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Durable outcomes in aggressive-variant prostate cancer treated with first-line carboplatin–docetaxel: A 10-year tertiary centre experience.
93 Background: Aggressive-variant prostate cancer (AVPC) is a rare but clinically significant subset of prostate cancer, often emerging after hormone therapy. There is no accepted first-line regimen for AVPC but often responds to platinum-based therapy. Carboplatin-docetaxel (CARBO-DOCE) is a recognised option with promising phase 2 results, but long-term outcomes are poorly defined. Methods: We retrospectively identified patients treated with both de-novo hormone-naïve (DN-AVPC) and treatment-emergent castrate-resistant AVPC (CR-AVPC) who received first-line CARBO-DOCE between 2015 and 2025. AVPC was defined with Aparicio et al’s (2013) criteria. Overall (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and univariate Cox regression. Due to presence of PSA non-secretors, biochemical response (BR50) was defined as a 50% reduction in PSA, CEA, and/or LDH. Results: 36 patients with AVPC were identified (23 CR-AVPC; 13 DN-AVPC). Baseline age (73 vs 74 years; p =0.7) and PSA (1.77 vs 9.72ng/mL; p =0.4) were similar in both groups. 36.3% and 22.2% had a performance status (PS) of 2 and 3 respectively. CR-AVPC was associated with higher rates of liver metastases (57% vs 15%; p =0.016 ) and anaemia (Hb 104 vs 131g/L, p =0.005 ). 34.8% of CR-AVPC patients had ≥2 prior therapy lines including AR pathway inhibitor (ARPI) (30.4%) and docetaxel (17.4%). Compared with DN-AVPC, CR-AVPC had shorter median OS (8.7 vs N.R months; p <0.001) and PFS (5.0 vs 15.5 months; p =0.001). Of the biomarker secretors in CR-AVPC (n=17/23) and DN-AVPC (n=8/13), BR50 occurred in 64.7% and 75.0% respectively. In non-secretors, overall response rate was 50% and 75% respectively. Univariate analysis showed only baseline Hb and albumin to be prognostic for OS in CR-AVPC. PS 2-3 did not correlate with inferior OS (HR 1.93; 95%CI 0.82-4.54) and PFS (HR 1.57; 95%CI 0.74-3.34). Median number of cycles were 4. Dose reductions occurred in 27.8% cases. 77.8% had grade ≥3 adverse events; commonly neutropenia (44.4%), anaemia (30.6%), and fatigue (13.9%). One death occurred from neutropenic sepsis. Of those who progressed, 50% and 88.9% received second-line treatment. In the CR-AVPC group, BR50 occurred with epirubicin-carboplatin-capecitabine (n=3/3) and cisplatin-etoposide (cis-etop) (n=2/2). Post-second line, there was no response to cis-etop (n=2/2), ARPI (n=2/2), or Lu-177 (n=1/1). BR50 occurred with diethylstilbestrol-dexamethasone (DAS) in second- and third-line (n=2/2). Conclusions: CARBO-DOCE achieves respectable response as first-line regimen for AVPC. DN-AVPC had higher chemosensitivity, suggesting biological differences. Platinum-rechallenge with other combinations achieved high response rates. Intriguingly, two CR-AVPC cases responded to DAS but not ARPIs, suggesting some sensitivity to oestrogen-based therapy in this heterogenous group.
Sequential flotufolastat-F18 PSMA-PET scans to enhance detection of prostate cancer in patients with early PSA recurrence following radical prostatectomy.
