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3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

ABSTRACT The initiation and sustained expression of motivated behaviour is strongly regulated by mesolimbic dopamine (DA) release within the nucleus accumbens (NAc). Deep brain stimulation (DBS) has demonstrated efficacy in treating refractory psychiatric disorders characterised by dysfunctional motivated drive and related behaviours. However, the neurobiological mechanisms underlying DBS effects at the local and circuit levels remain unclear. This study aimed to investigate the effects of NAc DBS on effort‐based decision‐making and local phasic DA neurotransmission in male Wistar rats. Male Wistar rats ( N = 8) were trained on a concurrent fixed ratio 5/chow effort‐related choice task (ERCT) until stable baseline performance was reached. On the test day, animals underwent a 2‐h session of high‐frequency NAc DBS (130 Hz; 90 μs pulse width; 500 μA) immediately prior to behavioural testing, with additional testing conducted on subsequent days to assess prolonged effects. In a separate experiment, the effects of identical NAc DBS parameters (or sham) on ventral tegmental area (VTA)‐evoked (120 pulses; 60 Hz; 2 ms pulse width; 200–500 μA) DA release in the NAc core were quantified using fast‐scan cyclic voltammetry in urethane‐anesthetised rats ( N = 12). Acute bilateral NAc DBS transiently reduced overall food‐related motivation while maintaining effort‐based choice bias. In parallel, NAc DBS significantly suppressed VTA‐evoked NAc DA release compared to sham, although a moderate reduction was also observed in sham controls. DA reuptake kinetics remained unchanged across groups. NAc DBS transiently suppresses overall food‐related motivation while maintaining effort‐based decision‐making. Attenuated phasic DA neurotransmission with active DBS may contribute to this behavioural effect. image

ABSTRACT Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2 . REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy. One Sentence Summary Homologous recombination reversion evolves through structurally tolerated, microhomology-driven alterations that restore DNA repair under therapeutic selection across cancers.

Abstract Context Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). Objective To develop an international reference range for plasma estradiol in postmenopausal women, support accurate assessment of concentrations during systemic and local (eg, vaginal) estradiol therapy, and improve risk prediction for diseases, including osteoporosis, breast, and endometrial cancers. Methodology Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in 5 international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n = 7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. Results Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0-66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0-45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI < 30). Reference ranges increased progressively with higher BMI categories. Conclusion Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.

Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Introduction: Chronic kidney disease affects nearly half of heart failure (HF) patients, underscoring the importance of regular kidney function monitoring. However, longitudinal trajectories of kidney function in HF are not well characterized. Identifying clinical factors linked to long-term changes is critical for improving monitoring and informing early clinical decisions. Hypothesis: We hypothesized that longitudinal kidney function and its associations with clinical variables in HF patients differ from that of demographically similar comparators from the same community. Methods: We analyzed patients with validated HF from a community-based cohort and comparators individually matched to age and sex selected from participants in the Mayo Clinic Biobank cohort. Individuals with end-stage kidney disease, dialysis or kidney transplantation prior to enrollment were excluded. Serum creatinine-based estimated glomerular filtration rate (eGFR) from outpatient and inpatient visits was assessed from enrollment for up to 10 years of follow-up. The median of eGFR for 90-day intervals was used to estimate the follow-up eGFR (Figure 1) . We modeled percentage change from baseline and fit linear mixed-effect models with time, HF status, and their interaction to test whether the eGFR trajectories differed between the two groups. In addition, we examined the association between eGFR trajectories and clinical variables. Results: We studied 1182 HF patients and 825 comparators with at least three eGFR measurements. Median follow-up was 5 years (IQR: 3-10) for HF patients and 8 years (6-9) for comparators. In total, 16245 serum creatinine measurements from HF patients and 9858 from comparators were analyzed. Median age at enrollment was 76 years (67-84) for HF patients and 78 years (70-83) for comparators. A greater decline in percentage change in eGFR was observed in HF patients (-4.23%, 95% CI: -4.75 to -3.70% per year) than in comparators (-1.90%, 95% CI: -2.51 to -1.29% per year; P<0.001, Figure 2 ). Among HF patients, the decline in percentage change in eGFR was greater in the presence of diabetes, hyperlipidemia, or a higher comorbidity burden. Conclusions: In this community study, HF patients exhibited a greater percentage decline in eGFR compared to community comparators. Among HF patients, eGFR decline was more strongly associated with comorbidities—particularly metabolic risk factors—highlighting the relevance of the cardiovascular-kidney-metabolic syndrome in HF.

ABSTRACT Bispecific T cell engagers (BTEs) induce MHC‐independent cytotoxicity by bridging T cells to tumor cells via binding a T cell–activating receptor and a tumor‐associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin‐13 receptor alpha 2 (IL13RA2), a tumor‐associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen‐dependent cytokine release and cytotoxicity against IL13RA2‐positive GBM cells. In vivo, hBTE showed robust target‐specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off‐target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2‐expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2‐expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

Background/Objectives: Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. Methods: The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Results: Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines ( p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. Conclusions: The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher. Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast

ABSTRACT Background Clinical T 2 ‐weighted (T2W) MRI of prostate cancer (PCa) usually implements a 2D fast‐spin‐echo (FSE) sequence, but understanding the echo‐time‐dependent contrast behavior is not straightforward due to the complicated FSE signal evolution. Consequently, consensus‐based recommendations on the optimal effective echo time (TE eff ) to maximize contrast are lacking. Purpose To investigate the effect of TE eff on PCa lesion contrast in prostate T2W MRI. Study Type Phantom and in vivo prospective study. Subjects A standard MRI phantom and 53 prostate cancer patients (29 for image evaluation and 24 for quantitative lesion analysis). Field Strength and Sequence Multi‐slice T2W FSE sequence at 3 T acquired at multiple TE eff values. Assessment Three readers (13, 25, and 27 years' experience) evaluated TE eff = 100 ms versus 150 ms on diagnostic quality and reader preference. The effective T 2 relaxation rates ( T 2,eff ) were measured using FSE sequences in the phantom and used to predict the optimal TE eff maximizing T2W contrasts. From multi‐TE eff scans of subjects with suspected PCa, T 2,eff values of PCa lesions and healthy tissue were measured and used to calculate the optimal TE eff maximizing the lesion contrast. In vivo contrast metrics were measured as a function of TE eff . Statistical Tests Wilcoxon test of reader scores, with p < 0.05 defining statistical significance. Results No statistically significant difference was found in diagnostic quality between TE eff = 150 ms and 100 ms images, but all three readers significantly favored TE eff = 150 ms. Phantom experiments demonstrated that TE eff ‐dependent FSE signal progression can be characterized by T 2,eff values typically 40% longer than actual T 2 values, allowing accurate prediction of optimal TE eff within 2%–5%. Applied to PCa imaging, in vivo measurements indicated that effective T 2 relaxation times of the prostate are on average 1.5× longer than published T 2 values. Data Conclusion The benefits of TE eff = 150 ms versus 100 ms in prostate T2W FSE were supported by reader preference, phantom experiments, in vivo measurements, and analytic optimizations. Evidence Level 2. Technical Efficacy 2.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.