Citations

Introduction Angina with no obstructive coronary artery disease (ANOCA) affects millions and is frequently under-recognised because diagnostic pathways and risk tools predominantly target obstructive coronary artery disease (CAD). This protocol describes shared methods for two machine-learning (ML) studies: (1) differentiating ANOCA from stable angina with obstructive CAD and (2) predicting long-term mortality among patients with ANOCA and obstructive CAD. Methods and analysis We will develop and cross-site validate ML classification models using a multicentre retrospective cohort drawn from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry and institutional datasets from the University of Ottawa Heart Institute and the University Health Network. Eligible participants are adults (≥18 years) undergoing initial cardiac catheterisation for chest pain/anginal equivalents since 1995, excluding prior revascularisation, major structural heart disease and predefined non-anginal indications. Outcomes are (1) ANOCA (0% to <50% stenosis) versus obstructive CAD (≥50% stenosis) and (2) 1, 3 and 5-year mortality, modelled separately for ANOCA and obstructive CAD. Model development will use nested cross-validation with stratified k-fold inner-loop tuning and leave-one-site-out cross-validation for repeated external validation. Candidate predictors will be harmonised across sites, filtered for missingness and refined using expert/directed acyclic graph-guided selection plus Boruta and Least Absolute Shrinkage and Selection Operator. Preprocessing includes appropriate encoding, missing-data imputation (multivariate imputation by chained equations) and feature scaling. Algorithms will include elastic-net logistic regression, random forest, LightGBM and multilayer perceptron models; hyperparameters will be optimised via Bayesian optimisation. Performance and threshold tuning will be reported. Explainability and subgroup fairness will be assessed using SHapley Additive exPlanations. Final models will be deployed as a web-based clinical risk calculator. Ethics and dissemination Ethics approval has been obtained from the University of Calgary and the University Health Network (#24-5916). Analyses will use deidentified data in secure environments; only aggregate results will be reported. Findings will be disseminated via peer-reviewed publications, conferences and a web-based calculator.

BACKGROUND In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, thalamic neuromodulation targeting structures such as the anterior nucleus of the thalamus (ANT), centromedian nucleus (CM), and pulvinar (PUL) has emerged as a promising therapy. The clinical investigation of these targets’ efficacy and side effect profiles is ongoing, complicating discussions between neurosurgeons, neurologists, and patients. The implementation of single-pulse and continuous stimulation protocols to conduct patient-specific side effect screens and generate prognostic biomarkers could offer guidance for target selection. OBSERVATIONS A 32-year-old male with extensive polymicrogyria and DRE underwent stereo-electroencephalography (SEEG) with multisite thalamic sampling to inform neuromodulation target selection. Single-pulse stimulation was conducted to screen for acute sensorimotor effects, followed by continuous (12- to 24-hour) stimulation using clinically relevant parameters. Intolerable paresthesia occurred during CM single-pulse stimulation, leading to its exclusion as a target. Single-pulse and continuous stimulation of the ANT and PUL were well tolerated. PUL stimulation offered superior suppression of epileptiform discharges during sleep. LESSONS These findings meaningfully informed the selection of the PUL as a neuromodulation target. This case illustrates the safety, feasibility, and utility of patient-specific single-pulse and continuous stimulation assessments during SEEG monitoring to evaluate efficacy and tolerability prior to chronic neuromodulation, particularly for novel thalamic targets. https://thejns.org/doi/10.3171/CASE25947

