Citations

Abstract Introduction: Pathological complete response (pCR) is a strong prognostic marker, but survival outcomes comparing treatment to control do not reliably align with treatment-control differences in pCR rates in breast cancer. A novel Bayesian hierarchical framework models treatments within trials, allowing us to predict treatment effects on distant recurrence-free survival (DRFS) from pCR with greater accuracy. Methods: We analyzed 12 neoadjuvant breast cancer trials (6,000 patients, all HR/HER2 subtypes; including I-SPY2). The framework of Burzykowski, Molenberghs & Buyse (2005) is extended to a novel arm-based hierarchical structure providing a distribution of pCR and DRFS treatment effects controlling for subtype (HR/HER2), N and T stage, grade, and calendar year. Three held-out trials (877 patients; 26 regimens; med follow-up >4 years) validate predictions of DRFS treatment benefit from pCR. All data was used to estimate treatment-effect correlation and the surrogate threshold effect (STE). Analyses were repeated for Residual Cancer Burden Index (binary RCB01, continuous RCB). Results: Predicted probability of DRFS benefit closely matched actual DRFS follow-up (mean absolute error 0.06; Pearson r = 0.9). Across all trials, pCR showed moderate surrogacy (ρ = 0.82, R2 = 0.67). A 60% increase in pCR odds achieves ≥95% probability of DRFS benefit (STE = OR of 1.60). RCB outperforms pCR across all metrics, with 92% sensitivity and 93% specificity for detecting DRFS benefit in 26 validation regimens (Table 1). Conclusion: This novel Bayesian meta-analytic framework reveals that pCR, RCB01 and continuous RCB reliably predict survival benefit across heterogeneous trials, with RCB performing the best in an external validation. This provides a statistical foundation for accelerated approval decisions using robust early biomarkers in modern neoadjuvant trial designs by accurately predicting survival at the treatment arm level. Citation Format: Keli S. Santos-Parker, Jessica R. Santos-Parker, W. Fraser Symmans, Laura J. Esserman, Christina Yau, Angie DeMichele, Laura van't Veer, Doug Yee, Fabien Reyal, Helena Earl, Jean Abraham, David Cameron, Peter Hall, Judy Boughey, Matthew Goetz, Gabe Sonke, Miguel Martín, Sara López-Tarruella, Priyanka Sharma, Rachel Freiberg, Jane Perlmutter, Aditya Bardia, Martin Eklund, Rachel Freiberg, Lajos Pusztai. A novel statistical framework for surrogate endpoint prediction of survival in neoadjuvant breast cancer trials [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 1401.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies due to its silent clinical onset, rapid progression, and limited responsiveness to current treatment options. These features underscore the urgent need for early detection strategies and for new molecular targets that can be exploited therapeutically. Epithelial Cell Transforming Sequence 2 (ECT2) is a Rho family guanine nucleotide exchange factor that was originally identified as an oncoprotein and later shown to regulate cytokinesis. In this study, we examined the clinical relevance of ECT2 expression in PDAC and determined its functional contribution to transformed growth and tumorigenicity. Our analyses revealed that ECT2 expression increases at the earliest stages of PDAC development, remains persistently elevated during disease progression, and associates with reduced overall patient survival. Furthermore, a substantial fraction of ECT2 is aberrantly localized to the cytoplasm of PDAC cells. Functional studies demonstrated that depletion of ECT2 suppresses three-dimensional growth, invasive behavior, and tumor formation in vivo, while having little impact on PDAC cell cytokinesis. Mechanistically, we found that ECT2 is required for activation of Rac1 and RhoA and downstream MEK/ERK and ROCK signaling, respectively. Consistent with these results, analyses of PDAC patient datasets revealed a strong positive association between ECT2 expression and Rho GTPase as well as MEK/ERK and ROCK pathway signatures. Together, our data identify ECT2 as an early driver of PDAC transformation and highlight it as a promising therapeutic target. Citation Format: Dania Al-Qasrawi, Nayya N. Murray, Ryan A. Argo, Alicia K. Fleming Martinez, Prita Pandya, Anaya Y. Clarke, Kayla C. Winter, Murli Krishna, Peter Storz, Nicole R. Murray, Verline Justilien, . The Rho-GEF ECT2 links Rho GTPases to MEK/ERK pathway activation in pancreatic ductal adenocarcinoma [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 5993.