25 Background: Flotufolastat-F18 is a novel radio hybrid PSMA PET imaging agent that is FDA approved for imaging in men with prostate cancer (PCa) who are candidates for initial definitive local therapy or suspected recurrence based on elevated PSA following local therapy. Given the potential of low urinary excretion to improve the interpretability and sensitivity of flotufolastat-F18 and the suboptimal sensitivity of PSMA-PET imaging at lower PSA <0.5, we hypothesized that the detection rate may be enhanced by using serial flotufolastat-F18 scans in post-radical prostatectomy (RP) patients (pts) with early PSA recurrence. Methods: A single-center prospective trial evaluating flotufolastat-F18 PET imaging was designed at AdventHealth including pts who displayed a post-RP PSA ≥ 0.1 ng/ml and <0.5 ng/ml. Those who exhibited a lesion defined as definite PSMA uptake >background blood pool on the initial scan proceeded to treatment. If the initial scan did not detect a lesion, pts were monitored off-therapy and offered a second 18F-flotufolastat-scan following the first subsequent PSA increase by ≥0.1 ng/ml. Other imaging, biopsy and therapy was per investigator discretion. The primary objective was PSMA+ lesion detection rate for those who underwent protocol-planned sequential double-scanning strategy and for those who underwent a single scan. The target accrual was 30 pts who underwent at least 1 scan. Results: 30 pts have been enrolled who underwent ≥1 flotufolastat-F18 PET scans. The median (range) age was 64 years (43-83), PSA at study entry was 0.21 (0.10-0.49) ng/ml and the PSA before second scan among evaluable patients was 0.37 (0.22-0.58) ng/ml. The first PET scan detected a PSMA+ lesion in 8 of 30 pts (26.7%). Of the remaining 22 patients with negative initial scans, 3 patients decided to start therapy without undergoing the second scan, 13 have undergone the second scan, of whom 6 exhibited a lesion (46.1%), and remaining 6 are undergoing PSA monitoring to trigger the second scan. Overall, a PSMA+ lesion was detected in 14 of 21 (66.7%) evaluable patients who underwent the protocol-planned sequential double-scan strategy. Of the 14 pts with a PSMA+ lesion with the double--flotufolastat-F18 scan strategy on trial, 5 pts (3 with PSMA+ lesion on first scan) with median PSA= 0.22 ng/ml had undergone a prior off-trial PSMA-PET scan using a different tracer and 4 of these had not revealed a lesion (1 other pt showed a possible lesion). Conclusions: In post-RP patients with early PSA recurrence ≥0.1 to <0.5 ng/ml, the PSMA+ lesion detection rate may be enhanced by employing a strategy of sequential double flotufolastat-F18 PSMA-PET imaging, which uses a tracer with low urinary excretion. Updates with further follow-up will be presented. Validation of these data in larger studies is warranted given the impact on informing potentially curative radiation therapy.
Comparison of prostate-specific antigen kinetics between androgen receptor signaling inhibitor doublet therapy and androgen receptor signaling inhibitor with docetaxel triplet therapy in patients with metastatic castration-sensitive prostate cancer.
159 Background: Doublet therapy consisting of androgen deprivation therapy (ADT) plus an androgen receptor signaling inhibitor (ARSI), or triplet therapy of ADT with docetaxel and ARSI, are recommended treatment options for metastatic castration-sensitive prostate cancer (mCSPC). However, real-world comparative data between these regimens are limited. This study aimed to compare prostate-specific antigen (PSA) kinetics between doublet and triplet therapy in patients with mCSPC. Methods: We retrospectively analyzed systemic treatment–naïve patients with mCSPC treated in Japan between 2018 and 2024 using a multi-institutional database. Patients received either doublet (ADT + ARSI) or triplet (ADT + docetaxel + ARSI) therapy. PSA nadir (≤0.02 ng/mL) and PSA response rates (≥90% and ≥99% decline from baseline at 3 months) were evaluated. Propensity score matching (2:1 ratio) was applied to adjust for baseline characteristics including age, disease volume, and visceral metastasis. Results: After matching 768 patients, 188 were included in the doublet and 94 in the triplet group. At 12 months, the proportion achieving PSA ≤ 0.02 ng/mL was significantly higher in the triplet group (p < 0.05), particularly in those with high-volume disease. PSA response ≥ 99% at 3 months was comparable between groups (p = 0.08). In contrast, triplet therapy showed favorable PSA kinetics in low-volume disease (p < 0.05). Grade ≥ 3 treatment-related adverse events occurred more frequently with triplet therapy. Conclusions: Triplet therapy demonstrated deeper PSA declines in selected subgroups but was associated with higher toxicity. Treatment selection should consider disease volume, comorbidities, and patient tolerability. Clinical trial information: R04-250 .
An Enthalpy‐Entropy Compensated Ionogel With a Broadband Viscoelastic Plateau for Non‐Invasive and High‐Fidelity Neurointerfaces
ABSTRACT Achieving non‐invasive and high‐fidelity electrophysiological recording, particularly electroencephalography (EEG), on dynamic and irregular human skin remains a central challenge in soft bioelectronics, as materials rarely reconcile liquid‐like adaptability with solid‐like stability. Here, we overcome this limitation by designing a viscoelastic ionogel governed by a dynamic enthalpy‐entropy balance. Salt‐bridge hydrogen bonds form a low‐entropy and high‐interaction network, intrinsically limiting the capacity for entropic energy storage. This network then self‐organizes with a soft phase into a bicontinuous nanostructure. Acting as a mechanical parallel circuit, this architecture introduces a broad molecular relaxation spectrum, providing broadband enthalpic dissipation and realizing broadband enthalpy‐entropy compensation. Consequently, the ionogel exhibits a frequency‐independent viscoelastic plateau (G′≈G′′) spanning over nine orders of magnitude in frequency (10 −4 to 10 5 Hz) and a wide temperature range (−30°C to 40°C). The ionogel reduces skin‐electrode impedance by more than an order of magnitude compared to commercial electrodes and maintains high‐fidelity electrophysiological recordings during 72‐h continuous wear. Integrated with a deep learning framework, it enables high‐precision decoding of EEG signals, achieving 95% accuracy in classifying eight distinct emotional states. This work establishes a generalizable thermodynamic design principle for soft bioelectronic interfaces, offering broad potential for neural diagnostics, emotional monitoring, and wearable neuroprosthetics.