Abstract Background X‐ray Induced Acoustic Computed Tomography (XACT) is an emerging imaging technique that provides 3D volumetric images from a single projection by detecting X‐ray‐induced acoustic (XA) waves with ultrasound (US) transducers. Unlike MRI or CT, XACT enables real‐time 3D imaging without long acquisition times, 2D limitations, or motion artifacts from mechanical rotation. Furthermore, when integrated with conventional pulse‐echo US through time‐sequenced operation, XACT provides complementary soft‐tissue contrast, establishing it as a promising platform for dynamic interventional radiology (IR) guidance. Purpose This study aims to evaluate the feasibility of XACT as a novel imaging tool for IR, specifically for guiding needle placement and monitoring contrast agent dynamics. Methods We developed a 3D XACT imaging system equipped with a 256‐element 2D matrix array and a portable X‐ray tube to visualize needle insertion and contrast agent dynamics. To capture both needle position and soft tissue anatomy, we integrated a dual‐modality system combining XACT with pulse‐echo US using a 128‐element linear US array. Experiments were conducted on both tissue‐mimic phantoms and soft tissue samples. GPU‐accelerated algorithm has been developed for 3D XACT image reconstruction. Results The results demonstrate the 3D capabilities of XACT imaging for interventional procedures, including monitoring of needle placement and tracking of contrast agent dynamics. The imaging speed reached up to 3∼4 s per frame, constrained by the repetition rate of the X‐ray source and signal to noise ratio. The dual‐modality approach provided clear visualization of the needle's position and the surrounding soft tissue structures, achieving imaging resolution around 2 mm. Conclusions This study demonstrates that XACT imaging is feasible to be used for IR. Its 3D imaging capability with faster imaging speed would be an alternative to cone beam CT and its capability to combine US imaging will provide richer information for soft tissue

Management of unstable upper lumbar fractures with corpectomy and posterior fixation is technically demanding, and conventional workflows may require intraoperative repositioning, increasing operative complexity. Lateral mini-open upper lumbar corpectomy (LMULC) paired with robotic-assisted (RA) posterior percutaneous pedicle screw fixation (PPPSF) can be performed in a single position to facilitate ventral spinal decompression and stabilization in the anatomically constrained upper lumbar spine. In this study, we describe the operative technique and report four illustrative cases of unstable L1 or L2 fractures treated with single-position LMULC, RA-PPPSF, and short-segment fusion. Clinical, radiological, intraoperative variables and postoperative outcomes were evaluated. The mean age was 52.3 ± 17.7 years. The median operation time was 314 min (range 268–361 min); the median estimated blood loss (EBL) was 225 mL (range 100–400 mL). The median preoperative kyphosis was 10.15° (range 8.4–14.6°), the median postoperative kyphosis measured 6.65° (range 1.7–10.8°) and the median correction achieved was 3.5° (range −2.4–12.9°). The median visual analog scale (VAS) pain score reduced from 7 (range 7–9) preoperatively to 4.5 (range 2–6) postoperatively at discharge. At a median follow-up of 12 months (range 6–15 months), all patients had uncomplicated recoveries, demonstrated solid fusion on imaging, and reported favorable MacNab outcomes. Single-position LMULC with RA-PPPSF was technically feasible in this preliminary illustrative series and resulted in favorable clinical and radiographic outcomes. However, further studies in larger cohorts are warranted to help confirm these findings and better define the potential advantages and limitations of this technique.

Objective To evaluate cancer risk in individuals with cleft lip and/or cleft palate (CL/P). Design Retrospective chart review of patients with CL/P, including abstraction of information on cancer diagnoses was conducted. Cancer risk was compared with national population-based estimates using standardized incidence ratios (SIRs) and exact binomial tests. Subgroup analyses compared demographic and clinical characteristics between patients with and without cancer. Setting Study was performed at a single tertiary academic center with multidisciplinary surgical, pediatric, and genetic care. Patients/Participants Total of 2121 patients with CL/P from 1970 to 2024 with complete medical documentation were included. Main Outcome Measures Main outcomes included prevalence of cancer diagnoses, childhood cancer incidence, and differences in cancer occurrence by age, cleft type, syndromic status, and family history. Results Total of 144 patients (6.8%) had pathologically confirmed cancer diagnoses. Twelve childhood cancers were identified, with 10 cases presenting before age 15. Children younger than 15 with CL/P had a significantly elevated cancer risk (SIR 4.7; 95% confidence interval: 1.8-7.6; P < .00001). Pediatric cancers occurred mainly in syndromic cases. Cancer prevalence was higher in cleft palate only and cleft lip/palate cases compared with cleft lip only ( P < .05). Cancer occurrence was not higher in adults with CL/P compared to the general population. Conclusions Cancer risk is not uniformly elevated over the lifespan in individuals with CL/P. Increased cancer risk is observed in our pediatric cohort. Clinical care should include careful assessment of childhood cancers, syndromic features, and family history, with consideration for genetic counseling and multidisciplinary follow-up.

