSA50) following Pluvicto treatment was observed in 47.8% of Black or African American patients (n=11) and 35.5% of White patients (n=11) (p=0.36). Among patients with homologous recombination repair (HRR) mutations, 33.3% achieved a PSA50 response versus 42.5% of patients without HRR mutations (p=0.72). Those previously treated with docetaxel (DTX) had lower PSA50 responses than untreated patients (40.4% vs 50.0%, p=0.72). Conclusions: Although many patients in our cohort identified as Black or African American, there was no significant difference in PSA response to lutetium Lu 177 vipivotide tetraxetan compared with White patients. Those with HRR mutations and prior DTX exposure had numerically lower PSA50 response rates, though differences were not statistically significant. These findings underscore the need for continued research on how patient characteristics and prior treatments influence lutetium Lu 177 vipivotide tetraxetan outcomes in advanced prostate cancer. Survival and safety data collection is ongoing. PSA50 Response to lutetium Lu 177 vipivotide tetraxetan treatment by race, homologous recombination repair (HRR) mutations, and prior docetaxel treatment (N=55). Totaln(%) PSA50 Response ≥50% Decline Yes n(%) PSA50 Response ≥50% Decline No n(%) p-value* Race Black 23(42.6) 11(47.8) 12(52.1) 0.3614 White 31(57.4) 11(35.5) 20(64.5) HRR Mutation Yes 9(18.4) 3(33.3) 6(66.7) 0.7199 No 40(81.6) 17(42.5) 23(57.5) Prior Docetaxel Treatment Yes 47(85.5) 19(40.4) 28(59.6) 0.7071 No 8(14.5) 4(50.0) 4(50.0) *Chi-square or Fisher’s Exact, as appropriate. Missing data: race (n=1), HRR mutation (n=6).

Primary retroperitoneal lymph node dissection for clinical stage IIA/B metastatic seminoma: A multi-centre Australian experience.

601 Background: Seminoma is highly chemo-sensitive and radio-sensitive. Contemporary guidelines describe chemotherapy and alternative radiotherapy regimens as standard treatment for clinical stage IIA/B metastatic seminoma. De-escalating strategies aim to maintain oncological safety whilst minimising treatment toxicity. Primary Retroperitoneal Lymph Node Dissection (RPLND) for retroperitoneum confined disease has emerged as an alternative to standard-of-care chemotherapy in this cohort. We present peri-operative and oncological outcomes of primary RPLND in an Australian context. Methods: Patients were identified in a prospectively maintained testicular cancer database (iTESTIS, Walter and Eliza Hall Institute, ACTRN12618000735257) who underwent primary RPLND between 2019-2025. All patients were chemotherapy-naïve with retroperitoneum confined retroperitoneal disease. RPLND were performed by two uro-oncologists in high-volume centres. Peri-operative outcomes, complication rates, recurrence free survival, pattern of relapse and adjuvant treatment were analysed. Results: A total of 20 patients were included, with a median age of 39.5 (IQR 35.5-4) and BMI of 25.1 (IQR 22.1-30.7). Median operative time, length of stay and estimated blood loss was 180 minutes (IQR 164.8-210.0), 1 night (IQR 1-2) and 75mL (IQR 50-100) respectively. One patient underwent open-RPLND after declining Robotic-Assisted RPLND (RA-RPLND). Histopathology confirmed seminoma in 18 patients and conversion to non-seminomatous germ cell tumour in 2 patients. One patient had chylous ascites requiring radiological drainage within 90-days of surgery. One patient underwent adjuvant chemotherapy for high-volume disease. After a median follow-up of 26 months (IQR 16-43), 4 patients had recurrence at 8, 9, 19 and 29 months post-operatively, with 2 in-field and 1 out-of-field recurrences, and 1 detected by rise in tumour markers only. The 2-year recurrence free survival in this cohort is 83.3%. Conclusions: Primary RPLND in clinical stage II metastatic seminoma is safe, and our outcomes are comparable with contemporary international data. Whilst further validation is required internationally, we support the integration of primary RPLND as an option in high-volume centres, to avoid toxicity and long term adverse effects associated with traditional treatments. Ongoing studies will clarify the long term oncological outcomes and further define the role of surgery in the contemporary management of metastatic seminoma.