Dual‐Window Broadband Near‐Infrared Mechanoluminescence in MgO‐Based Phosphors
ABSTRACT Near‐infrared (NIR) mechanoluminescence (ML) offers a self‐powered and non‐invasive route for stress visualization and biomechanical imaging, yet most NIR ML materials remain constrained by narrow emission bandwidths and reliance on dark‐field conditions. Here, we report two complementary MgO‐based ML systems spanning the NIR‐I and NIR‐II windows, establishing MgO as a robust platform for broadband mechanoresponsive emission. MgO:Cr 3+ delivers tunable NIR‐I ML (700–1000 nm; full width at half maximum, FWHM, 94–188 nm) under diverse mechanical stimuli, including friction, impact, tension, compression, bending, and twisting, while MgO:Ni 2+ produces ultrabroadband NIR‐II ML (1000–1700 nm; FWHM 225 nm) readily detectable under ambient lighting. Mechanistic studies reveal that ML arises from the synergistic interplay of local piezoelectric polarization, dislocation‐mediated charge separation, and triboelectric effects at organic–inorganic interfaces, whereas the observed spectral variations stem from crystal‐field modulation and lattice distortions. Co‐doping of Cr 3+ and Ni 2+ further differentiates optical and mechanical excitation pathways—optical excitation induces Cr 3+ ‐sensitized Ni 2+ emission, whereas mechanical excitation directly activates their low‐lying levels. These insights unify mechano‐to‐photon conversion in centrosymmetric oxides and provide design principles for broadband, durable, and environmentally adaptive ML materials, advancing applications in multimodal sensing, structural health monitoring, and noninvasive biomechanical imaging.
Antagonist nanobodies prevent protease inhibition by CD109
Multiomics approach for patient stratification and novel target identification in metastatic clear cell renal carcinoma (MeetUro 31): Preliminary analysis of radiomics features—A Meet-URO and AIRC study (NCT05782400).
425 Background: Artificial Intelligence can integrate clinic-pathological features, radiomics, genomic and transcriptomic analysis to define an optimal allocation strategy in first line treatment of metastatic renal cell carcinoma (mRCC). Methods: This is a multicenter Italian prospective translational study including patients (pts) with clear cell mRCC receiving first-line treatment as per investigator’s choice. Tumor tissue was collected at baseline, plasma samples and CT scan were collected at baseline and every 3 months until progression. Due to the short follow up, here we report the preliminary analysis of the radiomic features to identify signatures associated with Objective Response Rate (ORR). A subset of non-analytically correlated radiomic features was extracted from the selected regions of interest. This subset included first-order statistics, three-dimensional shape descriptors, and texture-based features. All features were computed on the original images using PyRadiomics v.3.1.0. The radiomic analysis pipeline consisted of feature variance filtering, multicollinearity reduction, data harmonization and standardization, and feature importance estimation through a Random Forest-based algorithm. Results: 100 pts were enrolled. For the radiomic analysis, 68 patients were included to ensure a more reliable data harmonization process and to improve the robustness of subsequent analyses. 18 (26%) received IO-IO, 38 (56%) received IO-TKI, 12 (18) received TKI monotherapy as first line treatment. According to IMDC score, 16(24%) were good risk, 39(57%) intermediate and 13(19%) poor. The most common site of metastasis were lung (55%, 38), bone (23%,16), nodes (20%, 14/68) and liver (13%, 9). In the overall population, ORR was 48% (33), 44% (18) in the IO-TKI group, 44% (8) in the IO-IO group and 42% (5) in the TKI group. The two most influential features identified by the Random Forest model were original_firstorder_Mean and original_glcm_Contrast (0.59 accuracy, 0.58 precision, 0.58 recall, 0.58 F1 score, 0.49 AUROC). Higher values of these features—reflecting increased tissue density and heterogeneity—were associated with a higher ORR. Conclusions: This preliminary analysis suggests that 2 radiomic signatures are associated with higher ORR and are promising as early biomarkers of response in mRCC. However, they do not appear to provide optimal predictive value when used alone, and should therefore be integrated with clinical, genomic, and transcriptomic data to refine predictive modeling. Acknowledgments: We thank AIRC (Associazione Italiana Ricerca sul Cancro) for the support received to conduct this trial. Clinical trial information: NCT05782400 .
Clinical significance of baseline serum IgG in metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy.