Abstract Breast and ovarian cancers are major causes of cancer mortality in women with frequent relapse after curative intent treatment, underscoring the need for novel therapeutics. To this end, we identified CTPS1 as an essential gene in multiple breast and ovarian cancer models, including those resistant to chemotherapy and PARP inhibitors. CTPS1 and CTPS2 are responsible for de novo synthesis of cytidine triphosphate (CTP) which is required for DNA/RNA polymerization, phospholipid synthesis and protein glycosylation. We found CTPS1 to be the predominant isoform expressed in cancer cells, with significantly higher levels in advanced and resistant disease models compared to normal tissue, benign lesions and treatment naïve cancers. Using CTPS1 siRNAs and CTPS1-dTAG (degradation tag) cell lines, we discovered that depletion of CTPS1 induces S-phase cell cycle arrest followed by apoptosis. Leveraging a first-in-class, highly selective, and orally bioavailable CTPS1 inhibitor (STP938) developed by Step Pharma, we identified nanomolar IC50 values across a panel of cell lines, both in 2D and 3D culture systems, and potent anti-neoplastic activity ex vivo and in vivo using patient-derived xenograft (PDX) models. STP938 also synergized with standard-of-care chemotherapy agents and PARP inhibitors, including in therapy-resistant models. Given the essentiality of CTP for biosynthetic processes, we performed bulk and single cell RNA-seq, total and phospho-proteomics, metabolomics, and lipidomic strategies to examine changes induced by acute and chronic STP938 exposure. This revealed that cancer cells are able to overcome pharmacologic CTPS1 inhibition by rewiring of pyrimidine and purine synthesis pathways, upregulation of the pentose phosphate pathway, and extensive remodeling of lipid synthesis pathways including shifts in PC/PE content, increased lysophospholipid production, and altered mitochondrial lipid composition (decreased cardiolipin and increased PG). To identify genetic drivers of STP938 resistance and synthetic lethal vulnerabilities, we performed a genome-wide CRISPR knockout screen together with a PRISM drug sensitivity screen. Genes regulating dNTP biosynthesis, S-phase progression, and RNA processing were identified as primary escape mechanisms, while DHODH inhibitors, purine and nucleoside analogs, and mitosis modifiers were implicated as synthetic lethal opportunities. Notably, we discovered that 25% of ovarian tumors lack CTPS2 protein expression, suggesting near complete reliance on CTPS1 for survival. Thus, a Phase 1a/b clinical trial of STP938 (NCT06297525) has been initiated, including an expansion cohort for patients with CTPS2-null ovarian tumors. These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Epp, Esther Rodman, Noa Odell, Hannah Smith, Nicole Pearson, Xiaonan Hou, Matthew Goetz, Scott Kaufmann, S. John Weroha, Phillip Beer, John Hawse. CTPS1 as a metabolic vulnerability and novel therapeutic target in breast and 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 4560.