Nanoscale Colloids Engineering for Minimizing Efficiency Loss in Scalable Perovskite Solar Cells

ABSTRACT Perovskite solar cells (PSCs) have achieved significantly high power conversion efficiencies (PCEs), approaching the performance of silicon‐based solar cells. However, scaling up PSCs while maintaining high‐efficiency remains a significant challenge. Here, we report a negligible efficiency loss in scalable PSCs by formate anions stabilized colloids. The formate anions enhance the charge density on colloidal surfaces, strengthening electrostatic repulsion and preventing particle aggregation. This significantly reduces colloidal size to around 30 nm and promotes homogeneous nucleation, allowing the scalable fabrication of high‐quality perovskite thin films from a small area to mini module size in ambient air. As a result, PSCs achieved PCEs of 24.30% (1 cm 2 ) and 24.10% (12.6 cm 2 , 5 cm  ×  5 cm mini module), with negligible efficiency loss upon scaling. To the best of our knowledge, this represents the highest efficiency reported for mini‐modules. Most importantly, the encapsulated mini module retained 95% of their initial efficiency after 1000 h of operation at maximum power point tracking in ambient air.

Dual‐Functional Optoelectronic Devices Composed of Cs ₃ Cu ₂ I ₅ /Graphene/Ge Multi‐Heterostructures Enabling Deep‐Ultraviolet Synaptic Behavior and Near‐Infrared Photodetection

ABSTRACT Multi‐functional optoelectronic devices that integrate the capacities of neuromorphic processing and photodetection are of pivotal importance for advancing optoelectronic techniques. Here, we present a dual‐functional optoelectronic device based on a multi‐heterostructure of Cs 3 Cu 2 I 5 /graphene/Ge, which realizes high‐performance deep‐ultraviolet (DUV) synaptic behavior and self‐driven near‐infrared (NIR) photodetection simultaneously. On one hand, the device leverages the photogating effect in the Cs 3 Cu 2 I 5 /graphene heterostructure to produce persistent photo‐conductivity, emulating synaptic behavior upon DUV light stimulation. Electron trapping by introducing B 4 PyMPM as capture sites significantly promotes spatial divorcement of photocarriers, guaranteeing remarkably improved synaptic characteristics. The utilizations in DUV fingerprint recognition with an accuracy of 97.8%, and optoelectronic reservoir computing with recognition accuracy reaching 100% for three 4‐bit numbers are demonstrated. On the other hand, the device utilizes the photovoltaic effect in the graphene/Ge heterostructure to generate photoresponse at zero working bias, enabling self‐driven photodetection upon NIR light illumination. The wide‐bandgap Cs 3 Cu 2 I 5 functions as an effective NIR anti‐reflection layer to induce a strong light trapping effect, giving rise to boosted photoresponse properties. The excellent photoresponse supports the device in performing single‐pixel NIR optical imaging. It is believed that this work is inspiring to the design of high‐performance multi‐functional optoelectronic devices toward integrated and intelligence applications.

Pex6 and ubiquitination regulate topological remodeling of the peroxisomal membrane protein Pex14

Membranous and cytoplasmic Nectin4 expression and outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

