Citations

Importance Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. Objective To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Design, Setting, and Population Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Exposure Device-enabled TTVR. Main Outcomes and Measures Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Results Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P < .001) and mean KCCQ-OS score (22.4 points; P < .001) from baseline to 30 days. There were no significant differences in 30-day mortality ( P = .47), heart failure hospitalization ( P > .99), and functional outcomes ( P = .55) when patients were stratified by baseline CIED status. Conclusions and Relevance Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.

Abstract INTRODUCTION Anti—amyloid‐β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real‐world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. METHODS Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019–Mar 2025) assessed trends in AD‐relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid‐beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. RESULTS Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (−25/quarter), and plasma p‐tau 217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive ( p < 0.006). APOE ‐ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001). DISCUSSION The adoption of anti‐Aβ therapies coincided with a rapid shift in diagnostic workflows.

Abstract Aims Routine aspirin use for primary prevention yields modest cardiovascular benefit but increases bleeding risk in average-risk adults. Whether individuals with elevated lipoprotein(a) [Lp(a)] levels or high-risk LPA variants derive greater benefit remains uncertain. Methods and results Following Cochrane and PRISMA guidelines, we systematically searched PubMed/MEDLINE, Embase, and Cochrane Central for studies of adults without ASCVD, elevated Lp(a) (≥50 mg/dL), high-risk LPA genotypes, or elevated genetic risk scores, comparing aspirin vs. no aspirin use. Random-effects meta-analyses using restricted maximum-likelihood (REML) estimation with Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment were used to pool hazard ratios (HR) and 95% confidence intervals (CI). In six studies, 6628 participants were included. Pooled random effects showed no significant reduction in major adverse cardiovascular events (MACE) with aspirin (HR = 0.60; 95% CI 0.31–1.17; P = 0.1) or clinical bleeding events (HR = 1.24; 95% CI 0.83–1.87; P = 0.18). Subgroup analyses showed a nonsignificant reduction MACE among elevated Lp(a) (HR = 0.63; 95% CI 0.16 to 2.49; P = 0.284) and statistically significant reduction among LPA rs3798220 carriers (HR = 0.37; 95% CI 0.19 to 0.71; P = 0.003), though this finding was not consistent in the sensitivity analyses. Conclusion Among adults without ASCVD but with elevated Lp(a) or high-risk LPA genotypes, aspirin use did not confer a statistically significant cardiovascular benefit and was associated with numerically higher bleeding risk. The apparent reduction seen in rs3798220 carriers was inconsistent and likely reflects small-sample bias.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with limited treatment options. CCA exhibits a distinct desmoplastic and tolerogenic tumor immune microenvironment (TIME) characterized by elevated bile acid concentrations resulting from obstructive cholestasis and dysregulated bile acid metabolism. TGR5 is an essential component of bile acid signaling. We hypothesize that bile acids promote CCA progression by establishing an immunosuppressive TIME through TGR5 signaling, which can be therapeutically targeted using SBI-364, a novel potent small molecule TGR5 inhibitor. Methods: Single-cell RNA sequencing (scRNA-seq) of immune cells from human intrahepatic (iCCA) and perihilar (pCCA) CCA tumors were conducted. Therapeutic studies were performed using syngeneic murine models of iCCA (PMID: 38458319), a novel syngeneic model of pCCA, and patient-derived xenograft (PDX) models. In collaboration with Sanford Burnham Prebys, SBI-364, a first in-class competitive TGR5 antagonist, was assessed in vivo. Additionally, we performed co-culture experiments with bile acid +/- SBI-364-treated murine bone marrow-derived monocytic myeloid-derived suppressor cells (M-MDSCs) and CD8+ T cells to assess functional immunosuppressive effects. Results: Human scRNA-seq revealed significantly increased TGR5 (GPBAR1) expression predominantly in myeloid cell populations within the CCA TIME. SBI-364 treatment significantly reduced tumor burden in both syngeneic orthotopic iCCA models and a novel pCCA model that recapitulates the anatomic characteristics of perihilar CCA. In contrast, NOD/SCID mice bearing PDX535 (predicted sensitive) and PDX136 (predicted resistant), SBI-364 treatment did not achieve tumor reduction, suggesting that TGR5 inhibition predominantly attenuates tumor progression through modulation of bile acid-immune cell interactions. SBI-364 treated murine tumors had a significant reduction in immunosuppressive macrophages expressing interleukin-10 and M-MDSCs compared to vehicle treated tumors. Furthermore, bile acid-treated M-MDSCs exhibited enhanced suppression of CD8+ T cell proliferation and function, an effect that was abrogated by SBI-364 co-treatment. Conclusion: We demonstrate that TGR5 inhibition represents a promising therapeutic strategy across multiple immunocompetent preclinical CCA models. We demonstrate that the bile-acid TGR5 axis promotes CCA progression via immunosuppressive myeloid cells. Specifically, TGR5 signaling potentiates the immunosuppressive capacity of M-MDSCs, contributing to an immunosuppressive niche that facilitates tumor progression. These results establish TGR5 as a rational therapeutic target for overcoming immune evasion in cholangiocarcinoma. Citation Format: Enis Hikmet Ozmert, Binbin Li, Jingchun Yang, Hannah Elizabeth Stumpf, Jessica R. Willhite, Danielle Carlson, Jennifer L. Tomlinson, Jon Covel, Raghuveer Ramachandra, Steven Olson, Rory L. Smoot, Sumera Ilyas. Therapeutic targeting of TGR5 abrogates bile acid driven myeloid cell immunosuppression in cholangiocarcinoma [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 2896.

