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Expanded access program of cretostimogene grenadenorepvec in patients with non-muscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin.

TPS902 Background: The current American Urological Association (AUA) guideline recommendation for patients diagnosed with High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (HR BCG-UR NMIBC) is radical cystectomy. However, many patients are unwilling to undergo such a morbid intervention or are unfit due to competing medical risks. Therefore, a considerable unmet medical need exists for clinically effective, well-tolerated, and readily available bladder-sparing treatment options for patients with HR BCG-UR NMIBC. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action. It selectively replicates and lyses bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations. The subsequent release of virus- and tumor- specific antigens initiate antitumor immune activation amplified by the GM-CSF transgene, a potent cytokine. Based upon preliminary efficacy and safety results from the ongoing Phase 3 BOND-003 study, cretostimogene received both Fast Track and Breakthrough Therapy Designations by the US FDA for BCG-UR NMIBC with CIS indication. The cretostimogene Expanded Access Program (EAP) ( NCT06443944 ) is an open-label, compassionate use clinical trial designed to provide cretostimogene to a diverse population of real-world patients with BCG-UR NMIBC with CIS who may not otherwise be eligible for currently enrolling clinical trials. Methods: Pragmatic real-world eligibility criteria include: age ≥18 years, ECOG performance status of 0-3, pathologically confirmed BCG-UR CIS +/- HG Ta/T1 disease after completion of adequate BCG treatment, as defined by the US FDA. Patients will receive intravesical cretostimogene in combination with n-dodecyl-β-D-maltoside (DDM), an excipient, that enhances adenoviral delivery for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 24. Re-induction is permitted. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and directed bladder biopsies as clinically indicated with local review of pathologic samples. The primary objective is to evaluate the safety of cretostimogene. The incidence of adverse events will be reported using Medical Dictionary for Regulatory Activities (MedDRA) and CTCAE v5.0. Secondary outcomes include Complete Response at any time and at 12 months, Duration of Response, high-grade Recurrence-Free Survival, Progression-Free Survival, and Radical Cystectomy-Free Survival. Exploratory outcome measures include Health-Related Quality of Life, Overall Survival, and biomarker assessments. A broad cross-section of geographically and socioeconomically diverse clinical sites have been identified. The study is open and actively recruiting. Clinical trial information: NCT06443944 .

Stacking-dependent tunable valley splitting in Janus SMoSiN2-based van der Waals heterostructure

Using the first principles calculation, we explore the modulation of valley-related properties of two-dimensional (2D) Janus SMoSiN2 monolayer by constructing van der Waals (vdW) heterostructure with the ferromagnet CrCl3 monolayer. The monolayered SMoSiN2 possesses excellent stability and direct bandgap at the K/K′ valley, making it a promising candidate for valleytronic semiconductor. The ferromagnet CrCl3 substrate induces a sizable valley splitting via proximity coupling. The valley-contrasting property of the top-stacking is significantly tunable by both in-plane sliding and vertical strain engineering, leading to extraordinary tunability of valley splitting in the range 1.6–9.4 meV. In contrast, the valley-contrasting property of the bottom-stacking is comparably robust due to the screen effect originating from the outmost N sublayer to reduce the proximity interaction. Our investigation reveals that the stacking order is a degree of freedom to manipulate the valley-related properties of various vdW heterostructures, facilitating the achievement of versatile valley-contrasting properties.

Grass pea dual purpose dry matter and seed yields in rainfed conditions across diverse environments

Modulation of enhancer of zeste homolog 2 (EZH2) pharmacodynamic markers and tumor gene expression by mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC).