Abstract Artificial intelligence (AI)-scores estimated from digital mammograms predict future breast cancer (BC) risk. MIRAI is a deep learning BC risk model that provides a continuous 5-year risk of overall BC from four screening full field digital mammograms. Common germline genetic variation in the form of a polygenic risk score (BC-PRS) is associated with increased BC risk and may improve MIRAI’s 5-year risk prediction. Our goal was to develop an updated MIRAI 5-year risk model that incorporates the BC-PRS (MIRAI+PRS) and to evaluate its discriminatory accuracy and calibration for both overall and invasive BC compared to MIRAI alone. We developed the MIRAI+PRS model by multiplying each woman’s 5-year MIRAI risk estimate by their relative risk based on their BC-PRS relative to the population mean. We evaluated the models within the Mayo Clinic Biobank mammography cohort, comprised of 12,307 women without a prior history of BC; 176 invasive and 250 overall BC were diagnosed within 5 years. MIRAI was estimated on screening mammograms closest to enrollment but at least 6 months prior to BC. Discriminatory accuracy, assessed by C-statistic, was high and similar for MIRAI+PRS vs. MIRAI models, for overall BC and invasive BC (Table). Calibration assessed by observed to expected (O/E) ratios was also similar for MIRAI+PRS compared to MIRAI predictions for BC outcomes (Table), although there was improvement in decile-specific O/E ratios across the lowest risk deciles (<1.67%) for MIRAI+PRS. Calibration for invasive cancer was poor for MIRAI with or without PRS. In summary, the MIRAI+PRS risk model did not result in significant difference of discriminatory accuracy or overall calibration compared to the MIRAI model, but there was evidence for improved calibration for women with 5-year risk below 1.67%. For invasive BC, the model had poor calibration regardless of whether PRS was included, underscoring the importance of training AI models for BC outcomes that are associated with a clinical intervention. Citation Format: Christopher G. Scott, Peter Kraft, Imon Banerjee, Ramon Correa Medero, Aaron D. Norman, Fergus J. Couch, Karla Kerlikowske, Stacey J. Winham, Celine M. Vachon. Development and evaluation of a MIRAI 5-year risk model with a breast cancer polygenic risk score [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 2779.

Abstract Introduction/Objectives: The CARMA1-BCL10-MALT1 (CBM) signalosome plays crucial role in mediating antigen receptor-induced activation of NF-κB transcription factor and subsequent lymphocyte activation. The effector protein of the signalosome, MALT1, functions both as a scaffold to recruit downstream NF-κB signaling machinery, and as a protease to cleave and inactivate multiple substrates including negative regulators of NF-κB. Constitutive MALT1 activation, which can occur as a result of gain-of-function mutations of the B cell receptor, CARMA1, BCL10 or chromosomal translocation involving the MALT1 gene, underlies the pathogenesis of multiple lymphoid malignancies including activated B-cell type-diffuse large B-cell lymphoma (ABC-DLBCL) and MALT lymphoma. We previously identified G-protein-coupled receptor kinase 2 (GRK2) as a tumor suppressor in MALT1-dependent lymphomas which binds MALT1 and inhibits MALT1 scaffolding and proteolytic activities. Accordingly, GRK2 mRNA levels are markedly lower in a subset of DLBCL tumors compared to normal B cells and lower GRK2 level in ABC-DLBCL is associated with reduced patient survival. In current study, we sought to investigate the mechanism of how GRK2 levels are regulated in ABC-DLBCL. Methods/Results: Using DICER1 depleted cells, we showed that globally impaired miRNA processing leads to increased GRK2 protein levels. We then conducted bioinformatic analyses of patient tumor samples and performed screening via microRNA Data Integration Portal to identify microRNAs that target GRK2 in ABC-DLBCL. Further GRK2 3’UTR reporter assay confirmed direct targeting of GRK2 by candidate miRNAs. ABC-DLBCL cell lines, OCI-LY3 and TMD8, which demonstrate reduced GRK2 mRNA expression compared to primary B cells, show elevated expression of candidate GRK2-targeting microRNAs. Stable overexpression of miR-125a, 125b, or 148b in OCI-LY3 or TMD8 cells led to reduced GRK2 expression, enhanced MALT1 activity and increased cell proliferation. Conversely, in vitro inhibition of candidate miRNAs using anti-miRNA Locked Nucleic Acids (LNA) inhibitors led to enhanced GRK2 expression, reduced MALT1 activity