Citations

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

Abstract Background: Deletions in MTAP occur in 10-15% of cancers and are associated with poor prognosis. MTAP deletion (MTAPdel) leads to accumulation of MTA which causes partial inhibition of PRMT5, creating a synthetic lethality approach with PRMT5 inhibitors. Multiple investigational MTA-cooperative PRMT5 inhibitors have demonstrated early clinical efficacy in MTAPdel NSCLC and other cancers. MTAPdel, PRMT5 expression, and clinical outcomes to standard of care immune checkpoint inhibitors (ICI) and chemotherapy (chemo) have not been well characterized. Methods: The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database and establish and subsequently analyze a cohort of patients (pts)with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) testing, treated with front-line (1L) ICI with or without chemo (N=3,676). PRMT5 expression was normalized as transcripts per million (TPM) and reported as log2(TPM + 1). Pts were classified into high vs low groups based on median PRMT5 expression and into MTAPdel vs intact (MTAPwt) based on MTAP biallelic loss. Immune infiltration was estimated using Quantiseq. Real-world overall survival (rwOS) was defined as the time from 1L start to death or last known follow-up. Real-world progression-free survival (rwPFS) was defined as the time from 1L start to death, progression or last known follow-up. Hazard ratios (HR) were calculated using Cox proportional hazards models and adjusted for age, sex, histology, smoking status and PDL1 status. Results: PRMT5 expression was moderately increased in pts with MTAPdel (6.65 v 6.70, p=0.012). Alterations in MYC, SMARCA4 and KEAP1 were enriched in PRMT5-high tumors in both MTAPdel and MTAPwt pts (p<0.03). Pts with PRMT5-high tumors had decreased infiltrate of multiple immune cells, including B cells, macrophages (M1 and M2), NK cells, CD4 and CD8 T cells (p<0.001). Pts with MTAPdel/PRMT5-high expression had shorter rwOS compared to MTAPwt/PRMT5-low when treated with ICI alone (HR 1.58, 95% CI 1.11-2.24, p=0.011) or with ICI + chemo (HR 1.65, 95% CI 1.34-2.03, p<0.001). These associations persisted on multivariate analysis. Pts with MTAPdel/PRMT5-high expression were also associated with worse rwPFS when treated with ICI + chemo (HR 1.5, 95% CI 1.22-1.86, p<0.001) on univariate and multivariate analysis, but did not associate with rwPFS in pts treated with ICI alone (HR=0.97, 95% CI 0.66-1.42, p=0.9). Conclusion: PRMT5 expression defines an immune suppressed subpopulation of pts with NSCLC. Pts with elevated PRMT5 expression and MTAPdel have poor outcomes with ICI+/- chemo, indicating PRMT5 RNA expression levels can be used to inform clinical trial designs, particularly those that are testing novel combinatorial strategies. Citation Format: Natalie Vokes, Stamatina Fragkogianni, Pooja A. Shah, Santiago G. Trevino, Konstantinos Leventakos, Lei Deng, Matthew Lee, Tali Azenkot, KAYLA LAYNG, JACOB MERCER, Jyoti Patel, Jordi Rodon Ahnert. High PRMT5 expression is associated with decreased immune infiltrate and worse outcomes to immune checkpoint inhibitors in non-small cell lung 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 2446.

Abstract Background: Tarlatamab, a Delta-like ligand (DLL3)/CD3-targeted bispecific T-cell engager (TCE) is FDA approved in patients (pts) with extensive stage small cell lung cancer (ES-SCLC), after progression on frontline chemoimmunotherapy. We aimed to evaluate the immune cell profile in pts who received this therapy in standard-of-care (SOC) practice with progression free survival (PFS) less than and greater than two months (mo). Methods: Patients who received tarlatamab at Mayo Clinic Rochester and consented to immuno phenotyping of blood are included in the present study. Immune phenotyping was performed on whole blood by flow cytometry and analyzed by Kaluza. Data analysis was performed with Microsoft Excel and PRISM. Results: Eighteen patients with median age 64 (range 37-79) were included in the study. 66% of our cohort were women and 83% had present or past history of smoking, with an average of 40 pack years (range 26-60). With a median follow-up of 2 months, the median PFS for the cohort was 1.5 mo (range 0.33-2.76 months). 61% (13/18) of patients had PFS <2mo. 39% (5/18) had PFS>2mo and of which, three patients had partial response with one maintaining stable disease and one patient with mixed response. At baseline (BL), there were no difference in T cell, CD4 or CD8 cell count between patients in the PFS<2mo and PFS>2mo groups. Patients with PFS<2mo had higher exhausted CD8 T cells compared to those in the PFS>2mo group (CD8+PD1+TIGIT+CD57+, PFS<3mo vs >3mo, cells/mL: 7.14±4.28, 1.58±1.37, p=0.009). Additionally, when analyzing the B-cell population, the PFS<2mo group had lower percentage of B cells compared to the group with PFS>2mo at baseline (6.0±7.5, 10.4±14, p=0.02). At day 7, the group with PFS<2mo had lower Treg compared to the group with PFS>2mo (2.88±1.38, 4.60±1.47, p=0.02). Also, the PFS<2mo group had an increase of B cells compared to the group with PFS>2mo at day 7(<2mo vs >2mo: 10.0±14, 4.37±3.07, p=0.04). Finally, the group with PFS>2mo had decrease in total monocytes (mono), classical mono, and immunosuppressive cells (PFS<2mo vs >2mo, Mono: 340±347, 253±106, p=0.04. Classical mono: 305±283, 155±109, p=0.02. CD14+HLA-DRneg: 105.8±96, 12±39, p=0.03) compared to the group with PFS<2mo by day 7. While no changes were seen between BL and day 7 for intermediate mono in PFS<2mo group, PFS>2mo group had decreased post treatment intermediate monocytes (BL vs day 7, cells/mL, intermed mono: 32.5±15,17.7±6.2, p=0.03). Conclusion: In this study investigating the SOC outcomes of tarlatamab, early progression was associated with higher presence of exhausted CD8 T cells, B cells, and immunosuppressive monocytes. Analysis of additional patients will be shared at AACR meeting. Citation Format: Dhauna Karam Prasad, Andre De Menezes Silva Corraes, Malvika Gupta, Audrey Ma, Chen Wu, Zuoyi Shao, Kevin Reagan, Rayaan Kamal, Ashley Potter, Abdullah Al-Ajmi, Syeda Mina, Sykler J. Taylor, Antonious Hazim, Anastasios Dimou, Kaushal Parikh, Mohammed Shanshal, Ailsa Luce, Anna Schwecke, Julian Molina, Aaron Mansfield, Katherine Smith, Lucy Holmes, Haidong Dong, Yi Lin, Konstantinos Leventakos. Immune cell profile changes in patients treated with tarlatamab for extensive stage small cell lung cancer in real world practice [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 3931.