146 Background: Mevrometostat (PF-06821497; M) is a potent and selective small molecule inhibitor of EZH2. Dose exploration of M in combination with enzalutamide (E) showed a manageable safety profile and promising activity in patients with mCRPC in a phase 1 study (NCT03460977). M exhibited dose-dependent pharmacokinetic (PK) exposure increases up to 1250 mg BID in combination with E (160 mg daily). We report the corresponding pharmacodynamic (PD) effects of EZH2 inhibition and tumor gene expression changes by M+E in patients with mCRPC. Methods: Serial whole blood and paired tumor biopsy samples were collected during dose escalation of M from 150 to 1250 mg BID in combination with E (160 mg QD) given on empty stomach in patients with mCRPC. Paired tumor biopsy samples were collected before the study and after 21 days of M+E or E. H3K27Me3 PD marker was evaluated in peripheral granulocytes by flow cytometry and in paired tumor biopsy samples by an immunohistochemistry assay. Tumor gene expression was profiled by whole transcriptomic RNA sequencing. Pre- and post-treatment sample gene expression levels and gene signature Gene Set Variation Analysis (GSVA) enrichment scores were analyzed by a simple linear model with transformation, if appropriate. Results: Dose-dependent H3K27Me3 PD marker reduction was observed in peripheral granulocytes and paired tumor biopsies by M+E in patients with mCRPC. Strong H3K27Me3 reduction (≥75%) in granulocytes was achieved at ≥375 mg of M+E. Tumor H3K27Me3 levels were effectively reduced from baseline in 6 patients receiving M at 1250 mg +E with a group mean change of –67% determined by H scores (95% CI: –86%, –23%; P =0.020) and –75% determined by H3K27Me3 staining (positive cells with high and medium intensity in tumor area) (95% CI: –93%, –11%; P =0.038). No significant change in tumor H3K27Me3 levels was observed in 4 patients receiving M at 500 mg +E. Consistent with strong EZH2 inhibition observed in tumor samples from patients receiving M at 1250 mg +E, M+E increased the expression of genes reported to be repressed by the PRC2/EZH2 complex (e.g., BMP7 , CPAMD8 , EYA4 , FHL1 , IGFBP3 and NOV ), and decreased expression of EZH2 and other genes involved in the E2F pathway, the G2M checkpoint, Myc responsive genes and/or cell cycle progression (e.g., AURKA , CDK1 , FOXM1 , RAD54L , TOP2A and TYMS ). Conclusions: These data indicate M at 1250 mg BID on empty stomach in combination with E effectively inhibits EZH2 in tumor tissue and may overcome drug resistance and/or enhance androgen targeting drug activity by restoring the function of tumor suppressor genes and blocking tumor cell proliferation and cell cycle progression. These data support dose recommendation for phase 3 pivotal studies and enhance understanding of mechanism of action for M+E in mCRPC. Clinical trial information: NCT03460977 .

Enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma: First results on outcomes and safety in a German multicenter real-world patient cohort (GUARDIANS).

715 Background: The prospective phase 3 study EV-302 demonstrated superiority regarding efficacy of Enfortumab vedotin plus Pembrolizumab (EVP) compared to platinum-based chemotherapy in patients (pts) that received first-line (1L) therapy for metastatic urothelial carcinoma (mUC). Since presentation of the data in September 2023 EVP was considered a new standard of care (SOC) however only approved in Europe in August 2024. We analyzed efficacy and safety outcomes of pts treated with EVP outside of clinical trials. Methods: Retrospective data were collected from 19 German academic and community hospitals for pts with metastatic UC who received EVP as off-label therapy when reimbursed by their insurance company before European Medicines Agency (EMA) approval, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Median progression-free survival (mPFS) and overall survival (mOS) were estimated using the Kaplan-Meier method by local investigators. Results: We identified 215 pts for the safety cohort (all pts who received EVP at least once) and 164 pts for the efficacy cohort (all pts who received at least one staging or died prior to first planned imaging).The median age for the eligible patients was 71 yr (range 25-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2/3-4/unknown for 46.0/31.6/17.2/4.7/0.5% of patients. The overall response rate was 60.7% (partial response 51.0%, complete response 9.7%). mOS was not reached and mPFS was 13 mo (95% confidence interval 4.5-21.5). Any-grade AEs were observed in 73.0% and CTCAE grade ≥3 AEs in 30.2%. Any-grade immune-related AEs were observed in 37.7% and CTCAE grade ≥3 AEs in 16.7%. The most common AEs were peripheral sensory neuropathy (all grade: 30.2%) and skin toxicity (all grade:24.2%). No treatment-related fatal event occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EVP in a real-world patient population showed promising effectiveness and an acceptable toxicity profile. No new safety signals were reported. Our results support the use of EVP in 1L in pts with mUC. Updated data with longer follow-up will be presented at the meeting.

Phase 1b/2 study of combination ¹⁷⁷ Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.

TPS614 Background: Complete response (CR) is a rare event in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for first-line treatment of ccRCC, demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR is only 9%. Drugs that could synergize with T cell anti-tumor activity can improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising mechanism. 177 Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9, expressed in >90% ccRCC, to deliver targeted radiation to cancer with minimal damage to surrounding healthy cells. As a single agent in metastatic ccRCC, 177 Lu-girentuximab was safe and effective in stabilizing disease in 57% of patients. We hypothesize 177 Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells and achieve higher CR rates. Methods: Up to 100 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta (0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab 1480 MBq/m 2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18 F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics, and proteomics studies. Clinical trial information: NCT05663710 .

Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate 9ER trial.