Abstract Background: Diffuse pleural mesothelioma (DPM) is a highly aggressive malignancy with limited treatment options and poor prognosis. Although immune checkpoint inhibitors have improved outcomes, particularly for non-epithelioid subtypes, there remains no approved targeted therapy for mesothelioma. EGFR and MET are receptor tyrosine kinases frequently overexpressed in DPM, suggesting susceptibility to targeted antibody therapy. Amivantamab is a bispecific EGFR/MET antibody, originally developed for EGFR-mutant lung cancer, that blocks growth signals and engaging immune mechanisms. Given the high levels of EGFR and MET expression in mesothelioma, we evaluated the therapeutic potential of amivantamab in preclinical models. Methods: EGFR and MET transcript levels in DPM were analyzed using TCGA. Eight human mesothelioma cell lines were assessed by Western blotting and flow cytometry. Amivantamab binding, internalization, and signaling inhibition were examined using flow cytometry, confocal microscopy, and ligand-stimulated phosphorylation assays. Cytotoxicity and immune-effector activity were quantified using PBMCs, NK cells, and monocytes from healthy donors, along with an ADCC reporter assay. In vivo efficacy was tested in a DPM patient-derived xenograft (PDX) model in NOD/SCID-γ (NSG) mice supplemented with human NK cells and treated with amivantamab or control IgG. Results: TCGA analysis showed frequent EGFR/MET co-expression in DPM. Mesothelioma cell lines expressed higher EGFR and MET levels compared with mesothelial cells. Amivantamab strongly bound both receptors, induced receptor internalization, and inhibited EGF- and HGF-stimulated phosphorylation of EGFR, MET, and downstream AKT/ERK signaling. Direct cytotoxicity was minimal; however, the addition of PBMCs or NK cells resulted in robust, dose-dependent tumor cell killing consistent with antibody-dependent cellular cytotoxicity (ADCC). Reporter assays demonstrated 7-11-fold Fcγ receptor activation in tumor cells compared with ∼2-fold activation in non-malignant mesothelial cells. Co-culture with monocytes revealed amivantamab-induced trogocytosis, evidenced by loss of EGFR and MET from tumor-cell membranes. In the DPM PDX model, amivantamab produced 89.1% tumor-growth inhibition (TGI) relative to controls (P &lt; 0.0001), with no overt toxicity observed in treated mice. Conclusions: Dual EGFR/MET targeting with amivantamab produced potent antitumor effects in mesothelioma through coordinated receptor-signaling blockade, ADCC, and monocyte-mediated trogocytosis. These results support amivantamab as a promising targeted therapeutic strategy for EGFR/MET-positive DPM, particularly epithelioid subtypes that currently derive limited benefit from immunotherapy. Citation Format: Shinichiro Suzuki, Kaushal Parikh, Ezequiel Tolosa, Kuan-Li Wu, Jennifer Ayers-Ringler, Lin Yang, Katherine E. Smith, Farhad Kosari, Aaron S. Mansfield, . Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab [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 5547.

Background Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate antitumor immunity and enhance immunotherapy response.

