Citations

Background The PREPARE trial (Pragmatic Randomized trial Evaluating Pre-operative Alcohol skin solutions in Fractured Extremities), published in February 2024, demonstrated that 0.7% iodine povacrylex in 74% isopropyl alcohol reduced surgical site infections in patients with closed fractures compared with chlorhexidine gluconate in 70% isopropyl alcohol. Prior studies have shown that the translation of clinical trial findings into routine clinical practice and surgical procedures frequently takes longer than a decade, and strategies to accelerate implementation in orthopaedic surgery remain poorly defined. Engaging in a multifaceted implementation strategy with minimal barriers to entry for providers may be able to reduce this time to widespread adoption. Questions/purposes (1) Can the low-cost single-center dissemination efforts of the PREPARE trial results change antiseptic usage? (2) If a true practice change occurs, can the change be sustained over time without additional dissemination efforts? (3) Does the adoption of new evidence vary between fellowship-trained orthopaedic trauma surgeons and orthopaedic trauma surgeons who are not fellowship-trained? (4) What is the economic impact of a practice change to iodine povacrylex on hospital purchasing costs? Methods This was a retrospective, historically controlled comparative study of patients who underwent operative treatment of an extremity fracture at a single, urban, Level I academic trauma center before and after a dissemination effort aimed at increasing PREPARE trial awareness. A multifaceted dissemination strategy consisting of surgeon and nursing education, posted reminders, and supply chain support was implemented at the study site in February 2024. Patients were analyzed across three time periods: before dissemination (January 2020 to January 2024), during the transition (February 2024), and after dissemination (March 2024 to July 2025). An electronic medical record query identified patients with operative fracture management procedural codes who had a recorded antiseptic skin prep in the surgical flow sheet between January 2020 and July 2025. A total of 4822 patients were identified, and 222 duplicate entries were excluded, leaving 4600 patients for analysis (3351 before dissemination, 49 transitional, and 1200 after dissemination). To validate the completeness of our electronic health record query, we performed manual random sampling of monthly operative case logs, confirming that this query strategy successfully identified all patients with the relevant Current Procedural Terminology codes (that is, there were no exclusions for lack of antiseptic documentation). There were no differences in patient demographics, including sex, ethnicity, open fractures, or the distribution of upper and lower extremity fractures. Choice of surgical skin antiseptic was compared before and after dissemination using a log-binomial model. Results Dissemination efforts changed antiseptic use patterns with an immediate increase in iodine povacrylex use from 0.8% (27 of 3351) before intervention to 86% (1033 of 1200) after intervention (OR 765 [95% confidence interval 488 to 1197]; p < 0.001). This high level of use remained stable throughout the 17-month postintervention period without any additional dissemination efforts (p = 0.20 for trend). Adoption was higher among fellowship-trained trauma surgeons (94.8% increase) compared with surgeons without trauma fellowship training (34.7% increase). Hospital antiseptic product purchasing data, which reflect usage and restocking and were used as a secondary metric of practice change, also demonstrated an increase in iodine povacrylex demand and decline in chlorhexidine demand. Conclusion A targeted and multifaceted dissemination strategy led to rapid adoption of iodine povacrylex for use as the preferred surgical skin antisepsis in fracture surgery at our institution, which was sustained over the 17-month postintervention period. This finding contrasts with a historically slow uptake of surgical trial evidence into clinical practice. Pragmatic, low-cost approaches such as surgeon leadership, team-based multidisciplinary education, workflow reminders, and supply chain readiness may help to accelerate translation of evidence into orthopaedic practice. Future studies should evaluate the long-term sustainability of practice changes, surgical site infection outcomes, and generalizability across institutions. Level of Evidence Level III, therapeutic study.