801 Background: Enfortumab vedotin plus pembrolizumab (EV/P) is the standard therapy for metastatic urothelial carcinoma (UC) irrespective of Nectin4 expression. The relevance of membranous (mNectin4) and cytoplasmic (cNectin4) expression remains uncertain. Methods: We retrospectively reviewed an institutional database of patients treated with first line EV/P. Specialized GU pathologists assessed Nectin4 expression by immunohistochemistry and quantified separate mNectin4 and cNectin4 H-scores. Outcomes were compared by high vs low expression (median cutoffs) using Fisher’s exact test (ORR) and Cox models (PFS, OS). Results: Nectin4 was evaluable in 143 of 232 patients. Median age was 74, 72% were male, 31% had upper tract (UTUC) primary, and 43% had UC with divergent histology. Median H-scores were 180 (IQR 100-265) for mNectin4 and 30 (IQR 0-80) for cNectin4. High mNectin4 (≥180) was associated with lower rates of divergent histology (33% vs 54%; p = 0.018), bone (22% vs 38%; p = 0.046) and lung metastases (17% vs 39%; p = 0.003), and higher rates of lymph node (LN) only disease (32% vs 13%; p = 0.009). High cNectin4 (≥30) was less frequently observed in UTUC primary (22% vs 41%; p = 0.018), ECOG 0 (22% vs 48%; p = 0.002), and LN only disease (14% vs 32%; p = 0.010). Outcomes are reported in table 1. Median follow-up was 18 months (95% CI 16-20). mNectin4 and cNectin4 were negatively correlated (spearman correlation -0.48; p < 0.001). High mNectin4 was associated with improved PFS and OS, but not ORR. High cNectin4 was associated with worse ORR, PFS and OS. Given the inverse correlation, further stratification by four combined dichotomized mNectin4/cNectin4 subgroups was conducted. Superior PFS was observed in High mNectin4/Low cNectin4 subgroup (HR 0.41 95% CI 0.22, 0.77; p = 0.006) compared to Low/Low; ORR and OS did not significantly differ between subgroups. Conclusions: High mNectin4/low cNectin4 expression was associated with improved PFS with EV/P and low cNectin4 is associated with improved ORR. Further studies are required to explore the relative contribution of membranous vs. cytoplasmic expression to predict outcomes with EV/P. N Response PFS OS ORR (95% CI) p Median, mo (95% CI) HR 95% CI p Median, mo (95% CI) HR 95% CI p Membranous (M) 0.4 Low (<180) 71 58% (45%, 70%) 6.1 (4.4, 9.4) — — 19 (14, —) — — High (≥180) 72 65% (53%, 76%) 10 (8.4, —) 0.55 0.37, 0.83 0.004 27 (26, —) 0.5 0.28, 0.87 0.014 Cytoplasmic (C) 0.016 Low (<30) 69 72% (60%, 82%) 11 (9.0, 17) — — 27 (26, —) — — High (≥30) 74 52% (40%, 64%) 6.4 (4.5, 8.8) 1.61 1.08, 2.42 0.020 20 (15, —) 1.92 1.10, 3.36 0.022 Subgroups 0.11 M Low/ C Low 19 72% (46%, 89%) 6.2 (4.5, 17) — — — (15, —) — — M Low/ C High 52 53% (39%, 67%) 5.8 (3.8, 10) 0.91 0.52, 1.61 0.7 19 (11, —) 1.44 0.63, 3.30 0.4 M High/ C Low 50 72% (57%, 83%) 12 (9.9, —) 0.41 0.22, 0.77 0.006 27 (26, —) 0.56 0.22, 1.43 0.2 M High/ C High 22 50% (31%, 69%) 6.7 (6.0, —) 0.83 0.42, 1.64 0.6 — (15, —) 0.91 0.32, 2.61 0.9

3-weekly docetaxel 75 mg/m ² vs 2-weekly docetaxel 50 mg/m ² in combination with darolutamide + ADT in patients with mHSPC: Subgroup analyses from the randomised phase 3 ARASAFE trial.

153 Background: Triple therapy with androgen deprivation therapy (ADT), darolutamide (DARO), and docetaxel (DOCE) is approved for metastatic hormone-sensitive prostate cancer (mHSPC). DARO triple therapy with DOCE 50 mg/m² Q2W is hypothesized to reduce grade 3-5 adverse events (AEs) vs standard 75 mg/m² Q3W. Methods: In this academic, randomized, open-label, multicenter phase 3 trial (NCT05676203), 250 men with mHSPC were randomized 1:1 (JUN 2023 – DEC 2024) to receive ADT, DARO, and 6 cycles of DOCE 75 mg/m 2 Q3W (3-week cycle; D75) or 50 mg/m² Q2W (4-week cycle; D50). Primary objective was to compare grade 3-5 AE rates 26 weeks after last patient first DOCE dose (LPFD) in the safety population, followed by the rate of grade 3/4 neutropenia or death from any cause (NAER) as secondary safety variable. We herein report primary endpoint data of pre-specified subgroups. Results: In the safety population, 128 patients received DOCE in the D75 arm and 121 in the D50 arm. ARASAFE met its primary endpoint (rate of grade 3-5 AEs p=0.0024; NAER p<0.00001, previously published). The benefits in favor of D50 were maintained across all subgroups and independent of extent of disease (low vs high volume), ALP levels (< vs ≥ upper limit of normal [ULN]), age (< vs ≥ median [68 years], see table), ECOG performance status at study entry (0 vs 1, see table), baseline PSA (< vs ≥ median), Gleason score at study entry (<8 vs ≥8), and presence of metastases at primary diagnosis ( de novo vs metachronous metastatic disease). The PSA response rate (PSA≤0.2 ng/ml, 26 weeks after LFPD) was higher in D75 (48.8% vs. 41.3%), the 1 year post-LPFD rate will be available at the time of presentation. Conclusions: The benefits of the D50 approach in reducing grade 3-5 AE rate and NAER (primary endpoints) were independent of patients' age and performance status, as well as of surrogate markers of tumor load. The ARASAFE approach (D50) may therefore represent a potential new standard of care for triple therapy across all mHPSC subgroups. Further follow-up is ongoing to determine its efficacy in terms of oncological outcomes. Clinical trial information: NCT05676203 (and EU CT number: 2022-502634-52-00) . Primary endpoint parameters per age and ECOG subgroups. Outcome parameter Characteristic Subgroup D75: N D75: Rate (95% CI), % D50: N D50: Rate (95% CI), % High grade (3-5) adverse events Age <68 yrs* 60 76.7 (64.0, 86.6) 61 55.7 (42.4, 68.5) ≥68 yrs* 68 80.9 (69.5, 89.4) 60 66.7 (53.3, 78.3) ECOG 0 100 77.0 (67.5, 84.8) 105 58.1 (48.1, 67.7) 1 28 85.7 (67.3, 96.0) 16 81.2 (54.4, 96.0) High grade (3-4) neutropenia or death Age <68 yrs* 60 60.0 (46.5, 72.4) 61 18.0 (9.4, 30.0) ≥68 yrs* 68 67.6 (55.2, 78.5) 60 30.0 (18.8, 43.2) ECOG 0 100 65.0 (54.8, 74.3) 105 22.9 (15.2, 32.1) 1 28 60.7 (40.6, 78.5) 16 31.2 (11.0, 58.7) *Cut-off = median age.