Abstract Background: Small cell lung cancer (SCLC) remains an aggressive malignancy with limited treatment options and a 5-year survival rate under 10%. Delta-like ligand 3 (DLL3), expressed in >85% of SCLC but absent from normal tissue, represents an attractive therapeutic target. Existing DLL3-directed antibody-drug conjugates suffer from poor payload stability and limited tumor penetration. To overcome these limitations, we engineered a DLL3-targeted nano-immunoconjugate (NIC) of SN38, the active metabolite of irinotecan, using an albumin-based nanoscaffold. Methods: SN38 was encapsulated in a human serum albumin (HSA) matrix and non-covalently coated with a recombinant anti-DLL3 monoclonal antibody to yield DLL3-SN38-NIC. Stable conjugation was confirmed by HSA-IgG interactions and zeta-potential shift. Binding kinetics were evaluated using Biacore surface plasmon resonance (SPR) and Octet bio-layer interferometry (BLI) employing AHC biosensors to determine DLL3-antibody affinity and specificity. Cytotoxicity was assessed using IncuCyte live-cell imaging across five SCLC cell lines (DMS454, SHP77, NCI-H82, NCI-H889, and NCI-H211) with varying DLL3 expression. Results: DLL3-SN38-NIC retained high-affinity DLL3 binding (KD ≈ 3 × 10-10 M) and demonstrated potent cytotoxicity in SCLC cell lines. NIC formation did not reduce cytotoxic activity compared with free SN38, confirming preserved potency. Cytotoxicity trends were consistent across lines with variable DLL3 expression, and DLL3 antibody alone exhibited negligible cytotoxicity. These findings confirm that nano-immunoconjugate formation maintains drug activity and DLL3 binding; additional in-vivo studies are underway to evaluate pharmacokinetics and tumor selectivity. Conclusions: Albumin-based DLL3-SN38-NICs represent a novel nano-oncologic platform that preserves SN38 potency and achieves high-affinity DLL3 engagement. Ongoing studies will assess in-vivo selectivity, biodistribution, and therapeutic potential in DLL3-positive SCLC and other neuroendocrine malignancies. Citation Format: Mohamed Shanshal, Lin Yang, Liyi Geng, Wendy Nevala, Aaron S. Mansfield, Bharath Wootla, Konstantinos Leventakos, Kyle Korshavn, Svetomir N. Markovic. Albumin-based DLL3-targeted nano-immunoconjugates of SN38 preserve potency and demonstrate high-affinity DLL3 binding in small cell lung 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 449.

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.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

INTRODUCTION: Advanced therapies infrequently achieve complete fistula closure in patients with Crohn's disease (CD). The primary objective of the STOMP2 clinical trial was to determine whether the implantable autologous cell therapy AVB-114 is effective in inducing remission of persistent Crohn's perianal fistulas versus standard of care. METHODS: Eligible patients had a single perianal fistula tract and had failed previous treatment or had documented medication intolerance to biologic or conventional CD therapy. All enrolled subjects underwent surgical fistula optimization and adipose tissue biopsy collection (to manufacture AVB-114) followed by 1:1 randomization to either standard of care (repeat fistula optimization including seton replacement) or AVB-114 implantation. The primary end point was combined fistula remission at 36 weeks, defined as closure of the external opening, no drainage of fluid despite gentle finger compression, and no collections >2 cm in at least 2 of the 3 dimensions on MRI. RESULTS: Subjects at 14 US sites were equally randomized to SoC (N = 24) or AVB-114 (N = 24). Week 36 combined remission was 8.3% and 45.8% for subjects randomized to SoC and AVB-114, respectively (38% difference, 95% CI 11%–60%; P = 0.0078). At week 36, MRI revealed no subjects with collections >2 cm, radiological improvement (≥50% decrease in the Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease (MAGNIFI-CD) score from baseline) in 1 SoC subject and 3 AVB-114 subjects, and radiological healing (complete resolution of T2-weighted hyperintensity in fistula tract) in 2 SoC subjects and 5 AVB-114 subjects. Through week 36, there were 40 and 56 treatment emergent adverse events for SoC and AVB-114, respectively. There were no serious treatment emergent adverse events in the AVB-114 group through week 36. DISCUSSION: A significantly higher proportion of patients treated with AVB-114 achieved combined remission vs SoC, and the treatment was well tolerated. These data support the safety and efficacy of AVB-114 in persistent Crohn's perianal fistulas.