Ronald Reagan UCLA Medical Center

Abstract Background: Ribosomal s6 kinase (RSK) is situated at the convergence of the PI3K and ERK-MAPK pathways and plays a crucial role in cell growth and survival. It has been reported that up to 70% of breast tumors have a high expression of RSK, which is an indicator of poor prognosis in patients with breast cancer. RSK2 binds directly to estrogen receptor alpha (ERα) to promote tumor growth and the development of breast cancer in mice. RSK 1-4 have been linked to endocrine therapy (ET) and CDK4/6 inhibitor (CDK4/6i) resistance, which are common in patients with HR+/HER2- advanced or metastatic breast cancer (mBC). RSK drives resistance by promoting the G2/M phase of the cell cycle and bypassing G1/S control. PMD-026 is a first-in-class oral small molecule RSK inhibitor that halts G2/M progression and blocks growth in pre-clinical models of CDK4/6i resistance. In addition, PMD-026 inhibits the nuclear translocation of RSK2 (with no change to levels of nuclear ERα), reduces ERα transcription as a single agent equal to or better than fulvestrant or elacestrant, and synergizes with fulvestrant, oral selective estrogen receptor degraders (SERDs) or vepdegestrant to substantially inhibit tumor growth in CDK4/6i sensitive and resistant models. Combining PMD-026 and fulvestrant reduced ERα transcription by 84% as demonstrated by ELISA and yielded a 7000-fold improvement in the inhibition of tumor growth in soft agar assays. Design: Dauntless-1 is a Phase 2a study of PMD-026 plus fulvestrant in locally advanced or metastatic HR+/HER2 breast cancer patients with high RSK expression (>50%) previously treated with a CDK4/6i + ET combination (NCT04115306). Primary objectives are safety and progression-free survival. Secondary objectives are duration of response, overall response by RECIST V1.1, and overall survival. Exploratory objectives will evaluate these endpoints in the context of select mutations (ESR1, PIK3CA, TP53) and bone-only metastasis. Results: To date for the Dauntless-1 study, 30 patients have been screened for RSK2 expression (67% high, 13% intermediate, 20% low). All patients with high RSK2 expression experienced >12-month durability of response while on treatment with a CDK4/6i + ET regimen. The pharmacokinetics of 2 patients receiving PMD-026 at the initial starting dose of 200 mg Q12h were evaluated and compared to Phase 1 monotherapy results. The combination with fulvestrant increased the levels of PMD-026 with a median of 2.5 µM across 24 hr compared to 1 µM as a monotherapy. Higher than expected exposure with the combination relative to PMD-026 monotherapy was also associated with G3 rash and elevated transaminases, which resolved when PMD-026 was held. To date, PMD-026 at the new starting dose of 100 mg Q12h has been well tolerated with no rash or hepatotoxicity. Based on pharmacokinetic modelling, PMD-026 exposure at 100 mg Q12h is expected to cover the synergy range with fulvestrant. Conclusions: RSK2 is highly expressed in most front-line mBC patients receiving CDK4/6i + ET therapy. PMD-026 inhibits ER signalling and is highly synergistic with fulvestrant in preclinical studies, the translation of which into potentially meaningful clinical benefit is being explored in the Dauntless-1 study. Citation Format: H. T. Khong, M. Beeram, R. Wesolowski, H. S. Han, N. J. Palaskas, J. Margolis, J. Peguero, N. Sharp, H. Rugo, A. Jayanthan, S. E. Dunn, J. Leveque, S. A. Wander. Dauntless-1: A Phase 2 Clinical Trial to Evaluate PMD-026, a First-in-Class Pan-RSK Inhibitor, Combined with Fulvestrant to Overcome Resistance to CDK4/6 Inhibitors in Advanced or Metastatic HR+/HER2- Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-15.

Durable outcomes with neurovascular stents require balancing antithrombotic performance with rapid endothelialization. We previously developed an amine-functionalized surface modification (Anti-thrombus formation, Endothelial-growth promotion, tissue Integration, and Surface; AEGiS Technology) with antithrombotic behavior. In this study we evaluated its pro-endothelialization properties and explore the mechanism. Adsorption of extracellular matrix proteins from human plasma was profiled on AEGiS-modified versus control NiTi surfaces with an a priori focus on vitronectin. Human umbilical vein endothelial cell (HUVEC) adhesion was quantified by attached cell numbers and post-wash retention as a measure of adhesion strength. Migration and surface coverage were assessed in an in vitro endothelialization model designed to mimic stents on vessel walls. For translation, self-expanding stents bearing AEGiS or control coatings were deployed in a porcine model and endothelial coverage at 1 week was quantified by angiography and histology. The AEGiS surface selectively increased vitronectin adsorption compared with the control surface. Consistent with this shift, AEGiS supported greater HUVEC adhesion and stronger retention. In the endothelialization model, AEGiS accelerated coverage of the substrate compared with the control. In vivo, AEGiS-modified stents showed greater endothelial coverage at 1 week than control stents. Amine functionalization enriched vitronectin adsorption and supported early endothelial coverage, indicating its potential to promote endothelialization of neurovascular stents.