439 Background: N+C showed significant benefits vs S in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for patients (pts) with previously untreated aRCC from the phase 3 CheckMate 9ER trial ( N Engl J Med 2021; 384:829–41). We report final results for the trial with a long-term follow-up (min, >5 y), including updated efficacy in intent-to-treat (ITT) pts and by International Metastatic RCC Database Consortium (IMDC) risk, and safety. Methods: Pts with aRCC were randomized to receive first-line N 240 mg every 2 wk + C 40 mg QD or S 50 mg QD (4 wk of each 6-wk cycle) until disease progression or unacceptable toxicity (2 y N max.). The primary endpoint was PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included OS, ORR per RECIST v1.1 by BICR, and safety. Results: Median follow-up was 67.6 (range, 60.2–80.2) mo. In ITT pts (N+C, n = 323; S, n = 328), PFS favored N+C vs S (hazard ratio [HR], 0.58 [95% CI, 0.49–0.70]). Median (95% CI) PFS (mPFS) was 16.4 (12.5–19.3) vs 8.3 (7.0–9.7) mo, respectively; 60-mo PFS rates were 13.6% vs 3.6%. OS also favored N+C vs S (HR, 0.79 [95% CI, 0.65–0.96]). Median (95% CI) OS (mOS) was 46.5 (40.6–53.8) vs 35.5 (29.2–42.8) mo, respectively; 60-mo OS rates were 40.9% vs 35.4%. ORR was greater with N+C vs S (55.7% vs 27.4%; complete response [CR], 13.9% vs 4.6%). Duration of response (DOR) rates at 60 mo with N+C vs S were 22.0% vs 10.0%, respectively. Efficacy by IMDC risk groups is reported in the Table. In all treated pts (n = 320 each arm), any-grade (grade ≥ 3) treatment-related adverse events occurred in 97.5% (67.8%) vs 93.1% (55.3%) with N+C vs S. No new deaths due to study drug toxicity occurred since the last database lock. Additional subgroup analyses will be presented. Conclusions: Long-term efficacy benefit was observed with N+C over S in this final follow-up from CheckMate 9ER. There were no new safety signals. The results continue to support N+C as a standard of care for previously untreated aRCC. Clinical trial information: NCT03141177 . FAVN+C; n = 74 FAVS; n = 72 INTN+C; n = 188 INTS; n = 188 PoorN+C; n = 61 PoorS; n = 68 PFS HR (95% CI) 0.67 (0.46–0.97) - 0.63 (0.50–0.80) - 0.36 (0.23–0.56) - mPFS (95% CI), mo 21.4 (12.8–24.6) 12.8 (9.4–16.6) 16.6 (11.3–21.7) 8.5 (6.9–10.4) 9.9 (5.9–17.7) 4.2 (2.9–5.7) 60-mo PFS rate, % 15.1 3.9 12.7 4.7 15.7 0 OS HR (95% CI) 1.08 (0.70–1.66) - 0.86 (0.67–1.11) - 0.49 (0.33–0.74) - mOS (95% CI), mo 53.7 (40.8–70.7) 58.9 (46.1–NE) 47.4 (38.2–55.8) 36.2 (25.7–46.3) 34.8 (21.4–53.4) 10.5 (6.8–20.7) 60-mo OS rate, % 46.3 49.4 41.2 38.2 33.1 12.9 ORR (95% CI), % 66.2 (54.3–76.8) 43.1 (31.4–55.3) 55.9 (48.4–63.1) 27.7 (21.4–34.6) 42.6 (30.0–55.9) 10.3 (4.2–20.1) CR, % 16.2 6.9 15.4 4.8 6.6 1.5 60-mo DOR rate, % a 22.0 NE 19.0 13.0 37.0 0 FAV, IMDC favorable; INT, IMDC intermediate; NE, not estimable; poor, IMDC poor. a Based on pts with objective response.

Significant orbit-to-charge conversion in CoFeB/Pt/SrIrO3 trilayer by terahertz emission spectroscopy

Orbitronics has been extensively explored theoretically and experimentally in orbital-charge conversion. The spin-charge conversion efficiency induced by the orbital Hall effect can be much larger than that of the spin Hall effect. However, orbitronics focuses primarily on light metal elements and their oxides, while exploring heavy metal elements and oxides is rare. In this Letter, we report significant enhancements in the ultrafast spin (orbit)-charge conversion for the CoFeB/Pt/SrIrO3 (SIO) trilayer using the terahertz emission spectroscopy, where the maximum enhancement calculated by the normalized terahertz emission amplitude is about three times that for the CoFeB/Pt bilayer. In addition, we observe a ∼2 orders of magnitude enhancement in the THz emission due to significant orbital transport in Pt-insertion heavy metal layer in the CoFeB/Pt/SIO heterostructure as compared to the CoFeB/SIO bilayer. Our findings not only demonstrate that the transition metals and their oxides exhibit strong inverse orbital Hall effect but also show that multilayer structures allow enhancing the spin-to-charge current conversion efficiency for THz applications, providing a direction to tailor THz emitters.

Impact of physiological and coronary artery disease risk factors on myocardial perfusion in stress computed tomography myocardial perfusion imaging

Evaluating social vulnerability as a key determinant of definitive treatment for Black men with clinically localized prostate cancer.