and decreased cell proliferation. Importantly, treatment of mice with inhibitors of miR-125b and miR-148b abrogates the growth of ABC-DLBCL xenograft tumors in vivo. Conclusion: We have identified miRNAs that negatively regulate GRK2 expression in ABC-DLBCL. These GRK2-targeting miRNAs serve a pro-tumorigenic role by promoting MALT1 oncoprotein’s scaffold and protease activity. Furthermore, inhibitors of these miRNAs can enhance GRK2 expression and thereby suppress MALT1 activity and MALT1-dependent tumor cell proliferation, both in vitro and in vivo. These studies suggest that microRNA inhibitors which enhance GRK2 expression could represent a novel approach for restraining MALT1-dependent lymphomagenesis. Citation Format: Jing Cheng, Mei Smyers, Matt Trotta, Neil M. Carleton, Lisa M. Maurer, Uma R. Chandran, Min Xia, Ari M. Melnick, Peter C. Lucas, Linda M. McAllister-Lucas. MicroRNAs targeting tumor suppressor GRK2: Novel potential therapeutic strategies for restraining MALT1-dependent DLBCL [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 2061.

Abstract The detection of genetic abnormalities is required during diagnostic workup and for potential individualization of therapy selection in multiple myeloma (MM) and its precursor conditions. At present, this relies on invasive bone marrow (BM) biopsies, severely limiting early detection, frequent longitudinal monitoring, and the precise selection of therapy. The current standard for detecting genetic alterations in MM is fluorescence in situ hybridization (FISH), which cannot detect point mutations and other clinically relevant alterations. Consequently, the IMS-IMWG guidelines were recently updated to require next-generation sequencing for the classification of high-risk MM. To address these needs, we recently launched GenoPredicta, a CLIA-approved LDT that enables routine monitoring, informing diagnosis, and treatment selection by comprehensively characterizing MM genomes with whole genome sequencing (WGS) from as few as 50 circulating tumor cells (CTCs) isolated from peripheral blood (PB) or tumor cells from BM. Briefly, tumor cells are isolated from samples using fluorescence-activated cell sorting and subjected to WGS, from which copy number alterations, structural variants, and short variants (SNVs/indels) are identified using a fully automated pipeline generating physician-ready clinical reports from raw sequencing data in ∼6h. Analytical validation of GenoPredicta showed complete concordance with FISH results. Identifying alterations in therapeutic targets (e.g., BCMA, GPRC5D) for guiding MM immunotherapies is becoming increasingly important. Here, we describe GenoPredicta results from relapsed/refractory MM patients, highlighting resistance-conferring alterations that can only be detected by WGS, such as deletions in the kilo- to megabase scales that are observed in conjunction with SNVs and indels, leading to biallelic loss/inactivation of the gene, including at subclonal levels. In addition to biallelic loss of BCMA and GPRC5D in response to CAR T or T cell engager therapies, we observed similar resistance mechanisms for targets of immunomodulatory drugs, e.g., CRBN. The observation of these resistance mechanisms was consistent with patients’ clinical histories. In summary, we demonstrate that low input WGS-based characterization of MM from BM or CTCs is a viable replacement for FISH for clinical diagnosis and monitoring, with CTC-based measurements enabling comprehensive profiling of the MM genome. Crucially, this includes genetic alterations that confer resistance to therapy, allowing for both early detection of such alterations and more precise selection and guidance of therapy. The dramatically improved variant calling ability from WGS, especially in low-input CTC applications, extends to other malignancies and will gain wider adoption as sequencing costs continue to decrease. Citation Format: Bruno Paiva, Peter Voorhees, Patricia T. Greipp, Danielle Sookiasian, Julian Hess, Marisa DeMeo, Vicki Pounder, Sarah Calkins, Reid Meyer, Linda B. Baughn, Christine-Ivy Liacos, Meletios-Athanasios Dimopoulos, Alexandra Papadimou, Taouxi Konstantina, Efstathios Kastritis, Jesus Berdeja, Daniel Auclair, Valentina Nardi, Thomas Mullen, Francois Aguet, Shaji Kunnathu Kumar. Whole genome sequencing of multiple myeloma genomes with a novel clinical assay enables identification of genetic alterations underlying immunotherapy resistance [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 1067.