Abstract Background: Most colorectal cancer (CRC) arises from polyps and is mainly prevented by polypectomy. The most important polyps to manage with colonoscopy are those with highest CRC risk- namely, advanced polyps (&gt; 1cm, villous histology or high-grade dysplasia (HGD). Yet, 48% of advanced polyps recur within 1 to 3 years of removal, and up to 5% of advanced polyps under surveillance still progress to CRC. We performed this pilot study to investigate molecular and microenvironment heterogeneities of polyps and how they might impact their clinical behavior. Methods: GeoMx spatial transcriptomics was performed on FFPE tissues from three different polyp outcome phenotypes (POPs) including the polyp that does not recur (POP-NR), that recurs following polypectomy but cured by colonoscopy (POP-R) or the polyp despite polypectomy develops CRC at the polypectomy(ies) site (POP-CRC). Normal colon and polyp with low or HGD from the index polyp were assessed from 6 patients with POP-NR, 9 with POP-R and 12 with POP-CRC with a minimum of 2 follow up colonoscopies at 3-year intervals. Epithelium was identified as PanCK positive, and stroma identified as PanCK negative and positive nuclear staining. Cell type deconvolution was implemented using single-cell adult human intestinal tract catalogue (Elmentaite et al., https://www.gutcellatlas.org/). Differential gene expression (DEG), cell type abundance and functional enrichment analyses was performed using linear mixed effects model, and observations with p-value &lt; 0.05 and log2FC &gt;= |1| are reported. Results: The greatest number of DEGs were identified in stroma of the index POP-CRC compared to POP-NR polyps (n = 17 down and 11 upregulated genes), followed by epithelium of the index POP-CRC vs POP-NR polyps (n = 10 down and one upregulated gene(s)). Between the index POP-CRC and POP-R, epithelium showed downregulation of 7 genes, and upregulation of no genes. In stroma two genes were down and none upregulated. Four genes were downregulated in stroma of the index POP-R vs POP-NR polyp and 3 in epithelium, and one gene was upregulated in stroma and another in epithelium. MZT2B was upregulated in stroma of both the index POP-R (log2FC = 1.09, p-value = 0.0014) and POP-CRC (log2FC = 1.29, p-value = 0.0001) and has been implicated as a prognostic marker associated with worse prognosis in certain cancers. IgM and IgA plasma cells, proximal progenitors, MMP9+ inflammatory macrophages and myofibroblasts were found to be downregulated in epithelium of index POP-CRC and POP-R compared to POP-NR polyps; while microfold cells were downregulated in stroma of index POP-CRC and POP-R compared to POP-NR polyps. Conclusions: The stromal microenvironment and less so, epithelial features present in the index polyp differ based on a polyp’s future clinical behavior. The polyp-immune interaction warrants further study as a potential prevention target against polyp progression. Citation Format: Mrunal Dehankar, Lisa A. Boardman, Daniel O'Brien, E. Aubrey Thompson, Jennifer M. Kachergus, Ji Shi, Alexej Abyzov, Milovan Suvakov, Rondell P. Graham, Chen Wang. Stromal immune composition significantly contributes to adenomatous polyp recurrence or progression to 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 4018.

Abstract Background: PD-L1 is best known for suppressing antitumor immunity at the cell surface, yet emerging evidence suggests additional nuclear functions. Previous studies from our laboratory demonstrated that nuclear PD-L1 interacts with the cohesin complex to maintain chromosomal stability. However, the upstream regulatory mechanism governing this interaction and its immunological consequences remain unknown. Methods and Results: Using acetylation-site prediction, mutagenesis, and structural modeling, we identified lysine 178 (human) / 177 (mouse) as a conserved acetylation switch regulating PD-L1 function. Deacetylation of PD-L1 (K178R/K177R) disrupted PD-L1-PDS5B/cohesin binding without affecting subcellular localization. This led to defective sister chromatid cohesion, micronuclei formation, and cytosolic DNA accumulation. RNA-seq, qPCR, and immunoblotting demonstrated robust activation of the cGAS-STING-IFN-γ signaling axis and enhanced MHC-I antigen-presentation machinery in PD-L1 K178R cells. Functionally, K178R cells proliferated more slowly and were highly susceptible to PBMC-mediated killing in co-culture assays, with further enhancement upon anti-PD-L1 antibody treatment. In xenograft models (NSG mice), tumors expressing PD-L1 K178R grew significantly slower than WT. In immunocompetent C57BL/6 syngeneic models, PD-L1 K177R tumors showed reduced growth and heightened responsiveness to PD-L1 blockade. Structural and biochemical analyses confirmed that PD-L1 acetylation at K178/K177 stabilizes its interaction with the cohesin complex, thereby preventing chromosomal instability-induced immune activation. Conclusions: We identify a conserved PD-L1 acetylation switch that couples cohesin stability to innate immune activation. PD-L1 deacetylation promotes chromosomal instability, activates cGAS-STING-IFN-γ signaling, enhances antigen presentation, and sensitizes tumors to PD-L1 immunotherapy. These findings uncover a previously unrecognized regulatory axis linking tumor genomic integrity to immune recognition, providing a mechanistic foundation for targeting PD-L1 acetylation in cancer treatment. Citation Format: Meijie Wang, Jia Yu, Liewei Wang. A pd-l1 acetylation switch coordinates chromosome cohesion and antitumor immunity [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 7391.