Abstract Gastrointestinal (GI) cancers are rising in people &lt; 50 and remain major causes of cancer mortality despite therapeutic advances. Chimeric antigen receptor T (CART) cell therapy has transformed treatment of hematological cancers. However, its efficacy in GI cancers has been hindered by antigen heterogeneity and immunosuppressive cancer associated fibroblasts (CAFs) in the tumor microenvironment (TME.) Here we aimed to 1) study CART-CAF interactions and 2) engineer CART cells capable of eliminating CAFs to overcome their inhibitory role and enhance their antitumor activity in GI cancers. We first analyzed primary CAFs from 20 GI cancer patients. CAFs showed high fibroblast activation protein (FAP) expression and significantly suppressed T cells proliferation (26-77%, p≤0.0001). We next generated CART cells capable of safely eliminating both GI cancer cells and CAFs. To target cancer cells, we developed a novel nanobody (VHH)-based CAR against Claudin18.2, a GI cancer specific target. To avoid off-tumor toxicity in healthy FAP+ tissues, we incorporated an inducible FAP-CAR using the synNotch platform, enabling conditional targeting upon engagement with Claudin18.2+ cells, restricting FAP targeting within the TME. VHH Claudin18.2 CART cells showed superior specificity and efficacy vs scFv-based CART cells (hu8E85 or zolbetuximab). In Claudin18.2+ SNU-C2B xenografts, tumors were 92mm3 (VHH) vs 48mm3 (huE85) vs 211mm3 (zolbetuximab) on day 23 post-CART, median survival undefined vs 17 days vs 23 days respectively; p=0005. In Claudin18.2+ LS411N xenografts, tumors were 315mm3 vs 106mm3 vs 382 mm3 respectively at 23 days post-CART, median survival undefined vs 19 days vs undefined respectively; p=0004. VHH Claudin18.2 CART cells showed no off-tumor effects, while hu8E85 CART induced significant toxicity. We next established a co-engraftment model. NSG mice received 1x106 SNU-C2B and 6x106 CAFs from a GI cancer patient. At 500 mm3 tumors, mice received 5x106 VHH Claudin18.2 or inducible Claudin18.2/FAP CART. Dual-targeting CART cells showed greater antitumor response (728mm3 vs 320mm3, p=0.0011 at day 20 post-CART), expansion (61 vs 2,350 CART/µl of blood, p=0.0037), and tumor infiltration (8.71 x 105 vs 1.03 x 106 CART/g of tumor, p&lt;0.0001). This was also observed in gastric, colon, and pancreatic PDX models, with no observable off-tumor cytotoxic effects with inducible dual-targeting Claudin18.2/FAP CART. Our findings demonstrate that our novel VHH-based Claudin18.2 CART cells are highly specific and effective against GI malignancies, and that inducible Claudin18.2/FAP dual-targeting CART cells safely remodel the TME into an immune-permissive state. This approach represents a mechanistically innovative and translationally relevant strategy to overcome CAF-mediated immunosuppression, enhance CART cell efficacy, and improve clinical outcomes in refractory solid tumors. Citation Format: Omar L. Gutierrez Ruiz, Jennifer Feigin, Brooke Kimball, R. Leo Sakemura, Elizabeth L. Siegler, Dominic A. Skeele, Ateka Saleh, Claudia Manriquez Roman, Ismail Can, Olivia Sirpilla, Kun Yun, Carli M. Stewart, Mehrdad Hefazi, Yoh Yamaguchi, Lionel Aurelien Kankeu Fonkoua, Long K. Mai, Truc Huynh, Sophia Y. Goldberg, Grace E. DeFranco, Sara Foote, Ekene Johnkennedy Newton Ogbodo, Hong Xia, Michael Redig, Matthew L. Matthew, Tamiel Nichole Turley, Skyeler Klinge, John Alton Copland, Saad J. Kenderian. Optimized CART cell therapy to remodel the tumor microenvironment and eliminate GI malignancies [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 1525.

Abstract BACKGROUND: Tumor-specific T cells are often characterized by reduced TCR signaling due to central and peripheral tolerance pathways that limit their responsiveness. These signals are further weakened by insufficient co-stimulation and active co-inhibitory pathways, collectively establishing a high threshold for activation. The integration of antigen recognition with co-stimulatory and inhibitory cues ultimately determines whether a T cell becomes activated or remains tolerant. Early TCR signaling must therefore be precisely regulated to prevent autoreactivity while still supporting protective immunity. Although phosphorylation and ubiquitination are well-established regulators of proximal TCR signaling, additional post-translational mechanisms remain less defined. SIRT2, a cytosolic NAD+-dependent deacetylase with emerging roles in immune regulation, has not been examined in the context of TCR signaling. METHODS: We evaluated proximal TCR signaling events in wild-type and SIRT2-deficient T cells using flow cytometry, immunoblotting, calcium flux assays, and RNA-sequencing. SIRT2-associated pathways were defined by mapping its interactome and acetylated substrates through mass spectrometry and immunoprecipitation. We screened LCK post-translational modifications by mass spectrometry and assessed SIRT2 enzymatic activity using an HPLC-based deacetylase assay. Conformational effects of LCK modification were examined using fluorescence-polarization binding assays and AlphaFold structural modeling. SIRT2 was deleted in human tumor infiltrating lymphocytes (TILs) via CRISPR/Cas9, and the impact of SIRT2 targeting was tested in lung cancer patient-derived xenograft models reconstituted with autologous TILs. RESULTS: SIRT2 deficiency amplified proximal TCR signaling, leading to elevated phosphorylation of early signaling mediators and increased calcium flux in both naïve and anergic T cells. Loss of SIRT2 also altered thymic selection dynamics and expanded TCR repertoire diversity. Mechanistically, SIRT2 interacted with and deacetylated LCK, the initiating kinase of proximal TCR signaling. Mass spectrometry identified lysine K228 in the LCK linker region as a SIRT2-regulated deacetylation site that governs LCK conformation and kinase activity. Functionally, SIRT2 inhibition in exhausted mouse and human TILs restored TCR signaling capacity and improved anti-tumor responses. CONCLUSION: Here we identify SIRT2-regulated deacetylation of LCK as a previously unrecognized mechanism that sets the strength and threshold of proximal TCR signaling. Accordingly, SIRT2 targeting reverses the exhausted phenotype of tumor-reactive T cells. Citation Format: Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Min-Hsuan Wang, Min Zhang, Odesha Taylor, Luis Lopez-bailon, Ismail Can, Bin Fang, Anders Berglund, Bradford Perez, Ben Creelan, Andriy Marusyk, Virginia Shapiro, Haitao Ji, Jose R. Conejo-Garcia, Sungjune Kim. Sirt2 dictates TCR activation thresholds through post-translational control of LCK conformational state [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 4250.