323 Background: Disparities in prostate cancer (PCa) outcomes have been documented extensively across different racial and ethnic groups and various social environments, yet interventions to address these concerns remain elusive. We aim to understand how race and social vulnerability influence the likelihood of definitive treatment for men diagnosed with non-metastatic PCa treated in community urology practices. Methods: Men diagnosed with clinically localized PCa in the CaPSURE registry were geocoded, deidentified, and combined with Social Vulnerability Index (SVI) data, a census-tract measure of communities' disadvantage, based on participants’ home address at enrollment. Patients were categorized by race [Black or non-Black (White, Hispanic, Asian, Mixed, Other, Unknown)] and SVI status (high/low): Black-high SVI, Black-low SVI, non-Black-high SVI, and non-Black-low SVI. The outcome was primary treatment: definitive (RP, RT) vs non-definitive (AS/WW). Multinominal logistic regression analysis assessed the association between SVI, race, and odds of definitive treatment, adjusted for age at diagnosis, education, income, insurance, comorbidities, BMI, smoking, alcohol use, year of diagnosis, clinical site, job type, and US Census subregion. Models were run separately for low and intermediate/high clinical PCa. A p-value <0.05 was statistically significant. Results: In total, 7854 men were identified with 714 (9%) Black and 3573 (45%) residing in high SVI communities; 72% of Black men had high SVI compared to 43% of Non-Black men (p<0.01). High risk disease was more common for Black men with high SVI compared to others (20% vs 9% for Black-low SVI vs 12% Non-Black high SVI vs 11% Non-Black low SVI, p<0.01). For low-risk disease, Black men with high SVI had lowest odds of definitive treatment compared to non-Black men with low SVI (OR 0.54, 95% CI 0.32-0.90); odds for other groups did not differ significantly. For intermediate/high risk disease, Black men with low SVI had the lowest odds of definitive treatment compared to non-Black men with low SVI (OR 0.24, 95% CI 0.10-0.56); odds for the other groups did not differ significantly. Conclusions: This study highlights the significant impact of social vulnerability on prostate cancer treatment outcomes among Black men, particularly those with high SVI, despite access to community urologic care. Black men with high SVI experiencing lower odds compared to their non-Black counterparts, even after adjustment for clinical risk, insurance coverage, comorbidities, geographic disparities, and age at diagnosis also contribute to treatment outcomes, emphasizing the intricate interplay of these factors. The unique combination of CaPSURE and SVI allows for the comprehensive assessment and geographic localization of multilevel drivers of treatment disparities which persist even in men receiving urologic care.

Phase Ib/IIa dose escalation and expansion study of [ ²¹² Pb]Pb-ADVC001 in metastatic castration-resistant prostate cancer: TheraPb–phase I/II study.

TPS275 Background: Prostate cancer (PC) is the second most common cancer and second leading cause of cancer-related death in men. A recent Lancet Commissionarticle predicts a rise in PC cases from 1.4 million in 2020 to 2.9 million by 2040. Despite ten new therapies being available for metastatic PC in the recent decade, the survival advantage from most agents in the setting of metastatic castration-resistant prostate cancer (mCRPC) is measured in months largely due to cross-resistance, and the 5-year survival is approximately 32%. The radioligand therapy 177 Lu-PSMA-617, which uses a beta-emitting isotope linked to a PSMA-targeting small molecule, has shown a median survival advantage in mCRPC of four months, underpinning the critical need for more effective treatments. Excitement has shifted towards the use of alpha-emitting isotopes that deliver a more lethal payload. Unlike beta particles, alpha particles have a short range of tissue penetration (< 0.1 mm) and high linear energy transfer that induces double-stranded DNA breaks and high levels of cytotoxicity to target expressing cancer cells irrespective of cell cycle or oxygenation state. Herein we describe the ongoing clinical trial of [ 212 Pb]Pb-ADVC001 – a novel PSMA-targeted radioligand labelled with the potent alpha-emitting isotope 212 Pb. Methods: This is a prospective, open-label, non-randomized, dose-escalation, dose optimization and expansion study. The study aims to determine the safety and tolerability of escalating doses of [ 212 Pb]Pb-ADVC001 administered every 6, 4 or 2 weeks during the dose-finding phase (Phase 1b) in participants with PSMA-positive mCRPC who have had exposure to at least one androgen receptor pathway inhibitor (ARPi) and taxane-based chemotherapy at any time in the course of their disease. The dose escalation phase will follow an i3+3 design, with each cohort able to backfill up to 20 participants for further characterization of the safety, tolerability and preliminary efficacy of dose and schedules. The expansion phase (Phase 2a) aims to assess the efficacy, safety and tolerability of [ 212 Pb]Pb-ADVC001 at the recommended Phase 2 dose in three groups of participants with PSMA-positive mCRPC. Group 1: Participants who have had exposure to at least one ARPi and have not received a taxane for the treatment of mCRPC. Group 2: Participants who have had exposure to at least one ARPi and received taxane-based chemotherapy for the treatment of mCRPC. Group 3: Participants who have had exposure to 177 Lu-PSMA. If data from Phase 1b demonstrates multiple dosing regimens are reasonably equivalent in terms of safety, tolerability and anti-tumor activity, the Phase 2a expansion study may include adaptive randomization to identify an optimized dose and schedule. The trial is currently enrolling at two clinical sites in Australia. Clinical trial information: NCT05720130 .