564 Background: This study aimed to explore the association between preoperative serum immunoglobulin G (IgG) levels and inflammation- and coagulation-related markers, including fibrinogen (FIB), C-reactive protein (CRP), and the neutrophil-to-lymphocyte ratio (NLR), in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy. The study further sought to clarify whether humoral immune activation driven by B cells is involved in the inflammatory and coagulation response in RCC, and to determine whether baseline IgG levels may serve as potential biomarkers for therapeutic efficacy and prognosis. Methods: A total of 64 patients with mRCC who underwent cytoreductive nephrectomy and received first-line targeted and immune therapy between January 2019 and September 2025 were retrospectively enrolled. Clinical characteristics and baseline peripheral serum levels of IgG, FIB, CRP, and NLR were collected. The associations between serum IgG and FIB, CRP, and NLR were evaluated using the Wilcoxon rank-sum test and Pearson correlation analysis. Kaplan–Meier survival analysis and Cox proportional hazards regression models were used to assess the relationships between baseline IgG levels and progression-free survival (PFS) as well as overall survival (OS). Results: Patients were divided into two groups according to whether serum IgG exceeded the upper limit of the normal range (8.6–17.4 g/L). The Wilcoxon rank-sum test showed that serum IgG levels were significantly associated with CRP, FIB, and NLR (all P < 0.005). Pearson correlation analysis demonstrated moderate positive correlations between IgG and both FIB (r = 0.525) and CRP (r = 0.428). Kaplan–Meier analysis revealed that patients with elevated IgG had significantly shorter overall survival compared to those with normal IgG levels (P = 0.013), whereas progression-free survival showed no significant difference (P = 0.69). In Cox regression analysis, elevated IgG was significantly associated with worse overall survival (HR = 5.53, 95% CI: 1.22–25.05, P = 0.026), but not with PFS (HR = 1.22, 95% CI: 0.47–3.17, P = 0.69). Conclusions: Elevated baseline serum IgG levels in mRCC patients indicate a pronounced humoral immune response that is closely linked to systemic inflammation and coagulation activation. Increased IgG is significantly associated with inferior overall survival, suggesting that serum IgG may serve as a potential prognostic and predictive biomarker for treatment outcomes in mRCC.
Clinical and genomic predictors of sipuleucel-T (sip-T) outcomes in men with metastatic castration-resistant prostate cancer (mCRPC).
228 Background: Survival outcomes with sip-T in mCRPC are variable, and mechanisms driving these differences remain unknown. Tumor genomics influencing immune response may explain outcome heterogeneity, with immunogenic features (e.g. CDK12 mutation [mut]) potentially conferring benefit, while immune-evasive alterations (e.g. MYC, PTEN, AR amplification) may predict poorer outcomes. Identifying clinical and genomic correlates of differential outcomes may enhance patient selection and optimize sip-T efficacy. Methods: This single-center retrospective study included men who received ≥1 sip-T infusion at Duke Cancer Institute (2014-2024) with tumor genomic data in the Duke Molecular Registry of Tumors. The primary endpoint was overall survival (OS), defined as time from first sip-T infusion to death from any cause. Secondary endpoints included real-world progression-free survival (PFS), time to next therapy, and PSA response. Kaplan-Meier estimates were used to calculate median time-to-event and 36-mo survival. Elastic net was used to identify and rank factors predictive of OS, which were then evaluated in a multivariable cox model. Results: Among 429 men treated with sip-T, 185 (43%) had molecular data (tumor tissue 43%, cfDNA 57%). Median age was 70 yrs (48-95); most were ECOG 0 (60%) and White (85%) or Black (14%). Frequent alterations included TP53 (48%), AR amplification (27%), PTEN loss (20%), and MYC gain (10%). Overall, median OS and PFS were 44.0 and 3.6 mos, respectively. MYC gain emerged as the strongest predictor of worsened OS. Among men with MYC gain (n=18) vs those without (n=167), median OS was 16.0 vs 44.0 mos and PFS 2.5 vs 3.9 mos. Median time to next therapy was 4.1 vs 7.4 mos, and median change in PSA post-sip-T was +111% vs +25%. At 36 mos, survival probabilities were: no detectable mutations 82%, MSS 64%, PTEN mut/loss 56%, TP53 mut/loss 51%, AR amplification 46%, MYC gain 28%, and RB1 mut/loss 25%. In multivariable analysis, longer time from diagnosis to therapy (HR 0.99, p=0.001) and higher hemoglobin (HR 0.83, p=0.013) were independently associated with improved OS, whereas ECOG PS >0 (HR 1.52, p=0.027), older age (HR 1.03, p=0.024), and MYC gain (HR 2.53, p=0.002) or AR amplification (HR 1.58, p=0.044) predicted worse OS. Conclusions: Among men with mCRPC treated with sip-T, MYC and AR gain had strong and significant independent associations with rapid post-treatment progression and poor OS. Lack of anemia, good PS, longer time since diagnosis, and no detectable genetic alterations associated with improved OS, consistent with prior studies of other mCRPC therapies. Rapid tumor proliferation and progression likely explain inferior outcomes and limited benefits, and concurrent or alternative therapies should be considered. Multicenter external validation of these findings is planned to better define the subset of men most likely to benefit from sip-T.