Blood- and urine-based ctDNA profiling and monitoring in bladder carcinoma in situ.

846 Background: Carcinoma in situ (CIS) of the bladder is a high-grade, flat urothelial carcinoma with significant risk of recurrence and progression, requiring intensive and invasive surveillance. Liquid biopsy offers a non-invasive alternative for disease detection and monitoring. This study utilizes a next-generation sequencing (NGS)-based ctDNA assay to profile somatic mutations and copy number alterations in bladder CIS patients, using both blood and urine samples for longitudinal monitoring. Methods: In this ongoing prospective study, 48 patients with CIS bladder cancer were enrolled, and paired blood and urine samples were collected prior to initiation of first-line treatment. Additionally, patients with suspected disease recurrence were encouraged to provide blood and urine samples during follow-up visits at the cancer center. The study utilizes PredicineCARE, a targeted NGS liquid biopsy assay, to detect somatic alterations in ctDNA and to enable longitudinal monitoring of molecular recurrence. Results: Of the 48 patients enrolled, baseline blood samples were collected from 46 patients, and matched urine samples were obtained from 12 out of these 46 patients. In the blood samples, the assay detected 42 somatic mutations and 37 copy number variations (CNVs). The five most frequently altered genes in blood were TP53 (17%), FGFR1 (11%), PTEN (9%), FGFR3 (7%), and POLE (7%). In the urine samples, 58 somatic mutations and 13 CNVs were identified, with the most commonly altered genes being ATM (33%), TP53 (33%), ARID1A (25%), BRCA2 (25%), and ERBB2 (25%). Tumor fraction was estimated based on the identified somatic mutations to assess molecular tumor burden. Urine samples demonstrated a higher ctDNA signal than blood, with a median tumor fraction of 4.1% versus 3.1% in positive samples (p < 0.001). In addition, follow-up blood samples were collected from five patients with suspected recurrent disease, with one of these patients also providing a urine sample at the second time point. Tumor fraction analysis revealed molecular progression in four patients, indicated by increased tumor fraction, while one patient showed a decreased tumor fraction (down to 0), suggesting a complete molecular response. The urine result from one patient also indicated molecular progression, supporting the findings observed in blood. These molecular findings were concordant with subsequent clinical diagnoses. Conclusions: This study demonstrates the feasibility of using a targeted NGS-based liquid biopsy assay to detect and monitor ctDNA in both blood and urine of patients with bladder CIS. Urine samples showed higher sensitivity than blood, and longitudinal ctDNA dynamics correlated with clinical outcomes, supporting the potential of liquid biopsy for non-invasive disease surveillance in bladder cancer.