Does treatment (Tx) for mental health illness (MHI) impact prostate cancer (PC) Tx and outcomes?

318 Background: We previously showed that men with MHI are 20% less likely to be diagnosed with PC, but when diagnosed, are nearly 2x more likely to have aggressive PC compared to non-MHI men (ASCO 2023). Subsequently, we showed that men with MHI prior to PC Dx are more likely to receive definitive treatment (DTx) compared to non-MHI men with PC, however have poorer post-Tx surveillance adherence and increased risk of biochemical recurrence (BCR; ASCO 2024). However, among MHI men with PC, whether MHI treatment impacts PC treatment or outcomes has yet to be determined. The objective was to test the association between (i) MHI Tx and time from PC Dx to receipt of DTx, (ii) MHI Tx (prior to DTx end) and adherence to surveillance, and (iii) MHI Tx and time from DTx to BCR among treated men. Methods: This national, retrospective study used a cohort of males who were active users of the VA (≥2 encounters with a VA provider within a 5-yr period, 2000-2020) and diagnosed with MHI between the age of 40-80. Men were included if diagnosed with PC following MHI and had no prior malignancy. Competing risks models were used to test the association between MHI Tx (time-dependent covariate) and time from PC Dx to receipt of DTx (radical prostatectomy (RP) or radiotherapy (RT)). Logistic regression models were used to test the association between MHI Tx (prior to DTx end) and adherence to surveillance (≥3 PSAs within the first year following DTx, and at least 1 PSA in each year for the next 4 consecutive years) among treated men. Competing risks models were used to test the association between MHI Tx and time from DTx to BCR among treated men. Results: 62,019 men diagnosed with PC and MHI (n=57,373 with MHI Tx) were included. MHI-treated men were more likely to receive DTx for PC than men without MHI-Tx in both univariable (HR: 1.11, 95% CI: 1.06-1.15) and multivariable (HR: 1.18, 95% CI: 1.13-1.23) analysis. Among men treated for PC (n=13,260), odds of adhering to surveillance did not differ between MHI-treated vs non-treated men in univariable (OR: 1.01, 95% CI: 0.92-1.11) or multivariable (OR: 1.03, 95% CI: 0.94-1.14) analysis. However, an interaction was present between MHI-Tx and year of Dx: MHI-treated men were more likely to adhere than non-treated men in earlier years (e.g., Dx 2001 – OR: 1.54, 95% CI: 1.22-1.94) but less likely in later years (e.g., Dx 2015 – OR: 0.85, 95% CI: 0.74-0.98). Risk of BCR was lower in MHI-treated vs. non-treated men in univariable (HR: 0.86, 95% CI: 80, 0.93) but not multivariable (HR: 0.95, 95% CI: 0.87-1.03) analysis. Conclusions: Men with PC who received treatment for MHI were more likely to receive DTx for their PC compared to men with PC and untreated MHI, however there was no difference in receipt of post DTx PSA surveillance among these groups. There was also no difference in risk of BCR in multivariable models. This suggests that treatment of MHI is important for receiving DTx for PC, but does not impact subsequent surveillance or BCR outcomes.

Validation of PAM50 for predicting progression in active surveillance: Results from the Miami MAST prospective clinical trial.