Abstract Introduction: Long intergenic noncoding RNAs (lincRNAs) and circular (circ) RNAs have been shown to play key roles in carcinogenesis and tumor progression. Urine represents a promising source of tumor-reflective signals shed directly from the urothelial microenvironment in bladder cancer (BC) patients. Here, we evaluate the urine cell-free (cf) RNA transcriptome in a cohort of 50 patients with localized BC. Methods: A total of 50 localized BC patients and 24 healthy adults were enrolled. Pre-operative urine (collected on the day of radical cystectomy) was processed to isolate cfRNA from urine supernatant. Libraries were prepared using an Illumina tagmentation-based RNA enrichment workflow and sequenced to 100M paired-end reads per sample on a NovaSeq X. FASTQ files were concatenated per sample and QC-checked with RNA-SeQC and Samtools. Reads were aligned to GRCh38/hg38 with STAR, and gene counts were generated using Feature Counts. Linear differential expression analysis (DEA) was performed with DESeq2. For discovery we used random halves of TCGA-BLCA and healthy urine cfRNA samples, alongside a second DEA with random halves of urine BC cfRNA vs. controls; overlapping upregulated genes were validated in the remaining samples. For circular (circ) RNAs, annotations from MiOncoCirc were used; junctions with ≥5 supporting reads were retained, and DEA was conducted with edgeR. Results: In this study, the median age was 68 years, and 80% (40/50) were male. Among the cohort, 66% (33/50) had muscle-invasive bladder cancer (MIBC), of whom 54% received neoadjuvant chemotherapy. Differential expression analysis of TCGA-BLCA tumors and BC urine cfRNA, identified 27 genes commonly upregulated, with 23 of the 27 shared genes strikingly being long intergenic noncoding RNAs (lincRNAs). These BC/urine-specific lincRNAs—including LINC00930, LINC01004, DLG5-AS1, APTR, PSORS1C3, and SERPINB9P1—have known roles in proliferation, EMT, metabolism, and immune signaling. Outside of lincRNAs, tumor-reflective coding transcripts in BC/urine were enriched for autophagy, driven by MAP1LC3B2.TCGA-BLCA survival analysis showed that LINC00930 and PSORS1C3 were associated with worse overall survival. Expanding beyond linear RNA sequences, analysis of urine circRNAs from BC patients revealed a strong cancer-specific dysregulation pattern, with 77 circRNAs significantly upregulated compared with healthy controls. Upregulated urine circRNAs arose from host genes involved in BC-relevant pathways, including invasion (DOCK1, ARHGAP5), autophagy/ER stress (VMP1, ERN1), and luminal differentiation (GRHL2, ESRP1). Conclusion: Cell-free RNA profiling reveals a distinct transcriptomic signature including differential lincRNA- and circRNA-driven autophagy, EMT, proliferation, metabolic, differentiation, and immune signaling programs in the urine of bladder cancer patients. Citation Format: Pradeep Chauhan, Li Lin, Irfan Alahi, Jessica Linford, Lilli J. Greiner, Ayesha Hashmi, Anushka Viswanathan, Nathan Colon, Faridi Qaium, Peter K. Harris, John Sheng, Jacob J. Orme, Eric H. Kim, Zachary L. Smith, Woodson Smelser, Christopher A. Maher, Aadel A. Chaudhuri. Urine cell-free RNA captures tumor-reflective long intergenic noncoding and circular RNA programs in bladder 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 1133.

