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Background: Left atrial (LA) strain is a marker of atrial myopathy and remodeling. While echocardiographic LA strain is increasingly used to assess atrial function, the prognostic value of change in LA strain before and after catheter ablation (CA) for atrial fibrillation (AF) remains underexplored. Objective: To evaluate the association between quartiles of LA strain parameters—including pre-ablation strain, post-ablation strain, and change in strain—with atrial fibrillation recurrence, stratified by ejection fraction (EF). Methods: This retrospective study encompassed AF patients who underwent their first CA at Mayo Clinic Arizona from Oct 2018 to Feb 2022. Transthoracic echocardiography parameters, including the three LA strain (LAS) phases—contraction, conduit, and reservoir—were collected using TOMTEC software on the closest date before the CA procedure. Logistic regression analysis was used to evaluate the association between LAS parameters and AF recurrence post-CA, adjusted for clinical covariates including age, gender, hypertension, diabetes, coronary artery disease, dyslipidemia, obstructive sleep apnea, thromboembolism, TIA/stroke, chronic kidney disease, and AF type. Results: Out of 335 patients who underwent CA, 222 had both pre- and post-ablation LA strain data. Among these, 71 of 222 patients (31.98%) experienced AF recurrence after CA. The mean age at time of procedure was 66.9 ± 10.3 years; 150 (67.57%) were male, and 83 (37.39%) had persistent AF. Significant associations were observed between specific quartiles of LA strain and AF recurrence. In patients with EF >50%, Q4 of contraction strain change (pre- vs. post-ablation) was strongly associated with increased recurrence risk (OR 8.80; 95% CI 1.80–42.98). Similarly, post-ablation contraction strain Q4 was associated with higher recurrence in both the overall group (OR 6.36; 95% CI 1.47–27.53) and the EF>50% subgroup (OR 8.80; 95% CI 1.80–42.98). In contrast, reservoir strain change Q2 (OR 0.10; 95% CI 0.01–0.86), and post-ablation reservoir strain Q3 (OR 0.09; 95% CI 0.01–0.69) and Q4 (OR 0.10; 95% CI 0.02–0.70) were protective. Conclusions: Greater increases in contraction strain post-ablation and higher post-ablation contraction strain were strongly associated with AF recurrence, particularly in those with preserved EF. Conversely, favorable reservoir strain post-ablation was protective. LA strain may offer key prognostic value in risk-stratifying AF patients undergoing ablation.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

Introduction Bipolar disorder (BD) is a chronic illness affecting approximately 2-3% adults worldwide. Mood stabilizers, such as lithium, valproate, carbamazepine, and lamotrigine are mainstays of the treatment. Despite their benefits, mood stabilizers carry a risk of side effects, which can lead to treatment discontinuation and non-adherence rates ranging from 10 to 60% in BD patients (Dols et al. Int Clin Psychopharmacol 2013; 28, 287-296). Dermatologic side effects, also known as cutaneous adverse drug reactions, are particularly distressing, often impacting patients’ self-esteem and social interactions, and contributing to non-compliance. These reactions can range in severity from mild rashes, acneiform eruptions, hair loss and psoriasis to severe, life-threatening conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (Mitkov et al. Psychosomatics 2014; 55, 1-20).Objectives Despite the well-documented association between mood stabilizers and dermatologic adverse effects (AE), the overall prevalence of these reactions across mood stabilizers remains unclear. This systematic review and meta-analysis aims (1) to estimate the prevalence of dermatologic AE associated with mood stabilizer (lithium, valproate, carbamazepine and lamotrigine) use in patients with BD, and (2) to summarize the available evidence on the onset and timing of these reactions.MethodsWe searched Ovid MEDLINE®, Embase, Cochrane Library, Web of Science, Scopus, and PsycINFO from 1970 onward for studies on dermatologic AEs in BD patients treated with lithium, valproate, carbamazepine, or lamotrigine (CRD42022357268). Study selection, data extraction, and bias risk assessment were performed by two reviewers. Meta-analyses were conducted to estimate the prevalence rates for dermatologic AEs.ResultsThe initial database searches yielded 5,354 studies. 47 articles were deemed relevant and included in this systematic review. Study designs included 16 randomized controlled trials, 10 non-randomized open-label trials, 12 cohort studies, and 9 cross-sectional studies. Lithium was associated with acneiform eruptions in 4.4% (95% CI: 1.0-17.0%), rash in 1.8% (95% CI: 0.7-4.8%), and hair loss in 1.7% (95% CI: 0.4%-6.4%) of patients. For valproate, hair loss was observed in 4.6% of patients (95% CI: 3.0-6.7%) and rash in 2.9% (95% CI: 1.6-5.3%). Carbamazepine was associated with rash in 6.0% of patients (95% CI: 4.4-7.6%), but severe reactions such as SJS and TEN were not reported. Lamotrigine had the highest rash prevalence with 9.2% (95% CI: 7.2-11.8%), while severe reactions were rare (0.04%, 95% CI: 0.00-0.63%).Conclusions Mood stabilizers showed varying levels of dermatologic AEs, but severe reactions were rare. Future studies should explore factors influencing these outcomes, their impact on quality of life and treatment participation, and potential management strategies.Disclosure of InterestNone Declared