238 Background: Active surveillance (AS) has emerged as an increasingly common management strategy for men with low- to favorable intermediate-risk prostate cancer. Although rates of prostate cancer mortality and metastasis remain low, some men experience cancer progression that necessitates treatment. Tools that improve the prediction of progression can enable more risk-adapted and timely treatment. We evaluated a PAM50 molecular classification profile for predicting cancer progression in men undergoing AS for prostate cancer. Methods: A total of 205 men enrolled in the Miami MAST trial who underwent a follow-up protocol involving serial multiparametric MRI and biopsies, including MRI-targeted and systematic biopsies. The highest-grade cores from each targeted and systematic biopsy were sent to Veracyte for genomic profiling. Patients were categorized into three groups based on the PAM50 genomic profile from the Decipher GRID. Time to progression, mutation analysis, and other prognostic signatures available on the Decipher GRID were compared across the three PAM50 classifier groups. Statistical analysis was performed using ANOVA and the rank-sum test, with significance defined as p<0.05. Results: Among the 205 patients enrolled in the trial, 128 had successful genomic profiling for baseline PAM50 classification. 46 were classified as Luminal A, 26 as Luminal B, and 56 as Basal subtypes. The Luminal B subtype demonstrated the highest risk of progression (77%), while the Basal subtype showed the lowest risk (45%) (p=0.011). Median time to progression was shorter in the Luminal B subtype (1.7 years) compared to the Luminal A and Basal subtypes (2.9 years each) (p=0.005). Decipher scores were lowest in the Luminal A group, followed by the Basal group, and highest in the Luminal B group (p=0.0015). Intra-patient variability based on subtyping of different cores within the same biopsy was observed in 37.1% of cases. Transcriptome analysis revealed distinct enrichment profiles for each PAM50 subtype, and mutation pattern analysis highlighted differences in mutation associations, with Luminal B showing a stronger association with SPOP and PTEN mutations. Conclusions: PAM50 shows promise as a molecular classification tool for predicting the risk of progression in prostate cancer. Given its stronger association with SPOP and PTEN mutations, as well as associations with higher progression risk, shorter progression times, and higher Decipher scores, the Luminal B subtype indicates a poorer prognosis compared to the Luminal A and Basal subtypes. This is the first study to validate PAM50 for predicting cancer progression in a prospective cohort of men undergoing active surveillance for prostate cancer. Clinical trial information: NCT02242773 . Progression rates among different PAM50 subtypes. PAM50 Group Non-progressor (%) Progressor (%) P VALUE BASAL 31 (55) 25 (45) 0.011 LUMINAL A 26 (57) 20 (43) LUMINAL B 6 (23) 20 (77)

Native antisite defects in <i>h</i>-BN

Hexagonal boron nitride (hBN) is an excellent host for solid-state single phonon emitters. Experimental observed emission ranges from infrared to ultraviolet. The emission centers are generally attributed to either intrinsic or extrinsic point defects embedded into hBN. Nevertheless, the microscopic structure of most of these defect emitters is uncertain. Here, through density-functional theory calculations, we studied the native antisite defects in hBN. We find that the neutral boron antisite might be a nonmagnetic single photon source with zero-phonon-line (ZPL) at 1.58 eV and such a line shape is often observed in experiments. Furthermore, the positively charged nitrogen antisite might be associated with a dim color center recently observed as a blue emitter with ZPL at 2.63 eV. These simple single substitution defects indicate the existence of out-of-plane phonon mode, which significantly affects the optical properties. Our results could provide useful information for the identification of quantum emitters in hBN.

Machine learning approaches for resilient modulus modeling of cement-stabilized magnetite and hematite iron ore tailings

Timely BRCA mutation testing in patients with metastatic prostate cancer: A comparative analysis between Medicare Advantage and traditional Medicare.

319 Background: BRCA mutations have emerged as critical biomarkers for guiding the use of PARP inhibitors in metastatic prostate cancer. Timely access to BRCA testing remains a challenge, especially for those enrolled in Medicare Advantage (MA) plans, which cover more than half of Medicare beneficiaries but often impose greater restrictions than Traditional Medicare (TM). This study compares the timeliness of BRCA testing in patients with metastatic prostate cancer (mPCa) across these two insurance types. Methods: A retrospective cohort study was conducted using the Flatiron Health deidentified Database, including electronic health record-derived data from ~280 cancer practices across the US. Our study population consisted of patients aged 65 or older, diagnosed with mPCa since 2018, and enrolled in either TM or MA. TM and MA were defined as patients enrolled in TM or MA health plans, respectively, either prior to or within 90 days following their mPCa diagnosis. BRCA testing was defined as either germline or somatic testing. We compared the rates of BRCA testing within 45, 90, and 180 days of diagnosis between TM and MA. Given the lack of clinical consensus, we defined timely BRCA testing using three-time windows—45-, 90-, and 180-days post-mPCa diagnosis. Multivariate logistic regression with inverse probability of treatment weighting was used, adjusting for demographics, year of mPCa diagnosis, practice setting, and baseline ECOG performance status. Results: Among the 1,582 MA patients (mean age: 75.9 ± 5.8) and 2,749 TM patients (mean age: 75.4 ± 5.8), significant proportions were from community practice (MA: 78%, TM: 80%) and were characterized by being White (MA: 59%, TM: 65%), aged 75 to 85 (MA: 54%, TM: 57%), having better socioeconomic status (SES 4 or 5: MA: 40.3%, TM: 47.5%), presenting with de-novo mPCa (MA: 53%, TM: 54%), and having better baseline functional performance (ECOG 0 or 1: MA: 70%, TM: 69%). Since 2018, 25.0%, 29.4%, 33.2% of MA patients and 25.9%, 29.1%, 31.9% of TM patients received BRCA testing at 45, 90 and 180 days, respectively. After adjusting for covariates, MA was associated with a 15.2% (OR=0.84, 95%CI 0.73-0.98), 11% (OR=0.89, 95%CI 0.77-1.02), 7.9% (OR=0.92 95%CI 0.80-1.06) lower chance to receive timely BRCA testing within 45 days, 90 days and 180 days, respectively. Conclusions: This study suggests that, compared to TM, mPCa patients enrolled in MA are less likely to receive timely BRCA testing. These findings highlight the needs for further investigation into how Medicare Advantage plans impact cancer care delivery and patient outcomes.