Abstract Introduction: Src Family Kinases (SFKs) have a crucial role in tumor proliferation, survival, and metastasis. NXP900 is a highly selective SFK inhibitor with a novel mechanism of action that locks SFKs in a closed, inhibited conformation, providing sustained suppression of catalytic and non-catalytic functions, which is distinct from other SFK inhibitors like dasatinib. A phase I clinical trial of NXP900 in patients with advanced solid tumors is ongoing. Our preclinical studies showed therapeutic efficacy of NXP900 in cholangiocarcinoma (CCA) through decreased YAP, RAF-MAP and PI3K-AKT signaling. Multiomic profiling (RNA-seq, proteomics, phosphoproteomics) of CCA patient-derived xenografts implicated AKT pathway activation in primary NXP900 resistance. NXP900-resistant CCA cell lines generated via prolonged sublethal dose escalation showed a strong IL13RA2-AKT signature on multiomic analysis. Thus, we hypothesized that IL13RA2-AKT signaling was a mechanism of NXP900 resistance. We aimed to define this mechanism and demonstrate that the combinatorial targeting of IL13RA2 or AKT resensitizes to NXP900 treatment. Methods: HuCCT1 or HuCCT1-Resisant (HuCCT1-R) cells were injected bilaterally into the flanks of NOD/SCID mice and were allowed to grow for 3 months prior to tumor collection and analysis. Tumor engraftment and growth between HuCCT1 and HuCCT1-R groups were compared. To delineate the mechanisms for acquired NXP900 resistance, in-vitro treatment studies were performed using siRNAs targeting IL13RA2 as well as combination treatment with capivasertib, a pan-AKT inhibitor. Results: The HuCCT1-R cell line exhibited a higher rate of tumor engraftment and formed significantly larger tumors compared to the parental HuCCT1 cell line, indicating enhanced tumorigenic potential associated with acquired resistance. Silencing of IL13RA2 in HuCCT1-R cells resulted in pronounced reduction of cell proliferation and partially restored sensitivity to NXP900 treatment. Immunoblot analysis demonstrated a corresponding reduction in phosphorylated AKT (Thr308), consistent with suppression of downstream PI3K-AKT signaling. Furthermore, combination treatment of HuCCT1-R cells with the AKT inhibitor capivasertib, and NXP900 led to a significant increase in cell death and a greater inhibition in cell proliferation compared to either agent alone, indicating enhanced responsiveness and improved therapeutic efficacy. Conclusion: These findings confirm the central role of IL13RA2 signaling and the PI3K-AKT pathway in mediating acquired resistance to NXP900, consistent with our previous multiomics analysis. Importantly, this study identifies combination strategies that may be able to overcome NXP900 resistance, supporting the development of combinatorial approaches to restore therapeutic efficacy in resistant tumors. Citation Format: Shelby K. Yee, Hendrien Kuipers, Danielle M. Carlson, Jack W. Sample, Enis Ozmert, Hidemi Nishi, Erik Jessen, Dong-Gi Mun, Aushinie M. Abeynayake, Jennifer L. Tomlinson, Amro M. Abdelrahman, Nathan W. Werneburg, Binbin Li, Mitesh J. Borad, Mark J. Truty, Sumera I. Ilyas, Gregory J. Gores, Rory L. Smoot. Resistance to the SFK inhibitor NXP900 in cholangiocarcinoma is characterized by IL13RA2-AKT signaling and can be overcome by combination therapy [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 7124.