Abstract Introduction: Detectable circulating tumor DNA (ctDNA) is associated with inferior outcomes in Ewing sarcoma (ES); however, ctDNA clears in nearly all patients within 2 of the 6 chemotherapy cycles before radiotherapy (RT) or surgery. Given a 3-year EFS of 37% on AEWS 1221 (metastatic) and 5-year EFS of 78% on AEWS 1031 (localized), current ctDNA testing fails to predict most relapses. Extracellular vesicles (EVs) are microscopic particles studied as a biomarker in multiple cancer types. We hope to improve the sensitivity of ctDNA in ES and provide the first application of EVs in ES. Methods: cfDNA was isolated from 1mL plasma, quantified by Qubit, and sequenced as NEBNext Enzymatic Methyl-seq v2 libraries. We performed a systematic unsupervised clustering analysis of 27 ES plasma cfDNA profiles using 4 differentially methylated regions (DMR) subsets (63 strong DMRs, top 30, top 15, and 10 promoter-proximal loci), 3 clustering algorithms (k-means, Ward hierarchical, PAM), and k=2-5 clusters, testing associations with tumor burden and progression. EV analysis involved antibody detection against ES surface markers, including LINGO1, ENPP1, CDH11, and CD99. Concentrations of EVs were determined by standardized and calibrated high-resolution flow cytometry then analyzed with custom-built software to automatically determine and apply gates. Samples were de-identified, randomly coded, and run in triplicates. The senior research technologist responsible for EV analysis was blinded to patient information and clinical data. Results: EV analysis included 36 pre-RT samples from 16 metastatic and 20 localized ES patients from a prospectively maintained biobank, with 27 pre-RT samples in the cfDNA analysis and 19 healthy donor (HD) samples. 35 of 36 patients had chemotherapy before sample collection. cfDNA concentrations were markedly elevated in ES patients compared with HD (24.4 vs 4.6 ng/mL, p<0.0001), and 74% of ES samples exceeded the HD 95th-percentile detectability threshold (7.0 ng/mL). Across clustering configurations, ES cfDNA profiles consistently exhibited reproducible methylation substructure. One configuration (PAM clustering, k = 5, 63 strong DMRs) showed a modest but permutation-supported association with primary tumor size (nominal p ≈ 0.04; empirical p ≈ 0.03-0.04). ES samples had increased EV concentration compared to HD (p<0.001), with AUC 0.988 for distinguishing between ES and HD ENPP1 (p<0.0001). The highest ENPP1 EV values were in patients with large primary tumors (>8 cm vs. ≤ 8cm) and metastatic disease (p=0.066). Conclusions: cfDNA- and EV-based liquid biopsy provide encouraging signals for high ES detectability pre-RT. We also show the first study of EVs as a novel biomarker in ES, which may provide complementary information to ctDNA. Multimodal liquid biopsy in ES may identify candidate patients for systemic or local therapy escalation and facilitate personalized care. Citation Format: Roman O. Kowalchuk, Lilli J. Greiner, Yohan Kim, Rubia Noori, Jeffrey Szymanski, William S. Harmsen, Pradeep S. Chauhan, Adam C. Amundson, Andrea M. McMahon, Peter J. Schoettler, Wendy A. Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly M. Bailey, Linda M. McAllister-Lucas, Anita Mahajan, Fabrice Lucien-Matteoni, Nadia N. Laack, Aadel A. Chaudhuri. Multimodal liquid biopsy of Ewing sarcoma reveals high sensitivity prior to radiotherapy [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 1149.

Abstract Background: Spatial cellular ecosystems in the tumor microenvironment (TME) form dynamic signaling hubs that critically influence cancer disease progression and response to therapy, including response to immune checkpoint inhibitors (ICIs). However, tumor sampling bias and the impracticality of acquiring serial tumor biopsies have made it challenging to profile the TME clinically. To address this challenge, we developed Liquid EcoTyper, a multi-analyte AI framework to quantify TME spatial cellular ecosystems—termed spatial ecotypes (SEs)—noninvasively from cell-free DNA (cfDNA) methylation data. Methods: In previous work, we discovered nine spatial ecotypes, including SEs associated with ICI response (e.g., SE7 with benefit, SE4 with resistance), and quantified them from 1,249 bulk tumor RNA-seq profiles of melanoma, non-small cell lung cancer (NSCLC), and bladder cancer (BC) patients (Cancer Res (2025) 85 (8_Supplement_1): 153). Here we trained Liquid EcoTyper, an interpretable deep learning model, to transfer SE profiling to cell-free DNA using CpG methylation