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Abstract Background A subset of risankizumab (RZB)-treated patients experience suboptimal or secondary loss of response to standard dosing. We explored factors associated with future RZB dose-optimization, and outcomes of optimization in a multicenter consortium of adults with Crohn’s Disease (CD). Methods Baseline characteristics at time of RZB initiation and subsequent clinical, endoscopic, and biochemical outcomes were collected in a multi-center cohort. Outcomes for dose-optimized RZB were reported as clinical response and remission (based on HBI or PGA when HBI unavailable), endoscopic remission (based on SEMA-CD or absence of ulcers when SEMA-CD not available), and biochemical response. Characteristics were compared between standard and dose-optimized groups using chi-square and two-sample t-tests. Additional models adjusting for age and sex assessed predictors of dose optimization. Results We identified 309 patients treated with standard dose and 58 for whom dose-optimized RZB was recommended. Of the 58, 29 were excluded from outcomes analysis due to lack of follow-up (n = 19) or insurance denial of dose optimization (n = 10). Demographic information is outlined in Table 1. Baseline characteristics associated with future dose optimization included number of prior advanced therapies (ATs) (OR, 1.29, p < 0.001), prior anti-TNF (OR,4.06; p = 0.022), and prior ustekinumab (UST) use (OR,1.82; p = 0.053) (Table 2). The 29 patients included in the outcome analysis received dose-optimized RZB for primary non-response (n = 2), partial response (n = 23), or secondary loss of response (n = 4) after a median of 321 days (IQR, 234-440) from index RZB start. Median follow-up after dose optimization was 217 days (IQR, 147-331). All patients were AT-exposed (Table 1). Baseline clinical symptoms were present in 27 patients (93.1%), with median HBI of 6.5 (IQR, 6.0-8.0). Active endoscopic disease was observed in 11/12 patients (91.7%) who had baseline endoscopy. Dosing was every 4 weeks in 19 (65.5%), every 6 weeks in 9 (31.0%), and combined IV re-induction plus every 4-weeks in 1 (3.4%) patient. Clinical response and remission was seen in 16 (55.2%) and 12 (41.4%) patients, respectively. A ≥ 50% CRP reduction was seen in 5/12 (41.7%) patients with baseline elevated CRP. Among 7 patients with baseline active endoscopic disease with available follow-up, 3 (42.9%) achieved endoscopic remission. No adverse events were reported. Conclusion In this multi-center retrospective cohort, prior AT-exposure (especially anti-TNF) was associated with need for RZB dose-optimization. Dose optimization successfully captured clinical response in a significant proportion of patients who experienced partial response or loss of response to RZB. Conflict of interest: Johnson, Amanda: Research grant: Abbvie, Spyre Therapeutics Ramesh, Prajith Raj: None Said, Hyder: No conflict of interest Huang, Katherine: No conflict of interest Devi, Jalpa: none Pekow, Joel R.: CVS Health - Consulting Abbvie, Eli Lilly, Pfizer, Johnson and Johnson - Stocks Alhobayb, Tamara: No conflict of interest Bassmeyer, Blake: No conflict of interest Mohamed, Mouhand: No conflict of interest Shivashankar, Raina: Abbvie and BMS - speaker bureau Janssen and Celltrion - grant for IBD fellowship funding Pfizer - consultant Rathi, Jaya: No conflict of interest Luu, Bryan: No conflict of interest Khan, Abdul: No conflict of interest Loftus, Jr, Edward: Grant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, UCB. Personal Fees: AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Sun Pharma, Takeda, UCB. Bishu, Shrinivas: None Patel, Anish: speaker: abbvie, J & J, Lilly, BMS, Pfizer, Phathom, Takeda consultant: abbvie Shukla, Richa: Speakers bureau - Abbvie and Lilly Yarur, Andres: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI.