aims: We assessed the diagnostic accuracy of the SVEAT score in predicting 30-day major adverse cardiac events (MACE) in comparison with the well-established HEART and TIMI scores. background: Acute chest pain (ACP) is a common symptom in emergency departments. Various risk stratification tools have been developed to assess patients presenting with ACP. The Simple Vascular Event Assessment Tool (SVEAT) is the most recent scoring system introduced, based on five variables: Symptoms of chest pain, history of Vascular disease, ECG, Age, and Troponin-I. objective: We assessed the diagnostic accuracy of the SVEAT score in predicting 30-day major adverse cardiac events (MACE) in comparison with the well-established HEART and TIMI scores. method: Following PRISMA guidelines, a systematic literature search was conducted across five databases until June 22, 2024. Four studies comprising 1,520 patients were included in this meta-analysis. The predictive accuracy of the SVEAT, HEART, and TIMI scores for 30-day MACE was assessed by the area under the receiver operating characteristic curve (AUC). Heterogeneity was evaluated using the I² statistic, with values over 75% indicating significant heterogeneity. Indirect comparisons among the scores were performed using the Z-test. result: Pooled AUC for the SVEAT score was 0.92 (95% CI: 0.86-0.98), indicating superior predictive accuracy compared to the HEART (AUC: 0.86, 95% CI: 0.81-0.92) and TIMI (AUC: 0.82, 95% CI: 0.69-0.96) scores. However, significant heterogeneity (I² = 90.6%) was observed across studies, potentially due to variations in patient demographics, clinical settings, and outcome definitions. Despite the higher AUC, indirect Z-test comparisons revealed no statistically significant differences between the scoring systems. conclusion: SVEAT score demonstrates potential as an accurate tool for predicting 30-day MACE in patients with ACP. other: N/A

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 + LSECs promote the recruitment of CD63 + monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

ABSTRACT Purpose Active lesion expansion is clinically important because it can indicate disease progression and influence management and treatment planning. However, sequential imaging is often unavailable, and rapid growth can only be inferred from indirect findings such as active perilesional tissue injury. This study aimed to implement and test the feasibility of an MR elastography (MRE)‐based technique for assessing the expansile nature of mass lesions by detecting stiffness changes caused by mechanical strain manifestations in adjacent tissues. Methods A tissue strain mapping (TSM) algorithm was developed using spatial–temporal directional filtering to reveal the presence of perilesional latent strain that is not apparent in conventional MRE inversions. The technical feasibility was tested in tissue‐simulating phantoms containing a mass that was progressively expanded. Preliminary feasibility for clinical application was also demonstrated in representative in vivo examples. Resulting TSM maps were compared with conventional MRE stiffness maps. Results In the phantom experiments, TSM revealed the presence of local strain at the periphery of the expanding mass, with the effect increasing proportionally to the degree of expansion. Conventional MRE did not demonstrate comparable localized stiffening patterns. In vivo examples showed similar perilesional strain features that were not apparent on conventional MRE maps. Conclusion The feasibility of the proposed MRE‐based TSM technique was demonstrated in phantom and preliminary in vivo studies. These findings suggest that the technique is a promising tool for assessing the expansile nature of mass lesions and motivate further development of the TSM processing and exploration of potential clinical applications.

Abstract Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction &gt; 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided. Citation Format: E. Blondeaux, A. Meacci, M. Fragío Gil, E. Klocker, F. Coussy, H. Kim, R. Bernstein Molho, F. Hilbers, A. Di Meglio, A. Kwong, K. Pogoda, J. Bajpai, H. Wildiers, E. Agostinetto, J. Balmana, H. C. Moore, K. Phillips, A. H. Partridge, C. Rousset-Jablonski, F. A. Peccatori, A. Toss, T. Renaud, C. Anghelone, A. Benitez Cruz, S. Paluch-Shimon, J. Lee, R. Fruscio, W. Cui, S. M. Wong, M. Lee, M. Rozenblit, C. Vernieri, C. Villarreal-Garza, A. Matikas, M. Dieci, L. De Marchis, J. K. Plichta, K. J. Ruddy, D. Can Guven, F. Puglisi, Z. Kemp, P. A. Meireles, L. Del Mastro, V. Delucchi, M. Lambertini. Association between age at diagnosis and survival among young BRCA carriers with breast cancer: results from an international multicenter hospital-based cohort study [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 PD4-07.