TulmiSTAR-01: A phase I/II dose optimization study of tulmimetostat in combination with luxdegalutamide versus standard of care (SOC) in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC).
TPS301 Background: Prostate cancer is the second leading cause of cancer death in men, and mCRPC remains difficult to treat due to acquired resistance to androgen receptor pathway inhibitors (ARPIs). Preclinical studies implicate enhancer of zeste homolog 2 (EZH2) in mediating resistance to ARPIs. Combining AR directed treatment with EZH2 inhibition could potentially overcome resistance. Tulmimetostat is an investigational, novel, oral, next-generation dual inhibitor of EZH2/EZH1. Luxdegalutamide is a proteolysis targeting chimera (PROTAC) AR degrader, demonstrated preliminary evidence of clinical activity. This phase I/II study evaluates the combination of tulmimetostat and luxdegalutamide in pts with progressive mCRPC (NCT07206056). Methods: This two-part, multicenter, open-label, global, phase I/II study will enroll ~188 male pts (≥18 years) with ECOG performance status 0-2, and life expectancy ≥6 months. Study details are described in the table below. In the phase I, pts may have received prior chemotherapy (CT) in the mCRPC setting, while in phase II, pts must be taxane-naïve (allowed in hormone-sensitive setting only). Phase I, part Ib will randomize pts to doses selected in part Ia, and pts will be stratified by prior CT. Phase II will evaluate tulmimetostat at the RP2D plus luxdegalutamide at 100 mg or 300 mg QD vs SOC. The time-to-event efficacy endpoints will be analyzed using Kaplan–Meier estimates. Dose escalation will be guided by Bayesian logistic regression model with overdose control. Clinical trial information: NCT07206056 . Phase Parts Treatment R N Objectives I Ia: Parallel dose escalation Tulmimetostat QD + luxdegalutamide (100 or 300 mg) - Primary: RDE, safety, tolerability Secondary: PK Ib: Dose expansion and optimization Tulmimetostat (RDE(s) from Part 1a) QD + luxdegalutamide (100 or 300 mg QD) 1:1 88 Primary: Safety, tolerability, RP2D, PSA50 at 6 mo at the RDEs Secondary: PK, rPFS, OS, OR, BOR, DOR, TTSSE II Tulmimetostat RP2D QD + luxdegalutamide (100 or 300 mg QD) vs SOC* (control arm) 1:1 100 Primary: PSA50 at 6 mo Secondary: Safety, tolerability, PK, PSA50 at 3, 9 and 12 mo, rPFS, OS, ORR, BOR, DOR, TTSSE *Choice of ARPI, chemotherapy or lutetium ( 177 Lu) vipivotide tetraxetan. BOR, best overall response; mo, months; DOR, duration of response; QD, once a daily; ORR, objective radiographic response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; R, randomization; RP2D, recommended phase II dose; SOC, standard of care; TTSSE, time to first symptomatic skeletal event.
Complex‐Concentrated Anion Doping Enables Ultra‐Stable Lattice Oxygen and Structural Integrity in Lithium‐Rich Layered Oxide Cathodes
ABSTRACT Lithium‐ and manganese‐rich layered oxides (LMR) stand out as next‐generation lithium‐ion cathode chemistries, which harness both transition‐metal and lattice‐oxygen redox processes to deliver exceptional capacity and energy density. However, their full potential is hindered by intrinsic oxygen instability and structural degradation, resulting in pronounced voltage fade and capacity decay. Here, we present a complex‐concentrated anion‐doping paradigm in which multiple anions, F, Br, and S, are incorporated into the oxygen sublattice to enhance oxygen‐redox and structural stability. X‐ray absorption spectroscopy and aberration‐corrected scanning transmission electron microscopy confirm ultra‐stable local oxygen coordination environments during long‐term cycling, with detrimental phase transformations and oxygen‐loss‐induced cavitation dramatically inhibited. Notably, we show that the characteristic LiTM 6 transition metal (TM) honeycomb ordering is preserved even after electrochemical cycling. Concurrently, this strategy yields an unprecedented volume change of only 0.63% upon charging to 4.8 V vs. Li + /Li, achieving the first zero‐strain LMR cathode. The resulting LMR cathode delivers ultralow voltage fade (1 mV per cycle during the first 100 cycles and becomes negligible in subsequent cycles) and outstanding energy retention (93% after 200 cycles) in a pouch cell configuration. Our complex‐concentrated anion‐doping concept establishes a broadly applicable strategy for resolving chemo‐mechanical failure mechanisms in ceramic intercalation electrodes for next‐generation energy storage.