A phase 2 trial of risk enabled therapy after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer (RETAIN-2).

815 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or chemoradiation (CRT) is the standard of care for patients (pts) with muscle invasive bladder cancer (MIBC). Mutations in DNA damage repair genes enrich for pathologic downstaging after NAC. In RETAIN-1, a risk-adapted approach was employed to identify patients for cystectomy-sparing active surveillance (AS) following NAC, reporting a 73% 2-year MFS rate. RETAIN-2 employs a similar approach but incorporates neoadjuvant chemoimmunotherapy. Methods: This is a phase II, multi-institutional trial in which pts with cT2-T3N0M0 MIBC, ECOG PS 0-1 and CrCl≥50 mL/min received neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) with nivolumab. Pre-NAC transurethral bladder resection (TURBT) specimens were sequenced for mutations (pathogenic or VUS) in ATM , ERCC2 or RB1 . Pts with &gt;1 mutation and clinical complete response (cCR) post-NAC (based on restaging TUR, urine cytology and CT imaging) initiated active surveillance (AS). Remaining pts underwent bladder-directed therapy: intravesical therapy (&lt; cT2 post-NAC), CRT or RC. The primary endpoint is 2-year metastasis-free survival (MFS) for ITT pts which is not mature. This interim analysis reports clinically meaningful secondary endpoint outcomes. Results: A total of 80 pts were treated over 40 months at four academic centers and 71 were evaluable per protocol. The median age was 69 years (range: 66-86), 77% were male, 80% had ECOG PS 0 and 87% were cT2. Of 80 treated pts, 60 (75%) completed 3 cycles of AMVAC with nivolumab; 7 tolerated only 1 cycle, and 2 died shortly after completing 3 cycles from treatment-related adverse events and were not evaluable for the primary endpoint. Grade 3-4 TRAEs occurred in 19% of all treated pts. Of 71 evaluable ITT pts, 31 (44%) had a mutation of interest and the cCR rate in those pts was 71%; 35 pts proceeded directly to RC, 10 received CRT, 3 received intravesical therapy and 23 pts started per protocol AS. Of 23 AS pts, 4 did not have mutation. Similarly, 3 pts with tumor mutation and cCR chose RC. In pts who underwent RC, pT0 rate was 46%, &lt;T2 rate was 63%, and 5 (14%) developed metastases. Of the 23 pts on AS, 6 required salvage local tx (3 salvage RC, 2 intravesical tx and 1 CRT). At data cut-off (Sep 1, 2024), with a median follow-up of 18.4 mo (range: 6.1– 42.6 mo), 86% of all evaluable ITT pts remain metastasis free. A total of 10 pts developed metastases – 5 in the RC, 1 in the CRT, and 4 in the AS groups. Twenty-nine pts remain metastasis free with an intact bladder (78% of AS pts, 41% of ITT pts). Conclusions: Interim results of RETAIN-2 show a 46% pT0 rate in those allocated to cystectomy and a 78% metastasis-free bladder-preservation rate in those allocated to AS. Follow-up is ongoing for the primary endpoint of 2-year MFS. Clinical trial information: NCT04506554 .

Genomic features of prostate cancer patients with and without ductal adenocarcinoma (DA) based on liquid biopsy.