7049 Background: Odronextamab, an investigational off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated pts with R/R FL in the primary analysis of the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). We present updated efficacy and safety data for odronextamab in pts with R/R FL from ELM-2 after >2 yrs follow-up. Methods: Odronextamab was administered intravenously until disease progression/unacceptable toxicity, with Cycle (C) 1 step-up dosing to help mitigate cytokine release syndrome (CRS) risk, as reported previously. Pts with a complete response (CR) for ≥9 months (mo) switched from maintenance dosing Q2W to Q4W. Primary endpoint: objective response rate (ORR) per Lugano criteria by independent central review (ICR); secondary endpoints: CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS). Results: At the updated data cutoff (Aug 15, 2024), 157 pts with centrally confirmed R/R FL Grade (Gr) 1–3a were enrolled. Median no. of treatment cycles: 19.0 (range 0.1–117.3); 96.2% (n = 151) and 82.8% (n = 130) of pts completed C1 and C4, respectively. The global cohort comprised 128 pts evaluable for efficacy. At a median efficacy follow-up of 28.3 mo, ORR was 80.5% (n = 103) by ICR and CR rate was 74.2% (n = 95); 92.2% of responders achieved CR. Responses were durable (median DOR, 26.0 mo; median duration of CR, 32.2 mo). ORR was consistent across high-risk subgroups (Follicular Lymphoma International Prognostic Index score 3–5, 78.4%; progression of disease within 2 yrs of frontline therapy, 81.0%). Median PFS was 23.0 mo (estimated 36-mo PFS rate, 37.5%), and median OS was 54.2 mo (estimated 36-mo OS rate, 62.6%). Median PFS was longer in pts who were minimal residual disease (MRD) negative (42.4 mo) versus MRD positive (21.6 mo) at Week 12. Of 47/128 pts who switched to Q4W dosing, 32 remained in CR. The odronextamab long-term safety profile was consistent with the primary analysis. All 157 pts had TEAEs (Gr ≥3, 86.0%), and 15.3% discontinued treatment due to TEAEs (most common: COVID-19 infection, 2.5%). With 0.7/4/20 mg step-up dosing (n = 89), CRS events were mostly low grade (Gr 1, 46.1%; Gr 2, 13.5%; Gr 3, n = 1; Gr ≥4, n = 0), occurred mostly in C1, and resolved in a median of 8.4 hrs. Immune effector cell-associated neurotoxicity syndrome was reported in one pt (Gr 2). Infections were reported in 79.0% of pts (124/157; Gr ≥3, 42.0%). COVID-19-related infections were reported in 38.2% of pts (Gr 5, 5.7%). Conclusions: With longer follow-up, odronextamab demonstrated durable responses in heavily pretreated pts with R/R FL from ELM-2, with robust efficacy in those with high-risk features, and a generally manageable safety profile. Overall, these compelling results support odronextamab as a potential off-the-shelf treatment option for pts with R/R FL. Clinical trial information: NCT03888105 .

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Pediatric regional anesthesia offers significant benefits, yet its adoption faces barriers, including perceived overcomplexity. This study aimed to identify and establish a set of core, high-value, low-complexity nerve blocks to improve perioperative pain management in pediatric patients. A four-round modified Delphi consensus study was conducted with an international panel of pediatric and regional anesthesia experts. An initial long list of regional techniques was compiled by the Steering Committee and refined through iterative input. Panelists rated each technique on a 10-point Likert scale for importance. Consensus was defined as ≥75% of panelists assigning a mean importance score of ≥8. Techniques receiving 50%–74% agreement were categorized as having strong agreement and considered for inclusion. The final selection was confirmed through a virtual roundtable discussion. Thirty-three experts representing 12 pediatric and regional societies participated. Consensus was reached on six regional techniques, with strong agreement (*) on two additional techniques, identifying eight core pediatric regional anesthesia blocks: supraclavicular brachial plexus block, rectus sheath block, transverse abdominis plane block*, suprainguinal fascia iliaca block*, femoral nerve block, adductor canal block, popliteal sciatic nerve block, and landmark-based caudal block. This consensus-driven framework defines a core set of pediatric regional anesthesia techniques that balance clinical effectiveness, feasibility, and accessibility. These findings provide a practical entry point for practitioners looking to incorporate pediatric regional anesthesia into their practice, regardless of prior experience. Future efforts should focus on standardized training, implementation research, and policy initiatives to support widespread adoption and improve perioperative pain management in children globally.

Abstract Background and Aims Classification and risk stratification in aortic (AR), mitral (MR), and tricuspid regurgitation (TR) remains a significant clinical challenge. This study aimed to develop an artificial intelligence (AI) system to assess valvular regurgitation and stratify MR-progression risk. Methods Using transthoracic echocardiograms (TTEs) at two sites (internal development/test, external test), the DELINEATE-Regurgitation system was developed to classify AR, MR, and TR severity using colour Doppler videos. Methods of summating video-level classifications into study-level predictions were tested, comparing single-view with multiview approaches integrating predictions across multiple videos. Model agreement with cardiologists was assessed by weighted kappa. A separate AI system (DELINEATE-MR-Progression) analysing colour Doppler videos was developed to predict which patients with mild, mild–moderate, and moderate MR were most likely to progress to moderate–severe or severe MR with analysis by Kaplan–Meier and Cox proportional hazards models. Results A total of 71 660 TTEs with 1 203 980 colour Doppler videos were included. The weighted kappa in internal/external test sets for regurgitation classification was 0.81/0.76 for AR, 0.76/0.72 for MR, and 0.73/0.64 for TR using a multiview approach taking all colour Doppler videos in a study, demonstrating substantial agreement with cardiologist interpretation with superiority of multiview over single view approaches. In the progression analysis, the AI score stratified MR-progression risk even when controlled for clinical factors known to be associated with MR progression [internal test set hazard ratio 4.1 (95% confidence interval 2.5–6.6)]. Conclusions An AI system can accurately classify AR, MR, and TR and predict MR progression beyond currently known risk factors.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

Introduction E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.