Abstract Introduction: Fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3) are metabolic genes overexpressed in malignant epithelia. In colorectal cancer (CRC), intimate crosstalk between FGFR2/3 and epidermal growth factor receptor (EGFR) pathways has been suggested but is not fully elucidated. As a result, this study investigated associations between FGFR2/3 expression levels and clinical outcomes in patients with metastatic CRC (mCRC) enrolled in the phase III clinical trial CALGB /SWOG 80405. Methods: Data from 433 patients with mCRC enrolled in the CALGB/SWOG 80405 trial were analyzed. Patients received either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) plus chemotherapy as first-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Ilumina) platform. Median overall survival (OS) and progression-free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high (H), medium (M), and low (L) FGFR 2 and 3 gene expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Both FGFR2 and FGFR3 expression levels were associated with outcomes in patients treated with cetuximab. FGFR2-L tumors showed significantly longer OS compared to the M (HR = 1.04; 95%CI 0.71-1.51) and H (HR = 1.56; 95%CI 1.06-2.28) expression groups (35.7 vs. 31.2 vs. 23.7 months, p = 0.017). In contrast, FGFR3-L tumors were associated with shorter OS compared to the M (HR = 0.63; 95%CI 0.44-0.92) and H (HR = 0.59; 95%CI 0.41-0.85) expression groups (24.7 vs 32.4 vs 37.1 months, p = 0.0009). Significant differences in PFS were not observed. A nominally significant interaction was found between treatment and FGFR3 expression for both PFS (p = 0.02) and OS (p = 0.0003), but no interaction with FGFR2 expression. No significant associations were detected in patients treated with bev. Neither FGFR2 nor FGFR3 suggested to be prognostic markers after multivariate adjustment analyses. Conclusions: Our findings suggest a predictive role of FGFR3 in patients with mCRC undergoing anti-EGFR treatment. Differences in survival within the cet subgroup suggest that EGFR inhibitor efficacy may be modulated by FGFR2/3 signaling activity. Interestingly, FGFR2 and FGFR3 expressions were inversely and positively correlated with improved OS. The findings suggest that FGFR2 signaling minimizes the specific effects of cetuximab, while FGFR3 signaling amplifies its therapeutic effects. Further studies should determine whether these associations are seen in other anti-EGFR inhibitors and detail the mechanistic interaction between FGFR and EGFR pathways. Citation Format: Steve Soto Trujillo, Yan Yang, Michela Bartolini, Shivani Soni, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Yitzhar Goretsky, Wu Zhang, Alan Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Differences in survival outcomes among metastatic colorectal cancer patients across fibroblast growth factor receptor 2 and 3 expression levels [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 6751.

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 Background. Mitophagy plays a crucial role in removing dysfunctional mitochondria to maintain cellular homeostasis but also has been implicated in cancer tumorigenesis. Previously, we showed that genetic variation in mitophagy pathway genes holds a predictive value in metastatic CRC (mCRC) patients (pts) treated with bevacizumab-based chemotherapy. In this study, we analyzed the correlation between tumor expression profiles of genes associated with PINK1/Parkin and BNIP3/NIX/FUNDC1 mitophagy pathways with clinical outcome in a large phase III randomized clinical trial CALGB SWOG 80405. Method. We analyzed 433 pts with mCRC treated with first-line chemotherapy in combination with the targeted agents bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207). Tumor RNA isolated from FFPE samples was sequenced using the HiSeq 2500 platform (Illumina). Median Overall survival (mOS) and median progression-free survival (mPFS) were compared across pts groups divided into high, medium, and low tertiles based on mitophagy-related gene (BNIP3, BNIP3L, PINK1, PRKN) expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, Consensus Molecular Subtypes, and treatment arm. Results: Overall, BNIP3L demonstrated significant prognostic value for both PFS and OS after adjustment for multiple testing (false discovery rate [FDR] &lt; 0.05). Tumors with low BNIP3L expression showed longer PFS and OS compared to those with medium or high expression levels (mPFS 14.8 vs. 10.0 vs. 9.2 months, HR 1.16, 95% CI 1.04 - 1.29p = 0.0182; mOS: 37.4 vs. 30.2 vs. 24.4 months, HR 1.22, 95% CI 1.09 - 1.38, p = 0.0036), independent of treatment. In pts treated with Cet, high PRKN expression was associated with improved PFS and OS (mPFS: 8.9 vs. 10.3 vs. 14.6 months, HR 0.79; 95% CI 0.69 - 0.91, p = 7.3e-05; mOS: 21.2 vs. 27.7 vs. 41.1 months, HR 0.87; 95% CI 0.75 - 1.01, p = 0.00084), whereas low PINK1 expression was significantly associated with longer OS (mOS: 24.9 vs. 30.9 vs. 39.2 months, HR 1.23; 95% CI 1.04 -1.46, p = 0.013). No significant associations were observed in Bev-treated patients for PRKN or PINK1. No significant results were found for BNIP3 expression analysis. Conclusion. Mitophagy is a crucial player in CRC biology due to its tumor-intrinsic (mitochondrial bioenergetics) and microenvironment (interacts with immune components) effects. Our study highlights the prognostic value of BNIP3L and predictive potential of PINK1 and PRKN, suggesting a potential combinatorial therapeutic approach using mitochondrial targeting drugs and targeted agents e.g Cet, which warrants further investigation. Support: Genentech; Clinicaltrials.gov Identifier: NCT00265850 Citation Format: Shivani Soni, Yan Yang, Michela Bartolini, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Steve Soto Trujillo, Yitzhar Goretsky, Wu Zhang, Alan P. Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Correlation of mitophagy related genes expression and clinical outcome in metastatic colorectal cancer patients enrolled in CALGB (Alliance)/SWOG 80405 [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 1011.