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e16159 Background: Pivotal trials established atezolizumab-bevacizumab and durvalumab-tremelimumab as first-line therapies for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab demonstrated superior survival outcomes compared to sorafenib for unresectable HCC in the IMbrave150 trial in 2020, while durvalumab plus tremelimumab showed superior survival in the HIMALAYA trial in 2022. However, data on head-to-head comparison of these two combinations as first-line systemic therapy for the patient with decompensated HCC are limited. This study aims to compare survival outcomes between these two treatment regimens in decompensated HCC patients to address a critical gap in the current literature, as decompensated patients have largely been excluded from clinical trials. Methods: This retrospective study utilized electronic health records from 146 U.S. healthcare organizations within the TriNetX Network. Adults aged ≥21 years diagnosed with decompensated HCC receiving atezolizumab/bevacizumab and durvalumab/tremelimumab from 10/21/2022 to 8/20/2024 were included. The comparison group received atezolizumab/bevacizumab, and the control group received durvalumab/tremelimumab. The primary outcome was all-cause mortality. A 1:1 propensity score matching was conducted to balance baseline characteristics (age, gender, race/ethnicity, lab results including liver function tests, platelet counts, INR, gamma glutamyl transferase, alpha-fetoprotein, and underlying liver diseases). Kaplan–Meier survival analysis and Cox regression was used to estimate the mortality risk. Subgroup analysis was stratified by HCC etiology. Results: A total of 302 and 664 patients received durvalumab/tremelimumab, atezolizumab/bevacizumab, respectively. After propensity matching, 253 patients per group were included. Median OS was 283 days with durvalumab/tremelimumab and 391 days with atezolizumab/bevacizumab. The two treatment regimens showed no significant difference in survival (hazard ratio [HR]: 0.875, 95% confidence intervals [CI] 0.696–1.101, p=0.254). Subgroup analyses demonstrated no significant differences in survival between the two groups of patients in MASLD (HR: 0.698, 95% CI: 0.468–1.040), alcohol associated liver disease (HR: 0.821, 95% CI: 0.603–1.118), and chronic viral hepatitis (HR: 0.852, 95% CI: 0.596–1.219). Conclusions: There was no statistically significant difference in survival outcomes between atezolizumab plus bevacizumab and durvalumab plus tremelimumab in patients with decompensated advanced HCC. These results support current real-world practice in which both regimens may be considered viable first-line treatment options in this high-risk population with liver decompensation.

ABSTRACT Introduction Hairy cell leukemia (HCL) is an uncommon hematopoietic stem cell disease known to have an underlying somatic BRAF V600E driver mutation. Currently, the most accepted treatment is five or seven consecutive days of outpatient infusion of cladribine (e.g., continuous infusion), despite frequent antibiotic use and hospitalization with this regimen. As a result, a few investigators have adopted weekly infusion of cladribine with similar or improved results and fewer side effects. Methods We conducted a retrospective, single‐institution cohort study of 36 treatment‐naïve patients with HCL treated at the University of Colorado Hospital. Eighteen patients received intermittent weekly cladribine (intermittent cladribine [IC]) for 5–7 doses and 18 received standard daily cladribine (continuous cladribine [CC]) over 5–7 days. We report clinical cohort characteristics, response rates, progression‐free survival, overall survival, toxicity, hospitalization rates, and measurable residual disease monitoring in select patients using peripheral blood quantitative BRAF V600E PCR. Results We report here our experience with 18 patients with newly diagnosed BRAF ‐mutated HCL treated with weekly cladribine at a single institution compared to 18 HCL patients who received continuous infusions. Baseline hematologic parameters and overall survival were comparable between groups ( p = 0.1135), but there was a higher rate of complete remission for patients treated with IC (94.4% vs. 61.1%) with significantly improved progression‐free survival ( p < 0.0001). We observed comparable rates of neutropenia, neutropenic fever, antibiotic use, and G‐CSF administration. There were fewer hospitalizations for patients treated with IC (4/18) compared to patients treated with CC (6/18). Rituximab exposure differed between groups, with 72% of patients in the IC cohort receiving rituximab compared with 27.2% in the CC cohort (although treatment status was documented for only 66.7% of patients in the CC cohort). Peripheral blood BRAF V600E allele burden significantly declined and correlated with clinical remission, but this was only performed in select patients who were treated in recent years. Conclusions In this retrospective analysis, IC dosed weekly was associated with improved progression‐free survival and higher rates of complete remission compared to CC with comparable toxicity and fewer hospitalizations. These findings suggest a potential clinical benefit from this regimen. However, interpretation of these findings is limited by the non‐randomized design and differences in rituximab exposure between groups, which may have contributed to the observed outcomes and limited definitive conclusions. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission

9021 Background: An escape room is a team-based activity in which participants collaborate to solve puzzles within a fixed time limit and escape. Prior studies demonstrate high learner satisfaction and improved teamwork and communication with medical education escape rooms. To date, no published reports describe an escape room designed specifically for hematology/oncology (hem/onc) fellows. As part of Hem/Onc Curriculum, we designed and implemented a hem/onc-focused escape room and evaluated learner satisfaction and perceived learning impact. Methods: The escape room was designed using evidence-based learning science principles (Table 1). Teams worked to solve sequential puzzles, centered on a patient case, addressing key hem/onc concepts, including transfusion medicine, peripheral blood smears, lymphoma classification, and coagulation disorders. Each solved puzzle revealed additional patient laboratory and pathology data. Successful completion required teams to diagnose the patient and select appropriate treatment. Following the activity, teams participated in a facilitator-led debrief focused on team dynamics, communication, and problem solving. Teams observed each other and shared feedback. A larger group debrief co-led by chief fellows and faculty reviewed learning objectives and key takeaways. Learner outcomes were assessed using a post-activity survey evaluating satisfaction, engagement, and impact on learning. Results: Eighteen learners participated, including 14 hem/onc fellows, 1 APP hem/onc fellow, and 3 internal medicine residents. Three of four teams escaped within 1 hour (mean completion time, 52 minutes). All participants provided positive verbal feedback. Fifteen learners completed the post-activity survey, and all respondents reported satisfaction with the activity and would recommend it for future fellows. One-word descriptors included “engaging,” “fun,” and “challenging.” Most respondents (93.3%) agreed that the activity reinforced key hem/onc concepts and improved confidence in clinical problem-solving. All learners felt the activity supported learning, and 93.3% reported that collaboration enhanced the learning experience. Participants identified team-based problem solving, clinical application, and interactive puzzles as the most effective components. Conclusions: A hem/onc escape room resulted in high learner satisfaction and reinforced hem/onc knowledge and clinical problem-solving. This feasible, fun, and innovative activity complements traditional fellowship education by leveraging adult learning principles through gamified, team-based learning and should be incorporated into training programs’ curriculum. Learning science principles applied in a hem/onc escape room. Active Learning Belonging Contrasting Cases Debriefing Deliberate Practice Elaboration Generation Listening and Sharing Reward Worked Examples

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

ABSTRACT Metallo-beta-lactamase (MBL)-producing Enterobacterales are a global public health concern. Infections caused by these pathogens are often hard to treat, with few effective agents currently available. While aztreonam-avibactam only recently gained U.S. and European regulatory approval, laboratories have implemented laboratory-developed tests (LDTs) using existing aztreonam and ceftazidime-avibactam reagents. We sought to compare the performance of four phenotypic methods, up to three reagent manufacturers, and two media manufacturers. One hundred two MBL-producing Enterobacterales isolates were evaluated at two sites (Centers for Disease Control and Prevention [CDC] and Johns Hopkins University [JHU] School of Medicine). The performance of four methods was evaluated: broth disk elution (BDE), disk stacking (DS), gradient diffusion strip stacking (SS), and a strip-to-disk proximity (strip-disk) method, which were compared to reference broth microdilution (rBMD) tested in parallel. Respective category agreement for CDC and JHU was 92.2% and 96.1% for BDE, 51%–76.5% and 31%–49% for DS, 71.6%–86.3% and 83.3%–86.3% for SS, and 82.4%–87.3% and 80%–89.2% for the strip-disk method. The SS essential agreement ranged from 46.1% to 62.7% for JHU and 54.9% to 92.2% for CDC. Interlaboratory reproducibility was 93.1% for rBMD, 92.2% for BDE, 47.1%–53.1% for DS, 76.5%–80% for SS, and 87.3%–88.9% for strip-disk. BDE was the only method that exceeded acceptable performance of >90% accuracy and reproducibility. DS had the lowest and most variable performance between sites and among the different disk manufacturers used. LDTs for combination testing can be highly variable, and further work is needed to improve standardization and harmonization to achieve accurate and reliable results for clinical purposes. IMPORTANCE Carbapenem-resistant Enterobacterales are classified as an urgent public health threat in the Centers for Disease Control and Prevention’s 2019 Antibiotic Resistance Threats Report. Among the most concerning resistance mechanisms are carbapenemase enzymes encoded on mobile genetic elements, which can spread rapidly between bacteria. Of the various carbapenemases, metallo-beta-lactamases are particularly challenging, as they confer resistance to nearly all beta-lactams, and current treatment options remain limited. While aztreonam-avibactam has been U.S. Food and Drug Administration (FDA)-approved for treating certain infections with limited or no alternative treatment options, no FDA-cleared susceptibility test is yet available. In this context, laboratory-developed methods, such as combination testing of aztreonam and ceftazidime-avibactam, play a critical role in guiding therapy. Our study evaluates several of the more common laboratory-developed tests compared to reference broth microdilution and found that broth disk elution was the most accurate; in contrast, other methods had variable performance, some demonstrating limited reliability and being prone to overcalling resistance.