Facet‐Selective Electrostatic Assembling of 2D MXene onto Anisotropic Single‐Crystal Metal Oxides for Enhanced Photocatalysis

ABSTRACT Designing composite photocatalytic systems with nanoscale precision is crucial. While conventional facet‐selective photo‐deposition successfully utilizes spherical co‐catalysts, the directed deposition of pre‐synthesized two‐dimensional (2D) materials onto specific facets remains extremely challenging. This work demonstrates an electrostatic assembly strategy for the precise deposition of 2D transition metal carbides (MXenes) onto anisotropic single‐crystal semiconducting metal oxides. By precisely controlling the solution pH, we modulated the surface charge of the MXenes and the distinct crystallographic facets of the metal oxides, enabling selective deposition driven by electrostatic attraction. Negatively charged Mo 4/3 C MXenes were selectively deposited on the electron‐rich (101) surface of TiO 2 at pH 3, the (100) surface of Cu 2 O exposed at pH 11, and the (010) surface of BiVO 4 at pH 1.5. The high facet selectivity was confirmed through a combination of advanced techniques, including electron microscopy, electron spectroscopy, and synchrotron‐based spectromicroscopy. This selective interfacial engineering promotes spatially separated charge carrier migration toward distinct facets, while Schottky barriers form at the MXenes/oxides interfaces. The MXenes act as efficient reduction co‐catalysts, facilitating the rapid consumption of electrons, thereby enhancing photocatalytic hydrogen evolution. This work establishes a generalizable, non‐photolytic method for integrating challenging 2D co‐catalysts with facet‐engineered semiconductors for designing composite photocatalysts.

CEP55 promotes prostate cancer progression via TPX2-dependent activation of AURKA–PI3K–AKT signaling and inhibition of ferroptosis

Metaproteomics based subtypes in muscle invasive bladder carcinoma and association with survival.

812 Background: Muscle-invasive bladder carcinoma (MIBC) is associated with high recurrence and mortality rates, and current neoadjuvant chemotherapy (NACT) regimens offer limited efficacy and considerable toxicity. These limitations underscore the need for reliable biomarkers to improve treatment management and patient outcomes. Metaproteomics profiling allows for the simultaneous characterisation of human and microbial proteins within tumors, offering a new perspective on patient-microbiota interactions in cancer. Our group has identified three microbiota-related metaproteomics clusters (Microbiota1-3) associated with response to NACT in MIBC. Our objective is to evaluate the prognostic relevance in terms of disease-free survival (DFS) of these microbiota-related metaproteomics clusters. Methods: Fifty-eight FFPE transurethral resection (TURBT) samples from patients diagnosed with MIBC were analyzed using data-independent acquisition (DIA) mass spectrometry. Protein identification was performed against a custom database including the human proteome and bacterial proteomes from bacteria genera identified by 16S rRNA gene sequencing in the same samples. After quality control, bacterial and human proteins were analyzed using Perseus software and probabilistic graphical models (PGMs) to identify functional relationships. Patients were classified into three metaproteomic clusters (Microbiota1-3) according to their tumor microbiota protein profiles by hierarchical clustering. Disease-free survival (DFS) was estimated by the Kaplan-Meier method and compared among clusters using the log-rank (Mantel-Cox) test. Results: Kaplan-Meier analysis revealed significant differences in DFS between the three defined metaproteomics subtypes (Microbiota1-3) (p=0.01). Patients classified as Microbiota3 had the most favorable DFS and a lower proportion of relapse events, with median DFS not reached during the follow-up period. This group was previously associated with a higher proportion of responders to NACT, consistent with the favorable DFS observed. In contrast, Microbiota2 was associated with earlier relapse and shorter DFS (median DFS: 23 months), in line with its higher proportion of non-responders to NACT. Conclusions: To our knowledge, this is the first metaproteomics study focused in biomarker discovery using FFPE samples from bladder carcinoma patients. Distinct MIBC metaproteomics profiles are associated with differential DFS following NACT. The identification of these three microbiota-related proteomics clusters highlights the potential prognostic relevance of the tumor-associated microbiota. These findings support metaproteomics as a promising approach for refining patient stratification and guiding future biomarker-driven strategies in bladder cancer.

Neoadjuvant chemotherapy of node-positive M0 urothelial bladder cancer.