Modulus Engineered Substrate With Vertical Soft Interconnects for Ultra‐Stable Stretchable Multilayer Electronic Systems
ABSTRACT Stretchable multilayer electronic systems hold transformative potential for next‐generation wearable electronics, soft robotics, and human‐machine interfaces. However, the stretchability and stability are severely hindered by the interfacial mechanical and electrical mismatch of different components. Herein, by simultaneously combining modulus‐engineered substrate with vertical soft interconnects, we report a multilayer electronic system design with both high stretchability and stability. The homologous soft‐bridge and rigid‐island design effectively reduces modulus mismatch and facilitates interfacial bonding, and the raw/hybrid liquid metal‐based vertical interconnects efficiently alleviate Poisson effect thus ensuring stable mechanical and electrical connections. As a result, such engineered multilayer electronics demonstrate high stretchability (800% strain limit) and high stability (over 4000 cycles at 100% strain) that outperform the results from previously reported multilayered flexible electronic devices. A three‐layer stretchable electronic system performs well as an electronic skin on a soft robot, and a wireless battery‐integrated intelligent haptic system is also demonstrated.
Unusual and atypical cyclooxygenase reactions
A real-world US community-based evaluation of recurrence among non-muscle-invasive bladder cancer patients treated with bacillus Calmette-Guérin.
669 Background: Patients with high-risk (HR) non-muscle-invasive bladder cancer (NMIBC) are often treated with Bacillus Calmette-Guérin (BCG). This study was conducted to evaluate real-world clinical outcomes of BCG-naïve HR NMIBC patients after BCG initiation. Methods: A retrospective cohort study was conducted using the N Power Real World Data Network consisting of cancer registry data from community oncology practices in the US, validated through chart review (January 2016 - April 2025). BCG-naïve (no BCG within 2-years prior to current diagnosis) HR NMIBC (T1, high-grade Ta, and/or carcinoma in situ [CIS]) patients were included. Index date was the date of BCG initiation. Disease recurrence and progression (muscle-invasive bladder cancer [MIBC], distant metastasis) after the index date were identified. Recurrence-free survival (RFS; time from the index date to first disease recurrence or death from any cause, whichever occurred first) was estimated using Kaplan-Meier analyses among all eligible patients and age 65+ subgroup. Patients were censored at earliest date of another cancer diagnosis or last abstraction, whichever occurred first. Time to radical cystectomy (RC; time from index date to RC date) is reported. Results: A total of 1,114 BCG-naïve HR NMIBC patients (n=883 65+ years) were included; median follow-up from index of 2.9 years (median age 73 years, 79% male, 93% White, 71% Medicare insurance [88% 65+]). 55% of the patients were stage T1 +/- CIS, 35% high-grade Ta +/- CIS, and 10% CIS only at HR NMIBC diagnosis. Median time from HR NMIBC diagnosis to index was 11 weeks. Table contains real-world clinical outcomes of BCG-naïve HR NMIBC patients after index. Conclusions: These findings highlight the substantial clinical burden for BCG-treated HR NMIBC patients and the need for more effective treatments that can reduce recurrence. Real-world clinical outcomes of BCG-naïve HR NMIBC patients after BCG initiation. All HR NMIBC Patients (n= 1,114) 65+ (n= 883) Any recurrence, N (%) 351 (31.5%) 288 (32.6%) Progression, N (%) MIBC Distant metastasis 79 (7.1%)40 (3.6%) 65 (7.4%)29 (3.3%) Death, N (%) 198 (18%) 182 (21%) median RFS, years (95% CI) 4.6 (3.9-5.4) 3.9 (3.2-4.6) 5-year recurrence rate, % 47 50 RC, N (%) 67 (6.0%) 55 (6.2%) Median time to RC, months (min, max) 13 (3, 69) 13 (3, 50) RC among recurred patients, N (%) 58 (17%) 47 (16%) MIBC, muscle-invasive bladder cancer; RFS, recurrence-free survival; RC, radical cystectomy.
Homologous recombination repair (HRR) mutation in de novo metastatic hormone sensitive prostate cancer (mHSPC).