Abstract Neuroendocrine prostate cancer (NEPC) is an increasingly prevalent manifestation of acquired resistance to next generation AR signaling inhibitors (ARSI), that arises via transformation from advanced prostate adenocarcinoma (PRAD) through a mechanism called lineage plasticity. Through characterization of isogenic PRAD and NEPC mouse tumoroid models generated using human-relevant driver mutations (Pten-/-;Rb1-/-;Trp53-/-), we revealed an extensive epigenetic reprogramming in NEPC versus PRAD, particular at enhancers. CRISPR screens focused on TFs and coactivators revealed a NEPC lineage TF survival network comprised of ASCL1, NFIB, SOX1/11, FOXA1/2 and MYCL with exquisite dependency on the TIP60 acetyltransferase complex. During the PRAD-to-NEPC transition, FOXA1, NFIB and TIP60 chromatin binding redistributes to NEPC specific enhancers, resulting in expression of NEPC target genes in a coordinate fashion with ASCL1 functioning as master regulator, culminating in activation of MYCL. MYCL then directly recruits the TIP60 complex to target sites, where it acts as a requisite MYCL coactivator for target gene activation for NEPC growth/survival. The acetyltransferase activity of TIP60 and acetylation of its substrate H2A.Z are both required for NEPC survival, as well as two chromatin reader subunits of the TIP60 complex, BRD8 and YEATS4. Targeted chemical degradation of TIP60 revealed >500-fold dependency in NEPC relative to normal prostate, credentialing the TIP60 complex as a potential therapeutic target in NEPC. Citation Format: Zhen Sun, Jimmy L. Zhao, Wazim M. Ismail, Zahra F. Khan, Teng Han, Subhiksha Nandakumar, Serina Young, Matthew Lange, Richard Koche, Alexandre Gaspar-Maia, Charles L. Sawyers. The TIP60 acetyltransferase complex is a critical dependency in neuroendocrine prostate cancer through its role as a critical coactivator of MYCL downstream of ASCL1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR036.

Abstract Introduction Cervical arterial dissections (CeAD) can involve either single (sCeAD) or multiple (mCeAD) arteries. Whether the involvement of a single versus multiple arteries is associated with outcomes remains unclear. We aimed to study associations between the number of affected arteries and clinical, imaging and outcome parameters. Patients and methods Patients with CeAD from the STOP-CAD multicenter registry study were included. Clinical, imaging, treatment and outcome parameters were compared between patients with sCeAD and mCeAD. Regression analyses were performed to identify associations with multi-arteries involvement. Results Overall, 3858 STOP-CAD patients were included in this analysis and 443 (11.5%) had mCeAD. The presence of mCeAD was associated with age (adjusted odds ratio [aOR] 95% confidence intervals [95% CI] 0.99; (0.98–1.00)), female sex (aOR 1.5; 95% CI 1.17–1.91), recent upper respiratory infection (aOR 2.25; 95% CI 1.55–3.27), presence of connective tissue disease (aOR 3.11; 95% CI 2.32–4.17), severe arterial stenosis (aOR 1.95; 95% CI 1.95–2.58), intracranial extension (aOR 1.47; 95% CI 1.04–2.09), vertebral artery involvement (aOR 2.50; 95% CI 1.94–3.22) and presence of dissecting aneurysm (aOR 2.59; 95% CI 1.95–3.42). In adjusted analyses, mCeAD was not associated with clinical outcomes (ischemic stroke, mortality, and sICH; all p > 0.05). Conclusions mCeAD does not appear to increase risk of subsequent stroke as compared to sCAD despite baseline risk factors suggestive of vasculopathy. mCeAD patients who did develop a stroke presented with milder strokes and less often had vessel occlusions compared to those with sCeAD. The presence of mCeAD did not impact outcomes.

Background: Rotator cuff tears are a common orthopaedic injury often resulting in shoulder pain and functional impairment. Despite the prevalence of rotator cuff tears, the incidence of retear after rotator cuff repair (RCR) remains high. There is growing interest in the use of structural augmentation in RCR to decrease retear rates and improve patient outcomes. Purpose: The purpose of this systematic review and meta-analysis was to compare the clinical and imaging outcomes of structural augmentation versus standard RCR in patients with full-thickness rotator cuff tears. The effectiveness of different augment subtypes was also assessed. Study Design: Meta-analysis; Level of evidence, 3. Methods: A comprehensive literature search was conducted in CENTRAL, Embase, and Medline from inception to November 13, 2024. Eligible studies included comparative trials evaluating structural augmentation in RCR for repairable full-thickness tears. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomized controlled trials and the MINORS (Methodological Index for Non-randomized Studies) score for observational studies. Meta-analyses were performed via a random effects model, with subgroup analyses performed by study design and augment type. Results: Twenty-four studies (12 randomized controlled trials and 12 cohort studies) were included in this review, all of which evaluated biologic augments (xenograft, allograft, autograft). Structural augmentation significantly reduced the risk of retear by 35% as compared with standard RCR (risk ratio, 0.65; 95% CI, 0.48-0.89; P = .01). Retears were confirmed radiographically by magnetic resonance imaging or ultrasound. Subgroup analysis revealed the greatest reduction in retear rates with allograft augmentation (risk ratio, 0.34; 95% CI, 0.21-0.56). No significant differences were observed in patient-reported outcomes, including pain scores, American Shoulder and Elbow Surgeons scores, or Constant scores. Conclusion: Structural augmentation in RCR significantly reduces retear rates, particularly with allografts, but does not improve short-term patient-reported outcomes. Further research is needed to identify which patient and tear characteristics may influence the effectiveness of augmentation.