684 Background: Patients (pts) with muscle-invasive bladder cancer (MIBC) who are initially candidates for radical cystectomy (RC) benefit from the neoadjuvant chemotherapy (NACT) if they receive a multi-agent regimen containing cisplatin. Most clinical trials that established role of NACT excluded pts with suspicious or positive regional lymph nodes (cN1-N3; cN+), which were then considered stage IV, now corresponding to stage III in the TNM 8 th ed. classification. Current guidelines largely extrapolate existing therapeutic strategies for patients with cN+ disease, although persistent ypN+ disease after NACT followed by RC shows high relapse rates with limited survival outcomes. The study aims to analyze combined radical treatment in cN+ pts and a role of NACT regimen: gemcitabine and cisplatin (GC) vs dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in real medical practice. Methods: Pts with MIBC stage ≥T2 who underwent NACT ddMVAC or GC from 11/2016 to 05/2025 were included in the study. Pts from clinical trials and treated with other NACT regimens were excluded. Complete clinical data were collected from 7 polish cancer centers. Retrospective survival analysis was performed using the Kaplan-Meier method, and log-rank, chi-square, or Fisher's tests were used to compare groups. Data cut-off was 14/10/2025. Results: Of the 330 pts treated with at least one cycle of NACT, 293 were included in the analysis: 132 (45%) received ddMVAC, 161 (55%) received GC; 76 (26%) were women. The number of cN+ pts at baseline was 71 (24%). A total of 247 (84%) pts underwent RC. A statistically significant difference in overall survival (OS) and disease free survival (DFS) favoring ddMVAC in whole study cohort was demonstrated, HR, 0.58; 95% CI, 0.40–0.84; p = 0.0034 and HR, 0.57; 95% CI, 0.40–0.80; p = 0.0014, respectively. cN+ patients had a non-significantly worse OS (HR, 0.69; 95% CI, 0.46–1.02; p = 0.0758) and a statistically significant worse DFS (HR, 0.60; 95% CI, 0.42–0.88; p = 0.0144). There was no difference in OS between ddMVAC cN+ and ddMVAC cN- (p = 0.8726), but a statistically significant longer OS was observed for ddMVAC cN+ vs GC cN+ (HR, 0.19; 95% CI, 0.05–0.76; p = 0.0127). The number of pts with cN+ at baseline who achieved ypN0 (downstaging) after RC was 40 (16%) and 25 (10%) of pts with initially cN0 who were found to have ypN+ (upstaging). GC group had poorer performance status, more comorbidities, and lower baseline GFR that may have affected survival outcomes. Conclusions: The use of NACT with the ddMVAC regimen in patients with MIBC showed a statistically significant prolongation of OS compared to GC. This superiority seems to be confirmed in the cN+ subgroup, which may indicate a higher activity of the ddMVAC in a population with a potentially worse prognosis. Further studies comparing the efficacy of standard NACT and novel perioperative regimens need to be conducted.

Micro-ultrasound compared with MRI-targeted biopsy in detecting clinically significant prostate cancer: Systematic review and meta-analysis.

318 Background: Prostate cancer is highly prevalent, and diagnostic pathways must maximize detection of clinically significant disease (csPCa) while minimizing overdiagnosis and resource burden. Micro-ultrasound (microUS) offers real-time, high-resolution lesion targeting and could reduce reliance on pre-biopsy MRI. We compared csPCa detection and diagnostic accuracy between microUS-targeted biopsy (microUS-TBx) and MRI-targeted biopsy (MRI-TBx). Methods: Systematic searches of MEDLINE (PubMed), Embase, and ClinicalTrials.gov were completed on July 4, 2025 and updated Aug 5, 2025. Eligible studies directly compared microUS-TBx with MRI-TBx in adults undergoing prostate biopsy and reported csPCa (typically ISUP ≥2). Primary endpoint: per-patient csPCa detection. Secondary endpoints: sensitivity and specificity for csPCa. Random-effects meta-analysis (Hartung-Knapp) estimated detection ratios (microUS/MRI); heterogeneity was summarized with I². Diagnostic accuracy was synthesized using a bivariate random-effects model. Prespecified analyses included biopsy-naïve status, use of concomitant systematic cores, and risk of bias (QUADAS-2). PROSPERO registration pending at submission. Results: Twenty-two studies (including one randomized trial) were included. Micro-US-TBx detected 2,194 csPCa cases; MRI-TBx detected 2,237. The pooled detection ratio (Micro-US vs MRI) was 0.99 (95% CI, 0.88–1.11; I² = 78.5%), indicating comparable yield. Pooled sensitivity/specificity were 0.86/0.38 for Micro-US-TBx and 0.84/0.40 for MRI-TBx. Heterogeneous biopsy triggers (e.g., PI-RADS ≥3 only vs biopsy-all) and frequent use of concomitant systematic biopsy introduced spectrum and partial verification/incorporation biases, which may shift detection rates, limit generalizability to routine care, and obscure standalone modality accuracy. Conclusions: Micro-US-TBx demonstrated csPCa detection and diagnostic accuracy comparable to MRI-TBx. Given potential advantages in access and cost, MicroUS is a viable alternative for integration into prostate cancer diagnostic pathways, particularly in resource-limited settings.