243 Background: Genomic alterations are becoming increasingly important to understand progression of disease and determine treatment in mHSPC. Homologous Recombination Repair (HRR) genes are of particular interest as they lead to decreased ability to repair DNA double-stranded breaks and can be used as a therapeutic target. We sought to understand the prognostic significance of HRR alterations in metastatic prostate cancer. Methods: In this retrospective study, we analyzed patients in the Veterans Health Administration with de novo hormone-sensitive prostate cancer from January 1 st , 2013 to December 31 st , 2022 that have undergone genomic sequencing. Veterans with HRR alterations included pathogenic alterations in BRCA1/2, CDK12, PALB2, CHEK2, and ATM. Tumor-suppressor gene (TSG) included TP53, PTEN, and RB1. Age, Charlson comorbidity index (CCI), PSA at diagnosis, first line therapy, and BMI were collected and used in multivariate models. Survival analyses were performed using the Kaplan-Meier method and Cox regression. Results: In 2027 veterans, there were 412 with HRRalt, 1040 with TSGalt, and 774 with neither. There was a decrease in median progression-free survival (PFS) from 32.4 months to 20.4 months in the HRR population (p<0.001) compared to veterans without HRR or TSG alterations. Similarly, there was a decrease in median overall survival (OS) from 70.2 months to 47.7 months in HRRalt (p<0.001). For comparison, individuals with a TSGalt had a median overall survival of 42.2 months On multivariate Cox regression analysis, HRR mutation was associated with increased risk of progression (HR 1.44, CI 1.19-1.74, p<0.001) and increased mortality (HR 1.41, CI 1.12-1.76, p=0.003), independent of first-line therapy choice, comorbidity index score, age, BMI, and PSA response. HRR mutation is also significantly associated with higher volume of disease compared to that of HRR-wild type (76.5% vs. 65.9%, p=0.007). Conclusions: HRR alterations were associated with shorter overall survival and progression-free survival in patients with metastatic hormone sensitive prostate cancer without TSG alterations. Genetic results are important for both estimating risk of adverse outcomes and predicting response to therapies.
Treatment (Rx) patterns and survival outcomes in patients with metastatic chromophobe renal cell carcinoma (mchRCC).
465 Background: Chromophobe RCC represents a rare subtype of kidney cancer, which very infrequently metastasizes. Once metastatic, prognosis is poor. Preferred Rx include clinical trial enrollment, VEGF-targeted therapies (TKI) alone or in combination with programmed cell death protein-1 (PD-1) inhibitor (NCCN Guidelines V1.2026). Given the lack of standardized treatment approach, we sought to characterize Rx patterns and survival outcomes of patients (pts) with mchRCC in a real-world setting. Methods: Using the US-based electronic health record-derived deidentified Flatiron Health Research Database, pts diagnosed with metastatic RCC with chromophobe histology and evidence of receiving approved first line (1L) Rx were eligible. Rx patterns up to 5L, real-world time to next treatment (rwTTNT), and real world overall survival (rwOS) by line (L) of therapy were analyzed. Results: Overall 155 pts with mchRCC diagnosed from 1/18/2011 to 10/31/2024 were eligible and included in the analysis. Median age was 65 years (IQR 57, 73), 101 pts (65.2%) were non-Hispanic White and 107 pts (69%) were male. TKIs were the most common 1L regimen (71; 45.8%), followed by PD-1 inhibitor + TKI (18; 11.6%), and PD-1 inhibitor + CTLA-4 inhibitor (17; 11.0%). In 2L, TKI (37; 34.3%) and single-agent PD-1 inhibitors (19; 17.6%) were the most common Rx. By 3L, Rx was more heterogeneous, with TKIs (17; 27.9%), single PD-1 inhibitor (15; 24.6%), and everolimus (7; 11.5%) representing the main Rx. Among 1L-treated pts, median OS was 30 months for TKIs, not reached for PD-1 inhibitor + TKI, and 21 months for PD-1 inhibitor + CTLA-4 inhibitor. Further characterization of Rx patterns by line of Rx and survival outcomes will be provided at the meeting. Conclusions: In this largest series of mchRCC to our knowledge, survival outcomes varied across regimens. The substantial heterogeneity in Rx patterns and outcomes underscores the lack of a clear optimal sequencing of therapies and highlights the urgent need for randomized trials to define optimal Rx sequencing in this setting.
Performance of circulating tumor DNA as a biomarker in testicular seminoma and non-seminomatous germ cell tumor patients undergoing primary retroperitoneal lymph node dissection.