Despite advances in percutaneous coronary procedures, in-stent restenosis remains a significant challenge. Although sirolimus- and paclitaxel-coated balloons are promising alternatives, their comparative safety and efficacy remain uncertain. PubMed, Embase, and Cochrane databases were searched using relevant keywords from inception until August 2025. A total of 11 studies (7 randomized controlled trials and 4 observational cohort studies) were included, comprising 3633 participants overall. The primary outcomes assessed were target lesion revascularization and target lesion failure. Meanwhile, the Secondary outcomes included stent thrombosis, all-cause mortality, myocardial infarction, major adverse cardiovascular events, survival, binary restenosis, and angiographic endpoints (acute gain, diameter stenosis, in-segment late lumen loss, in-lesion late lumen loss, and in-segment minimal lumen diameter). Interstudy heterogeneity was assessed using I ² and X ² statistics ( I ²>50% = significant heterogeneity). Interstudy heterogeneity was low for most outcomes, including all primary clinical endpoints, with moderate heterogeneity observed only for select angiographic measures (notably in-segment late lumen loss and diameter stenosis). Statistical analysis was conducted using R software and RStudio (version 4.4.2), with a P value of < 0.05 indicating statistical significance. This meta-analysis examined studies that compared paclitaxel-coated balloon (PCB) versus standard balloon [sirolimus-coated balloon (SCB)] angioplasty. Regarding primary outcomes, there were no notable variations in target lesion failure [risk ratio (RR), 1.08, 95% CI, 0.90–1.29, P = 0.36] or target lesion revascularization (RR, 1.16, 95% CI, 0.98–1.37, P = 0.08). With all aggregated estimates being nonsignificant, secondary outcomes such as stent thrombosis, all-cause mortality, myocardial infarction, major adverse cardiovascular events, and survival were similar between groups. Angiographic endpoints revealed no discernible variations in late lumen loss (in-lesion and in-segment), acute gain, or diameter stenosis. Nonetheless, the SCB group’s minimal lumen diameter was significantly smaller than that of the PCB group (MD, −0.08 mm, 95% CI, −0.14 to −0.01, P = 0.02). In treating coronary in-stent restenosis, SCB and PCBs show similar overall safety and effectiveness; lesion-specific angiographic variations indicate that customized selection may improve patient outcomes.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Abstract Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality worldwide, and there are limited molecular screening options. Following a prior discovery and validation studies in subjects from the United States, China, and Iran, we aimed to validate methylated DNA markers (MDM) for ESCC detection in Malawi, a country with one of the highest ESCC incidence. Fourteen MDMs were tested on 177 tissue samples. Ten MDMs showed excellent performance (AUCs ≥ 0.85); a random forest model achieved an AUC of 0.97. The consistent cross-population performance suggests potential for universal application of these MDMs and further justifies exploring nonendoscopic sampling methods, such as swallowed cell collection devices in combination with MDMs, for efficient and cost-effective screening in high-incidence populations. Prevention Relevance: This study validates MDMs for early detection of ESCC in Malawi, supporting their potential role in noninvasive, population-based screening strategies in Africa to enable early detection and timely intervention for cancer interception, potentially reducing cancer burden in high-incidence, resource-limited regions.