profiles. Performance was quantified using simulated and real data, including methylation profiles (EM-seq) of plasma cfDNA paired with tumor biopsy-derived SE levels determined by EM-seq (n=20 pairs) or 10x Visium (n=15 pairs). Clinical outcome prediction was evaluated using pretreatment plasma from patients treated with ICI alone (n=78 melanoma pts), chemotherapy and ICI (n=25 NSCLC pts), and enfortumab vedotin and ICI (n=10 localized muscle-invasive BC (MIBC) pts). Tumor mutational burden (TMB), tumor PD-L1, or circulating tumor DNA (ctDNA) were profiled as a comparator where possible. Results: We observed striking concordance between plasma-derived SE levels and tumor biopsy-confirmed SE levels from the same patients, demonstrating that liquid biopsy analysis of cfDNA methylomes can recapitulate TME spatial biology. Underscoring specificity, no reliable SE signal was detectable from peripheral blood mononuclear cells. In pre-ICI plasma, liquid SE levels were significantly associated with ICI-based response (SE7) versus resistance (SE4) in patients with melanoma, NSCLC, and MIBC, with a mean cross-cancer area under the curve (AUC) of 0.87 for SE7 (range 0.8-0.97) and 0.81 for SE4 (range 0.76-0.85)—far surpassing TMB, tumor PD-L1, and ctDNA in evaluable patients, both in binary analyses of response and multivariable models of survival. Our results also showed potential to predict pathologic complete response in the neoadjuvant setting. Conclusion: Liquid EcoTyper is a scalable noninvasive AI-based framework for spatiotemporal assessment of the TME. By enabling TME-informed risk stratification without surgical biopsies, Liquid EcoTyper has potential to enable more precise and actionable decision making in patients with solid tumors. Citation Format: Erin L. Brown, Wubing Zhang, Abul Usmani, Noah Earland, Ayesha Hashmi, Chibuzor Olelewe, Anushka Viswanathan, Pradeep S. Chauhan, Minji Kang, Chloé B. Steen, Hyun Soo Jeon, Susanna Avagyan, Irfan Alahi, Nicholas P. Semenkovich, Matteo Bergsagel, Janella C. Schwab, Chloe M. Sachs, Faridi Qaium, Peter K. Harris, Antonella Bacchiocchi, Qingyuan Cai, Andrew J. Gentles, Rondell P. Graham, Peter C. Lucas, Ryan C. Fields, Jacob J. Orme, Aaron S. Mansfield, Mario Sznol, Ruth Halaban, David Y. Chen, Aaron M. Newman, Aadel A. Chaudhuri. Liquid biopsy profiling of the tumor microenvironment to determine response to immunotherapy regimens across solid tumors [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 94.

Aims A type III internal hemipelvectomy includes resection of the pubic rami. Although bony reconstruction is not necessary, the integrity of the abdominal wall is deficient following resection. The aim of this study was to report the outcome of soft-tissue reconstruction following these resections. Methods We retrospectively reviewed all isolated type III internal hemipelvectomies which were undertaken at the Mayo Clinic (Rochester, USA) between January 2002 and December 2022. The group included 25 patients, of whom 14 (56%) were male. Their median age was 45 years (IQR 61 to 31) at the time of surgery. Most patients (n = 18; 72%) underwent resection for a sarcoma. Soft-tissue flaps were used in 21 patients (84%) and nine also had a mesh reconstruction. Results The five-year disease-specific survival was 65% following surgery, with significantly worse survival in patients with locally advanced tumour (35% (95% CI 12 to 100) vs 76% (95% CI 59 to 99); p = 0.036). Complications were common, with 21 patients (84%) having at least one complication, and 12 (48%) having several complications. Most commonly, this included seroma or haematoma (44%), wound dehiscence (40%), and infection (40%). The use of a soft-tissue flap did not significantly reduce the risk of infection (hazard ratio (HR) 0.68 (95% CI 0.14 to 3.28); p = 0.638) or seroma or haematoma (HR 0.31 (95% CI 0.30 to 4.14); p = 0.088), but patients who did not have a soft-tissue flap were significantly more likely to develop a hernia (odds ratio 9.0 (95% CI 1.14 to 71.03); p = 0.027). A total of three of 21 patients (14%) whose reconstruction involved a flap had donor site complications. Conclusion Soft-tissue reconstruction following a type III internal hemipelvectomy reduces the risk of postoperative hernia formation, with a low rate of donor site complications. This additional procedure should be considered for all patients undergoing this type of resection. Cite this article: Bone Joint J 2026;108-B(4):561–566.

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.