These consensus guidelines by the American Clinical Neurophysiology Society (ACNS) describe best practices for performing intraoperative Electrocorticography (ioECoG) using subdural or depth electrodes for adult and pediatric population. A group of ACNS members was convened to develop technical standards for performing ioECoG. PubMed searches were performed to identify pertinent peer-reviewed literature. Sections were assigned to individual authors based on expertise. Consensus was achieved during subsequent group discussions to develop evidence-based recommendations to the extent possible. Communication between the neurosurgical and the neurophysiology teams is essential in verifying and documenting the location of the contacts. Most authors recommend ioECoG recordings of at least 5 and up to 30 minutes in duration to allow for sufficient observation of interictal activity. The anesthesia should be adjusted to allow continuous EEG activity and to minimize the effect on the ioECoG recording during general anesthesia or awake surgery. The surgical procedure and technical report should separate ioECoG recordings to define the irritative zone from ioECoG findings during functional mapping. The neurophysiology physician's physical presence in the operating room is required in the definition of the services. These consensus guidelines by the ACNS describe best practices for performing intraoperative ECoG based on published literature and expert consensus.

Co-first

Understanding of pathologic findings associated with the severity and chronicity of drug-induced liver injury (DILI) remains limited. We explored pathologic findings associated with the severity and chronicity in a biopsy-based cohort. We reevaluated medical records and liver histology of hospitalized patients clinically diagnosed with DILI. The severity was classified into five grades; among 301 DILI patients, only eight patients presented with acute liver failure, but no one died. Grades 3–4 were associated with confluent necrosis, ductular reaction, a higher grade of cholestasis and fibrosis, whereas grades 1–2 were associated with the presence of granulomas. 244 patients achieved biochemical normalization within 6 months, 31 patients within 1 year, 17 within 2 years, and 3 within 3 years. This study demonstrated that specific histological features are associated with the severity and chronicity of DILI. Importantly, an interlobular duct loss >25% seems to be an early risk factor for continued biochemical abnormalities.

Patients with heart failure (HF) remain at high risk for hospitalization and death, in part, due to underuse of available HF pharmacological therapy. Digital interventions may facilitate rapid initiation and titration of HF pharmacological therapy, but they have not been systematically evaluated in adequately powered, randomized, control trials. In the AIM-POWER study, we evaluated the safety and efficacy of the BiovitalsHF DTx decision-support platform as a strategy to guide optimal initiation and titration of pharmacological therapy in patients with HF with reduced ejection fraction (HFrEF). We enrolled 122 participants with symptomatic HFrEF (left ventricular ejection fraction ≤ 40%) who had not yet been optimized on HF pharmacological therapy. Participants were randomized 1:1 in an open-label fashion to management; they were supported by BiovitalsHF or usual care. Using wearable home-based monitors and digital scales, the BiovitalsHF platform assembled data regarding patients' status and formulated suggestions regarding initiation and titration of HF pharmacological therapy per published guidelines. These recommendations were provided to site clinicians, but final decisions about prescribing and titration were left to the sites. The primary outcome was the between-group difference in the change in an HF optimal medical therapy score from baseline-90 days. The results of the AIM-POWER study will provide important insights into digital interventions for HF management and will evaluate the effectiveness of BiovitalsHF in improving the use and dosing of pharmacological therapy for participants with HFrEF.

The ideal resection strategy for rectal neoplasms extending to the dentate line (RNDLs) remains unclear. Transanal surgical approaches and endoscopic mucosal resection (EMR) have their limitations related to inadequate visualization, device maneuverability, and securing an adequate margin on the anal side. Endoscopic submucosal dissection (ESD) appears to overcome some of the limitations of transanal surgical and snare-based endoscopic techniques. Therefore, we evaluated the safety and efficacy of ESD for resection of distal rectal lesions within 2cm of the dentate line. This is a large-scale multicenter retrospective study of patients who underwent ESD for RNDLs between 2015 and 2023. The primary outcomes were the rates of R0 and en bloc resection. Secondary outcomes were immediate and delayed adverse events. A total of 255 patients across 20 institutions were included (mean age 63.60, women 52.20%). The median lesion size was 40mm (IQR: 30 to 55), and the median resection time was 110 minutes (IQR: 81 to 169). The en bloc resection rate was 93.70% (n=236), and the rate of R0 resection was 85.40% (n=216). The rate of overall adverse events was 8.70% (n=22, 95% CI: 5.22% to 12.17%), with 13 cases of bleeding (5.10%), 4 cases of full-thickness perforation, and 1 case of postprocedural pain requiring intervention. All AEs were managed conservatively without the need for subsequent surgical or endoscopic interventions. ESD is safe and effective for resecting RNDLs with high en bloc and R0 resection rates, offering the potential for complete resection with minimal morbidity. It offers advantages over TEN, TAMIS, and other forms of transanal surgery due to the anatomy being less conducive to the equipment required for these techniques, lower cost, and lower rates of complications. However, careful patient selection, meticulous procedural planning, and close follow-up are essential to ensure optimal outcomes and minimize the risk of complications. Long-term follow-up studies and additional prospective controlled trials are warranted.