589 Background: Serum tumor markers have been the cornerstone in the detection and surveillance of testicular germ cell tumors (GCT). However, the sensitivity of specificity of STM for detecting GCT is poor. Circulating tumor DNA (ctDNA) has demonstrated ability to detect GCT in both primary and post-chemotherapy retroperitoneal lymph node dissection (RPLND). Herein, we sought to determine the ability of ctDNA to predict GCT on P-RPLND by comparing patients’ RPLND histology with their ctDNA status stratified by seminoma and non-seminomatous germ cell tumor (NSGCT). Methods: Patients undergoing primary (P-RPLND) had prospectively collected plasma ctDNA. Patients were stratified to seminoma or NSGCT based on orchiectomy and STM. The association between ctDNA positivity and P-RPLND histology was assessed. Sensitivity (SN), specificity (SP), and positive (PPV) and negative predictive values (NPV) were calculated for ctDNA to detect GCT on RPLND. Results: 64 patients undergoing P-RPLND had a pre-operative ctDNA with a median age of 37 (IQR:29-42). Plasma was collected on average, 8 days pre-operatively. 27 (42.2%) patients underwent P-RPLND for seminoma and 37 (57.8%) for NSGCT. In the seminoma group, 16 and 11 patients had CS 2A and 2B disease. 24 (89%) of these patients had a (+) ctDNA. All seminoma patients had GCT present on P-RPLND. Of NSGCT patients, 10 had CS 1, 21 patients had CS 2A and 6 had CS 2B disease. 23 (62%) patients had a (+) ctDNA. 2 NSGCT patients had (+) ctDNA and negative RPLND. One of these patients developed a lung recurrence and the second had a rising ctDNA with negative surveillance imaging at 9 months. The SN, SP, PPV, and NPV in the NSGCT cohort were 88%, 85%, 91%, and 79% and in the seminoma cohort were 89%, 0%, 100%, and 0%. The 0% SP and NPV in the seminoma cohort were due to the lack of patients with negative RPLND histology. Conclusions: This is the first study evaluating test statistics of ctDNA in relation to RPLND histology, when stratified by seminoma or NSGCT. These findings suggest that ctDNA may be a useful tool in predicting retroperitoneal histology in patients being considered for P-RPLND. Persistently positive ctDNA after RPLND may be indicative of disease outside of the retroperitoneum. Contingency tables for ctDNA ability to predict GCT in patients undergoing P-RPLND, stratified by seminoma and NSGCT. All P-RPLND (N=64) Disease positive (n=51) Disease negative (n=13) Test Positive (n=47) 45 2 PPV=96% Test Negative (n=17) 6 11 NPV=65% SN=88% SP=85% NSGCT only (N=37) Test Positive (n=23) 21 2 PPV=91% Test Negative (n=14) 3 11 NPV=79% SN=88% SP=85% Seminoma only (N=27) Test Positive (n=24) 24 0 PPV=100% Test Negative (n=3) 3 0 NPV=0% SN=89% SP=0% SN: Sensitivity; SP: Specificity; PPV: positive predictive value; NPV: negative predictive value.
Separation of Hydrogen and Graphite from Natural Gas Through Nickel Atomic Lattice
ABSTRACT The sustainable use of fossil fuels requires simultaneous efficient utilization of both energy and matter. Traditional fossil fuel processes primarily harvest energy through combustion, leaving much of the matter—especially carbon—unexploited and released in the form of greenhouse gas (carbon dioxide). Here, we develop an atomic lattice separation method using a nickel foam‐nickel foil structure to simultaneously extract both energy and matter from natural gas with high efficiency. In this design, hydrogen in natural gas is catalytically converted to hydrogen gas on nickel foam, while carbon is transformed into crystalline graphite via transport through the atomic lattice of nickel foil. This approach achieved efficient (> 99% conversion), stable (≥ 300 h stability), and reusable (≥ 5 cycles) hydrogen gas generation, coupled with the production of high‐value graphite with an ultrahigh crystal quality and superior thermal and electrical properties. Further integration with a solid oxide fuel cell system demonstrated an electricity generation efficiency of ∼57%. This strategy establishes a sustainable pathway for separating energy (hydrogen) and matter (graphite) from hydrocarbons, thus providing new opportunities for high‐efficiency and zero‐emission natural gas utilization.
Artificial Symbiosis for Bulk Production of Bacterial Cellulose Composites
ABSTRACT Symbiotic relationships between micro‐organisms are key to the function of all global ecosystems. Here we extrapolate this concept for biomaterial fabrication by creating artificial symbiotic relationships between species that are usually not grown synergistically in nature. Specifically, we combine the cellulose‐producing bacterium Komagataeibacter hansenii and the green microalga Chlamydomonas reinhardtii to obtain bulk growth of bacterial cellulose. Usually, bacterial cellulose is produced as floating pellicles at the air‐liquid interface of the growing media, because free oxygen, together with the nutrients in the culture medium, is required for the bacteria to synthesize the cellulose fibers. In the co‐culture, bacterial cellulose production can be achieved in bulk beyond the spatial restriction of the air‐liquid interface as the motile microalgae with photosynthetic activities act as oxygen‐generating sites within the culture medium. In exchange, the highly porous and mechanically robust scaffold provided by the cellulose allows the algal‐bacterial community to form a bio‐composite up to several centimeters in thickness. We demonstrate that this symbiotic growth platform allows the simultaneous production of bulk bacterial cellulose in static incubation conditions, taking up an arbitrary and yet tunable 3D shape, dependent on the geometry of the culture vessel.