158 Background: PIK3CA mutations are common in CRC and may be a negative prognostic factor. INAVO is a potent and selective PI3Kα inhibitor that also promotes mut p110α degradation. BEV and CETUX are standard treatment (tx) components for RAS mut and RAS -wildtype (wt) mCRC, respectively. The Phase I/Ib INTRINSIC open-label umbrella study (NCT04929223) evaluates targeted therapies in biomarker-selected mCRC subpopulations. We report INAVO + BEV and INAVO + CETUX results. Methods: Patients (pts) with PIK3CA mut, RAS mut mCRC received INAVO (9 mg oral once daily) + BEV (intravenous [IV] 15 mg/kg every 3 weeks). Pts with PIK3CA mut, RAS wt mCRC received INAVO + CETUX (IV 400 mg/m 2 then 250 mg/m 2 weekly thereafter). Primary endpoint: confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), and safety. Progression-free survival (PFS) and overall survival (OS) were exploratory. Results: At the clinical cut-off dates, 16 pts were enrolled in the BEV arm; 35, in the CETUX arm. Most had ≥2 metastatic sites at enrollment (n = 16 [100%] and 30 [85.8%], respectively) and ≥2 prior lines of metastatic therapy (16 [100%] and 28 [80.0%]). In the BEV arm, 3 pts (18.8%) had no prior BEV. In the CETUX arm, 25 pts (71.4%) had no prior CETUX; 17 (48.6%) had prior anti-EGFR therapy. All pts in the BEV arm and 34 in the CETUX arm were evaluated for efficacy and safety. Median follow-up was 9.4 months (mo; interquartile range: 5.5–14.4) and 12.6 mo (8.9–16.6), respectively. Efficacy is shown in the Table. All pts had adverse events (AEs); 15 (93.8%) and 34 (100%), respectively, had tx-related AEs (TRAEs); 5 (31.2%) and 12 (35.3%), grade 3–4 TRAEs; 2 (12.5%) and 11 (32.4%), serious AEs. One grade 5 AE (infusion-related reaction) occurred (CETUX arm). Dose reduction/interruption due to AEs occurred in 12 (75.0%) and 27 (79.4%) pts; tx withdrawal due to AEs, in 0 and 4 (11.8%) pts, respectively. Hyperglycemia was the most common AE, TRAE, and AE leading to dose reduction/interruption in both cohorts. Hypertension was observed more frequently with BEV; dermatitis acneiform and dry skin, with CETUX. Conclusions: INAVO + BEV and INAVO + CETUX showed encouraging efficacy in pts with PIK3CA mut mCRC, with no new or unexpected safety signals. Clinical trial information: NCT04929223 . INAVO + BEV(n = 16) INAVO + CETUX(n = 34) cORR, all PR, n (%) 1 (6.3) 7 (20.6)* SD, n (%) 10 (62.5) 17 (50.0) Progressive disease, n (%) 3 (18.8) 9 (26.5) Missing/NE, n (%) 2 (12.5) 1 (2.9) mDoR, mo (90% CI) 7.7 (NE) 4.4 (4.2–5.3) DCR, n (%) 11 (68.8) 15 (44.1) mPFS, mo (90% CI) 4.2 (2.8–6.8) 3.5 (2.8–4.4) mOS, mo (90% CI) 11.0 (8.5–14.5) 12.8 (10.7–13.8) CI, confidence interval; m, median; NE, not evaluable; PR, partial response; SD, stable disease. *3 pts with PRs received prior anti-EGFR therapy; 1 had a best prior response of SD (last dose 233 days before study tx) and 2 had best prior responses of PRs (last doses 134 and 171 days before study tx).

Living donor liver transplantation (LDLT) is an established therapy with curative intent for pediatric and adult patients with acute liver failure and end-stage liver disease. Donor safety remains paramount and commences during preoperative evaluation and assessment. Given the importance of the topic, the International Liver Transplantation Society and International Living Donor Liver Transplantation Group consensus conference on Living Liver Donor Safety was convened in March 2025 (Toronto, Canada). Recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus was followed. This report presents 28 recommendations from the working group focused on addressing clinically relevant questions related to the preoperative aspects of living donor safety including assessment of donor acceptability (age, body mass index and hepatic steatosis; medical conditions and contraindications), medical and surgical workup (liver function and procoagulant workup; anatomical considerations and safe remnant), and psychosocial evaluation (timing and team; underlying conditions; non-directed, paired, and anonymous directed donors; urgent living donor workups for acute liver failure).

Abstract Iron-deficiency anemia (IDA) affects nearly one-third of women globally, with heavy menstrual bleeding (HMB) being a significant risk factor among those of reproductive age. Despite the substantial burden of HMB-related IDA, patients often face delays in receiving effective treatment. Oral iron is typically used as first-line therapy, despite frequent gastrointestinal side effects and challenges in treatment adherence. This study evaluated the reproductive life span cost-effectiveness of first-line intravenous (IV) vs oral iron therapy for women with HMB and IDA. We developed a Markov model simulating a cohort of women aged 18 to 51 years, comparing first-line treatment with IV iron dextran, IV ferumoxytol, IV iron sucrose, or oral ferrous sulfate. Costs and quality-adjusted life years (QALYs) were estimated from the societal perspective. IV iron dextran was the cost-effective treatment, yielding 19.26 QALYs at a cost of $157 500, compared with 19.10 QALYs at $152 900 for oral ferrous sulfate. The incremental cost-effectiveness ratio for IV iron dextran was $28 600 per QALY. Treatment with IV ferumoxytol and iron sucrose cost $158 300 and $163 500, respectively, and did not provide additional QALY benefit compared with IV iron dextran, which remained the cost-effective treatment across a range of scenarios and sensitivity analyses. Our findings indicate that first-line treatment with IV iron dextran is the cost-effective strategy for managing IDA in women with HMB at commonly accepted willingness-to-pay thresholds. These results support expanding access to IV iron as a first-line option, and highlight the need to reduce treatment delays and insurance-related barriers.