Citations

Abstract High-grade serous ovarian cancer (HGSOC), the most prevalent and lethal ovarian cancer subtype, is typically diagnosed at an advanced stage due to the absence of effective early detection strategies. Mounting evidence indicates that HGSOC originates from the fallopian tube (FT), particularly from secretory epithelial cells in the fimbria. However, incomplete understanding of the cellular and molecular origins of HGSOC continues to hinder early interception efforts. To address this, we established a clinically and genetically annotated living FT organoid biobank at Mayo Clinic, representing over 200 patient donors. Using optimized enrichment protocols, we isolated FT epithelial stem/progenitor cells from tissue and Tao brushings, generating organoids independent of anatomical site or laterality that recapitulate native FT epithelial architecture and lineage differentiation. We applied integrated multi-omic analyses, including single-cell RNA sequencing, single-nucleus RNA/ATAC sequencing, and bulk RNA-seq, across fresh cells and organoids. Integration with public datasets produced the largest single-cell atlas of normal and high-risk FTs to date. This analysis defined high-specificity gene signatures for secretory and multiciliated lineages that outperform canonical lineage markers (e.g. PAX8, FOXJ1), identified lineage-defining transcription factors and regulatory networks, and showed concordant protein expression in the human FT epithelium. Notably, subcluster-level analysis revealed a rare hybrid epithelial-mesenchymal population transcriptionally and proteomically aligned with the mesenchymal-like subtype of HGSOC. Spatial immunoprofiling demonstrated that these cells express multiple defining markers and reside above the basement membrane, intercalated between epithelial cells and lack luminal contact, reminiscent of the histologically described peg cell population. Comparative analyses with fetal mesonephric tissues uncovered developmental parallels, and this population was stably maintained in 3D organoid cultures, providing a robust ex-vivo model to study early transformation. Together, our findings identify a rare, multipotent epithelial population with mesenchymal features as a candidate origin for mesenchymal-like HGSOC and establish the FT organoid biobank as a powerful platform for mechanistic and translational studies in ovarian carcinogenesis. Citation Format: Megan L. Ritting, Wenmei Yang, Syed Mohammed Musheer Aalam, Hui Zhao, Liang Feng, Jianning Song, Mihai G. Dumbrava, Wazim M. Ismail, Kenneth Schaufelberger, S. John Weroha, Scott H. Kaufmann, Alexandre Gaspar-Maia, Mark E. Sherman, Jamie N. Bakkum-Gamez, Nagarajan Kannan. A rare multipotent peg-like epithelial cell is a candidate cell-of-origin for high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7636.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P < .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P < .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Abstract Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity and plasticity. GBM tumors contain neoplastic cells within a fluid spectrum of diverse transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we develop scFOCAL (Single-Cell Framework for -Omics Connectivity and Analysis via L1000), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identify compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states, and leverage this capability to predict combination synergy. We validate the significance of these findings in vitro, ex vivo, and in vivo, and use the Olig2 inhibitor CT-179 as a reference drug to identify additional small molecules that would maximize the cell-drug discordance across the GBM transcriptional landscape. Our analysis leads to the combination of Olig2 inhibition with treatment with Depatux-M, of with which we demonstrate synergy in vivo. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations. Citation Format: Robert K. Suter, Anna M. Jermakowicz, Rithvik Veeramachaneni, Matthew D'Antuono, Longwei Zhang, Rishika Chowdary, Simon Kaeppeli, Madison Sharp, Pravallika Palwai, Vasileios Stathias, Grace Baker, Luz Ruiz, Winston Walters, Maria Cepero, Danielle Burgenske, Edward B. Reilly, Anatol Oleksijew, Mark G. Anderson, Sion Ll. Williams, Michael E. Ivan, Ricardo J. Komotar, Macarena I. De La Fuente, Gregory Stein, Alexandre Wojcinski, Santosh Kesari, Jann N. Sarkaria, Stephan C. Schürer, Nagi G. Ayad. Drug and single-cell gene expression integration identifies heterogeneity-aware synergistic combinations for glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B032.

BACKGROUND AND OBJECTIVES: The artery of Davidoff and Schechter (ADS) is a dural branch of the posterior cerebral artery, supplying the falcotentorial junction. It is not commonly depicted on angiography due to its small size; thus, its visibility is usually indicative of a pathology, such as a dural arteriovenous fistula (DAVF). Recognizing the ADS as a feeder could be vital in enhancing management success, and understanding its anatomy is important for preventing complications during embolization or microsurgery. We present a scoping review of DAVFs fed by the ADS followed by an illustrative case report encountered at our institution. METHODS: An extensive literature review was conducted using PubMed, Embase, Web of Science, Scopus, and Cochrane databases. The search included the keywords: “Davidoff,” “Schechter,” “Davidoff and Schechter,” “dural branch,” “tentorial branch,” “medial branch,” and “meningeal branch,” in combination with “arteriovenous fistula,” “posterior cerebral artery,” and “superior cerebellar artery.” Only articles published in English or Spanish were included, with no restriction on publication date. Case reports and series were further screened based on best relevance. Data extraction and synthesis were performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. RESULTS: A total of 16 articles describing 32 cases of DAVFs supplied by the ADS were identified. The most common onset was headache (43.8%), followed by altered mental status (21.2%). Most DAVFs were classified as high grade based on Borden/Cognard scales. Transarterial embolization was the most used treatment (81.3%), achieving complete occlusion in 76.9% of cases. Among patients with complete occlusion, approximately half experienced full resolution of symptoms. In a mean follow-up of 27.4 months (IQR: 30), 2 cases reported complications due to reflux of the embolic agent. CONCLUSION: A comprehensive understanding of the ADS's angioarchitecture is essential to take full advantage of this artery's features in the treatment, mitigating potential complications and optimizing patient outcomes.

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at &lt; 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance. A large unmet need exists especially when resistance occurs following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), which is potentially driven by a mutation in the ERα-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al. Ann Oncol 2023;34:1141‒51). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S et al. Ann Oncol 2023;34:1131‒40). The phase 3, registrational, ELAINE 3 trial was initiated based on these promising earlier-phase data. Recent results from postMONARCH confirmed superior efficacy of fulv/Abema over fulv/placebo (mPFS 6.0 mos vs 5.3 mos, HR 0.73 [0.57‒0.95], nominal P-value 0.017) in non-biomarker‒selected, mBC patients after progression on a prior CDK4/6i and aromatase inhibitor (AI), with similar HR in an ESR1-mutated cohort (Kalinsky K et al. J Clin Oncol 2025;43:1101‒12). Additionally, recent data from EMBER-3 demonstrated meaningful PFS with a novel ET combined with abemaciclib after progression on AI/CDK4/6i (Jhaveri KL et al. N Engl J Med 2025;392:1189‒202). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation‒selected, mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Patients are being enrolled at approximately 152 sites in 13 countries (Australia, Belgium, Canada, China, France, Italy, Israel, Poland, Romania, Spain, Taiwan, United Kingdom, United States). Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM (days 1, 15, and 29, then once monthly) plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS per RESIST 1.1 by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Safety, time to cytotoxic chemotherapy, and quality of life (including vaginal health) will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target sample size of 500 patients. Citation Format: M. P. Goetz, S. A. Wander, T. Bachelot, G. Curigliano, A. de Nonneville, E. N. Gal-Yam, K. Jhaveri, S. L. Sammons, S. Shen, C. J. Twelves, G. Gasper, P. V. Plourde, D. J. Portman, S. Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [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 PS5-07-30.