191 Background: Ductal adenocarcinoma (DA) is relatively rare and highly co-existed with prostate adenocarcinoma (AC). This study aims to investigate the distinctive genomic profiles of patients with DA compared to those without it. Methods: Blood samples were obtained from 144 patients (36 with DA and 108 without DA) who were diagnosed with prostate cancer from 2017 to 2023 at West China Hospital. We performed cell-free DNA sequencing to investigate the genomic differences between patients with DA (DA[+]) and those without (DA[-]), and explored the potential associations between their mutational status and prognosis. Pathogenic and likely pathogenic alterations were included for analysis. Results: We identified that AR pathway (16/36 [44.4%] vs 24/108 [22.2%], p=0.017) and WNT pathway (6/36 [16.7%] vs 5/108 [4.6%], p=0.029) mutations were significantly enriched in DA(+) compared to DA(-), with AR pathway featured by FOXA1 (9/36 [25%] vs 5/108 [4.6%], p=0.0012). DDR mutation rate and the HRD scores appeared to be comparable between DA(+) and DA(-). TP53 was associated with a deteriorating prognosis for both DA(+) and DA(-) in terms of castration-free survival (CFS). Conclusions: Our findings provide further genomic insights in prostate cancer with ductal morphology and are instructive for the diagnosis and treatment of DA. Baseline characteristics of the DA (+) and DA (-) cohorts. Variable DA (-), N = 108 1 DA (+), N = 36 1 p-value 2 Treatment line 0.4 HSPC 34 (31%) 7 (19%) CRPC 18 (17%) 6 (17%) Treatment-naive 56 (52%) 23 (64%) Metastasis at detection 0.6 M0 52 (48%) 19 (53%) M1 56 (52%) 17 (47%) Visceral metastasis 8 (7.4%) 8 (22%) 0.028 Bone metastasis 0.7 &lt;5 12 (11%) 6 (17%) ≥5 38 (35%) 12 (33%) 0 55 (51%) 18 (50%) Not available 3 (2.8%) 0 (0%) ISUP 0.055 1 3 (2.8%) 0 (0%) 2 6 (5.6%) 3 (8.3%) 3 16 (15%) 11 (31%) 4 12 (11%) 7 (19%) 5 71 (66%) 15 (42%) Age 68 (61, 73) 68 (61, 73) &gt;0.9 Baseline PSA 0.007 &lt;50 41 (38%) 23 (64%) ≥50 67 (62%) 13 (36%) 1 n (%); Median (IQR). 2 Pearson's Chi-squared test; Fisher's exact test; Wilcoxon rank sum test. DA: dutal adenocarcinoma of the prostate; HSPC: hormone-sensitive prostate cancer; CRPC: castration-resistant prostate cancer; ISUP: International Society of Urological Pathology grading; PSA: prostate-specific antigen.

Concordance between clinical and pathologic staging of T2a–b and T3a renal cell carcinoma.

600 Background: Among patients with renal cell carcinoma (RCC), 5–23% of those with cT1 and smaller cT2 tumors may be upstaged to pT3a disease after surgery. The pathologic restaging rate of larger or clinically more invasive tumors is understudied and has implications for perioperative systemic therapy clinical trial enrollment. We examined rates of pathologic restaging for cT2a-b and cT3a RCC after surgery. Methods: Using the National Cancer Database, we identified adult patients with cT2a, cT2b, and cT3a RCC undergoing partial or radical nephrectomy. We compared pathologic restaging rates between the clinical stage groups using a Chi-square test. Subgroup analysis of restaging rates was performed for histology (clear cell vs non–clear cell), clinical nodal status (cN1 vs cN0), and clinical metastatic status (cM1 vs cM0). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the overall cohort and subgroups. Multivariable logistic regression was performed to assess predictors of pT3a upstaging among patients with cT2a and cT2b tumors. Results: We identified 31,912 patients who met inclusion criteria (13,840 cT2a, 8,079 cT2b, and 9,993 cT3a). he overall rate of restaging was 47.4% for cT2a disease (10.7% downstaged and 36.7% upstaged) for a sensitivity and specificity of 89% and 72%, respectively. The overall rate of restaging was 52.5% for cT2b disease (10.6% downstaged and 41.9% upstaged), for a sensitivity and specificity of 85% and 96%, respectively. The overall rate of restaging was 9.5% for cT3a disease (5.1% downstaged and 4.4% upstaged), for a sensitivity and specificity of 55% and 94%, respectively (p &lt; 0.001). The positive predictive value was 52.5%, 47.5%, and 90.6%, and the negative predictive value was 95%, 97%, and 67% for cT2a, cT2b, and cT3a disease, respectively. On multivariable analysis, among patients with cT2 tumors, the presence of clinically node-positive (OR 2.8 [95% CI 2.43–3.17]) metastatic (OR 2.4 [95% CI 2.18–2.65]) or cT2b disease (OR 1.18 [95% CI 1.10–1.26]) was associated with pathologic upstaging (p &lt; 0.001). Conclusions: Restaging is common for patients with cT2a and cT2b tumors, but the specificity of cT3a staging is high. These findings suggests that opportunities exist to improve the accuracy of clinical staging for cT2 tumors, which will have implications for future adjuvant/perioperative RCC clinical trials.

Methane sensing via unbalanced nonlinear interferometry using a CMOS camera and undetected mid-infrared light

Here, we present a high-sensitivity, rapid, and low-cost method for methane sensing based on a nonlinear interferometer. This method utilizes signal photons generated by stimulated parametric downconversion (ST-PDC), enabling the use of a silicon detector to capture high-precision methane absorption spectra in the mid-infrared region. By controlling the system loss, we achieve more significant changes in visibility, thereby increasing sensitivity. A low-cost CMOS camera is employed to capture spatial interference fringes, ensuring fast and efficient detection. Thereby, we demonstrate an accurate measurement of methane concentration within a gas cell. In addition, we show that ST-PDC enables long-distance sensing and the capability to measure open-path low ambient methane concentrations in the real world.