BACKGROUND: Compared to standard labor epidurals, placement of a dural puncture epidural (DPE) has been shown to improve labor analgesia efficacy, speed onset of analgesia, and decrease failure rates. However, there is a concern of increased post-dural puncture headache (PDPH) risk. A 25-gauge or larger spinal needle is typically needed for a DPE to have improved efficacy over a standard epidural. A prior meta-analysis comparing combined spinal-epidurals (CSEs) with epidurals did not identify a difference in PDPH rates, but many of the included randomized controlled trials (RCTs) used smaller diameter (27–29 gauge) spinal needles. This systematic review and meta-analysis of RCTs evaluates headache frequency following CSE or DPE labor analgesia techniques with 24- or 25-gauge spinal needles. METHODS: Medline, EMBASE, Scopus, Database of Abstracts of Reviews of Effects, Web of Science Core Collection, and Cochrane databases were searched on May 7, 2024, for RCTs comparing either DPE or CSE techniques using 24- or 25-gauge spinal needles with epidural labor analgesia. The primary outcome was headache. The risk-of-bias 2 tool was used to assess bias. The odds ratio (OR) was the chosen effect size using binomial family Bayesian estimation. The reference category for estimation was the conventional epidural technique group. RESULTS: Encompassing 3278 patients, 1765 (53.8%) received labor epidurals, 971 (29.6%) received DPEs, and 542 (16.5%) received CSEs. The rate of headaches in both groups was low, with headache rates of CSE/DPE and epidural groups (0.59% vs 0.34%), respectively. Headache was a secondary outcome in all the RCTs. In 10 of the 16 RCTs (62.5%), no patients of 1428 (0%; 95% credible interval [CI], 0.00–0.25) reported a headache. A total of nine (0.6%) headaches were reported in the DPE/CSE patients (denominator 1513) and six (0.3%) headaches were reported in the traditional epidural patients (denominator 1765). The posterior distribution of the treatment effect ( θ ) showed that the log OR of 0.35 favored the control group as having fewer events, but the number of events was rare, and the 95% CI was wide (−0.49 to 1.22). CONCLUSIONS: Headache was a rare event in both groups. Although these results are reassuring that either technique is clinically safe, they should be interpreted cautiously. A large RCT examining PDPH as the primary outcome with long-term follow-up is needed to more precisely determine if placement of a DPE or CSE with a 24- or 25-gauge spinal needle increases the risk of PDPH.

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

ABSTRACT Aims We aimed to examine the association between GLP‐1 RA use and suicidal ideation or behaviours through a systematic review of observational studies. Materials and Methods A comprehensive search of MEDLINE, PubMed, EMBASE, CINAHL and PsycINFO was conducted from database inception through December 11, 2025. Observational studies investigating suicidal ideation, suicide attempts or complete suicide among adults using GLP‐1 RAs were included. Eligibility screening, data extraction and risk of bias assessments were performed independently and in duplicate, with disagreements resolved by a third reviewer. Results Forty‐three studies were included. Findings varied by study design. Some case reports suggested a temporal relationship between GLP‐1 RA use and suicidal ideation. Cross‐sectional studies and case–control studies identified a negative association between GLP‐1 RAs and suicide attempts. Pharmacovigilance and cohort studies showed more mixed results, with some studies identifying a positive association between semaglutide or liraglutide and suicidal ideation, while others paradoxically reported a negative association with suicidal behaviours (i.e., attempts and intentional self‐harm) or completed suicide. Conclusions While evidence does not support GLP ‐1 RAs as a causative agent for suicidality, due to multiple risk factors in this population, clinicians should routinely assess mental health status before and during GLP ‐1 RA treatment regardless of indication. Importantly, a history of concurrent mental health conditions should not preclude use of a GLP ‐1 RA ; rather, individual patient factors should be accounted for when making prescribing decisions.

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation