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ImportanceWhile the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited.ObjectiveTo evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors.Design, Setting, and ParticipantsThis cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022.ExposuresMetastatic colorectal cancer.Main Outcomes and MeasuresSurvival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years.ResultsIn the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002).Conclusions and RelevanceIn this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Background: Latissimus dorsi transfer (LDT) has been purported to restore motion in patients undergoing reverse shoulder arthroplasty (RSA) who have preoperative combined loss of forward elevation (FE) and external rotation (ER). This systematic review summarizes the available evidence for the functional outcomes and complications after RSA with LDT. Furthermore, the effect of implant design and whether a concomitant teres major transfer (TMT) was performed were studied. Methods: A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify articles reporting on LDT with RSA to restore ER. Our primary outcomes were ER, FE, Constant score, and complication incidence. Secondarily, we reported postoperative internal rotation (IR) and compared ER, FE, and Constant score based on lateralized versus medialized global implant design and whether concomitant TMT was performed. Results: Nineteen studies were evaluated; functional outcomes were assessed in 16 articles reporting on 258 RSAs (123 LDT, 135 LDT-TMT). Surgical indication was most commonly cuff tear arthropathy and massive irreparable cuff tear. Mean ER was −12° preoperatively and 25° postoperatively, FE was 72° preoperatively and 141° postoperatively. Mean postoperative Constant score was 65. Of 138 patients (8 studies) describing IR, only 25% reported a mean postoperative IR ≥L3. Subanalysis comparing lateralized versus medialized implants and whether TMT was concomitantly performed demonstrated no significant difference in postoperative ER, FE, and Constant score, nor preoperative to postoperative improvement in ER and FE. The complication rate was 14.1% (of 291 shoulders from 16 studies), including tear in the tendon transfer (n = 3), revision tendon repair (n = 1), nerve-related complication (n = 9), and dislocation (n = 9). Conclusions: RSA with LDT is a reliable option to restore motion, with a comparable complication rate with standard RSA. The use of medialized versus lateralized implants and whether the TM was concomitantly transferred may not influence clinical outcomes. Level of Evidence: Level IV . See Instructions for Authors for a complete description of levels of evidence.

Introduction: Repeated 6MWT in clinic are inconvenient for patients and disruptive to usual clinic throughput. Digital measures may be a means to overcome these challenges and reliably measure functional capacity. Methods: As part of an observational clinical trial (NCT04191356), during an 8-week observation period, patients with heart failure (HF) utilize arm-band biosensors (Biofourmis Everion®) for at least 15 hours daily while carrying out daily activities and complete an in-clinic investigator-guided 6MWT on the first and last days of participation. Interim data (N=30, age 56.17 ± 11.26; 24 males; 3 NYHA I, 25 NYHA II, 2 NYHA III) are used for validation, where the distance of baseline 6MWT is used as reference standard. Results: Passive 6MWT, which is the maximum 6-minute step count derived from daily accelerometer data (Fig 1), is strongly correlated with the reference standard (R=0.7501, P<0.0001, N=30) (Fig 2). Further analysis (Fig 2) reveals that regardless of the duration of the step count, the digital measures consistently have strong correlations with the reference standard, with the highest correlation obtained by Passive 10MWT (R=0.7746, P<0.0001, N=30). Conclusions: Early data highlights that accelerometer data collected during daily activities appears to indicate functional capacity of HF patients. Continued data will validate digital measures against various patient outcomes. Fig 1 Aggregation of Passive 6MWT from step count recorded during daily activities Fig 2 Correlation between accelerometer-derived passive step count digital measures and distance manually measured during baseline investigator-guided 6MWT as reference standard (N=30)

Abstract Introduction: Autophagy pathway activation and upregulation is an important mechanism for cancer cell survival upon exposure to chemotherapeutic agents. LC3, a ubiquitin-like protein, plays a key role in the regulation of cargo selection and autophagosome formation. Given small molecule inhibitors have not been well developed to target LC3, we aim to design and synthesize an LC3 binder and evaluate its activity in the inhibition of autophagy pathway in cancer cells. Methods: The crystal structure of LC3 and p62 complex (PDB: 2ZJD) was used to assist our design of helical sulfonyl-γ-AApeptides to the LC3 interacting region of p62. The peptidomimetics were synthesized on the solid phase and purified by HPLC. We used fluorescent polarization assay to assess the binding affinity of the peptidomimetics to LC3. We then utilized an LC3 HiBiT reporter cell line (U2OS) from Promega, which was engineered to have a fused human LC3-HiBiT with a HaloTag in between to study the effect of the lead LC3 binder on autophagic flux. In addition, confocal microscopy enabled direction visualization of the colocalization of FITC-labeled LC3 binder with LC3 and lysosome, respectively. Cytotoxicity of LC3 binder was evaluated in colorectal cancer cell line HCT116. Results: We designed and synthesized 6 helical sulfonyl-γ-AApeptides (JC1-6) to target the binding interface of LC3 and p62. These peptidomimetic compounds were designed to retain essential LC3 and p62 interactions at the W and L regions and yet have different functional groups on the helical scaffold. Compounds JC1 and JC6 have binding affinity of Kd 280 nM and 150 nM with LC3, respectively. FITC-labelled JC6 was able to penetrate U2OS and HCT116 cells. It had intracytoplasmic colocalization with not only lysosomes but also LC3 aggregates. Direct visualization of intracytoplasmic LC3 aggregates showed that JC6 at 50 µM significantly inhibited the autophagic degradation of LC3 aggregates. This effect was augmented by the presence of 2 µM autophagy activator PP242. Lastly, JC6 demonstrated cytotoxicity with IC50 approximately 50 µM in HCT116 cells bearing baseline autophagy activation compared to lack of cytotoxicity in U2OS cells with no baseline autophagy activity. Conclusion: We designed and synthesized novel helical sulfonyl-γ-AApeptide LC3 binders. With the ability of cellular penetration, they demonstrated inhibition of autophagic flux and preliminary cytotoxicity in cancer cells. Future studies may focus on structural activity relationship and further evaluation of its mechanisms of action in cancer cells. Citation Format: Mentalla Mahmoud, Jianyu Chen, Jianfeng Cai, Hao Xie. Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3101.

Background Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. Methods We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. Results Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3–4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. Conclusion With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. Trial registration number NCT02315612 .

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

AbstractIt has been challenging to target mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity. In this regard, SOS1 inhibition has arisen as an attractive approach for mKRAS CRC given its essential role as a guanine nucleotide exchange factor for this GTPase. Here, we demonstrated the translational value of SOS1 blockade in mKRAS CRC. We used CRC patient‐derived organoids (PDOs) as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406. A combination of in silico analyses and wet lab techniques was utilized to define potential predictive markers for SOS1 sensitivity and potential mechanisms of resistance in CRC. RNA‐seq analysis of CRC PDOs revealed two groups of CRC PDOs with differential sensitivities to SOS1 inhibitor BI3406. The resistant group was enriched in gene sets involving cholesterol homeostasis, epithelial−mesenchymal transition, and TNF‐α/NFκB signaling. Expression analysis identified a significant correlation between SOS1 and SOS2 mRNA levels (Spearman's ρ 0.56, p < 0.001). SOS1/2 protein expression was universally present with heterogeneous patterns in CRC cells but only minimal to none in surrounding nonmalignant cells. Only SOS1 protein expression was associated with worse survival in patients with RAS/RAF mutant CRC (p = 0.04). We also found that SOS1/SOS2 protein expression ratio >1 by immunohistochemistry (p = 0.03) instead of KRAS mutation (p = 1) was a better predictive marker to BI3406 sensitivity of CRC PDOs, concordant with the significant positive correlation between SOS1/SOS2 protein expression ratio and SOS1 dependency. Finally, we showed that GTP‐bound RAS level underwent rebound even in BI3406‐sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1‐targeting agents in CRC.

AbstractBackgroundPhoton‐counting‐detector CT (PCD‐CT) enables the production of virtual monoenergetic images (VMIs) at a high spatial resolution (HR) via simultaneous acquisition of multi‐energy data. However, noise levels in these HR VMIs are markedly increased.PurposeTo develop a deep learning technique that utilizes a lower noise VMI as prior information to reduce image noise in HR, PCD‐CT coronary CT angiography (CTA).MethodsCoronary CTA exams of 10 patients were acquired using PCD‐CT (NAEOTOM Alpha, Siemens Healthineers). A prior‐information‐enabled neural network (Pie‐Net) was developed, treating one lower‐noise VMI (e.g., 70 keV) as a prior input and one noisy VMI (e.g., 50 keV or 100 keV) as another. For data preprocessing, noisy VMIs were reconstructed by filtered back‐projection (FBP) and iterative reconstruction (IR), which were then subtracted to generate “noise‐only” images. Spatial decoupling was applied to the noise‐only images to mitigate overfitting and improve randomization. Thicker slice averaging was used for the IR and prior images. The final training inputs for the convolutional neural network (CNN) inside the Pie‐Net consisted of thicker‐slice signal images with the reinsertion of spatially decoupled noise‐only images and the thicker‐slice prior images. The CNN training labels consisted of the corresponding thicker‐slice label images without noise insertion. Pie‐Net's performance was evaluated in terms of image noise, spatial detail preservation, and quantitative accuracy, and compared to a U‐net‐based method that did not include prior information.ResultsPie‐Net provided strong noise reduction, by 95 ± 1% relative to FBP and by 60 ± 8% relative to IR. For HR VMIs at different keV (e.g., 50 keV or 100 keV), Pie‐Net maintained spatial and spectral fidelity. The inclusion of prior information from the PCD‐CT data in the spectral domain was able to improve a robust deep learning‐based denoising performance compared to the U‐net‐based method, which caused some loss of spatial detail and introduced some artifacts.ConclusionThe proposed Pie‐Net achieved substantial noise reduction while preserving HR VMI's spatial and spectral properties.

Abstract Glioblastoma (GBM), a lethal astrocytic brain tumor, has limited available treatment options. A major hindrance to the progress of new therapies is the selectivity of the blood brain barrier (BBB) which limits drug access to the tumor. Further, there are currently no minimally-invasive tests that can quickly and accurately determine whether novel therapeutics have crossed the BBB during clinical trials. Therefore, development of a non-invasive test that can identify drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase trials of a new compound’s pharmacological suitability and potential efficacy. This study proposes that cargo contained in GBM-derived extracellular vesicles (EVs), which are small membrane-bound particles released from cells, may serve as one such pharmacodynamic reporter. We analyzed RNA-seq data for EVs isolated from two GBM patient-derived xenograft models grown as short-term in vitro cultures, GBM10 and GBM120, following treatment with either temozolomide (TMZ) or pevonedistat (MLN). We assessed whether EV RNA payloads vary with different drug concentrations (EC50 vs EC80) and at different time points (4hr vs 24hr) post treatment. In the samples treated with MLN, a few long non-coding RNAs are commonly upregulated across the different time points and two models. Under different TMZ concentrations, differentially expressed genes are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis. We also found a negative correlation between the TMZ concentration and Y RNA expression level, which are functionally involved with DNA replication. Additionally, using CIRI2, we predicted the amount of circular RNAs in the EV cargo; we found that the ratio of circular RNAs to their linear counterparts (CLR) varies under different treatments. In GBM10, the percentage of circRNA with CLR &gt; 1 decreases with increasing drug effect. Thus, our preliminary results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To apply such an assessment to patients, we have simultaneously pursued the development of an immunoprecipitation (IP) approach to enrich GBM-derived EVs that can then undergo cargo profiling. Potential biomarkers were screened across isolated GBM EVs from in vitro supernatant by western blot and ExoView analysis. B7H3 has emerged as a lead candidate for GBM-EV enrichment. To validate the ability of EV cargo to reflect drug distribution across the BBB in patients, current efforts are focused on applying IP enrichment of GBM-EVs in longitudinally-acquired cerebrospinal fluid samples from patients during their disease course. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts. Citation Format: Valerie DeLuca, Nanyun Tang, Yue Hao, Anjali Raju, Charles Shaffer, Cecile Riviere-Cazaux, Terry C. Burns, Jann Sarkaria, Ian Parney, Patrick Pirrotte, Kendall Van Keuren-Jensen, Michael E. Berens. Extracellular vesicles as a pharmacodynamic reporter in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2788.

ImportanceChronic hemodynamically significant aortic regurgitation (AR) is associated with excess risk of death, yet data for Asian patients are lacking, and whether Asian patients can abide by Western guidelines as to when aortic valve surgery should be performed is unknown.ObjectiveTo assess AR presentation and cutoffs of left ventricular ejection fraction (LVEF), LV end-systolic dimension index (LVESDi), and LV end-systolic volume index (LVESVi) that are associated with risk of death in Asian patients with AR.Design, Setting, and ParticipantsThis retrospective cohort study included consecutive patients with chronic, moderately severe to severe AR from 3 tertiary referral centers (2 in Japan and 1 in Taiwan) from June 11, 2008, through November 19, 2020, with follow-up through November 11, 2021.ExposuresAortic regurgitation severity, graded by a comprehensive integrated approach.Main Outcomes and MeasuresThe primary outcome was the association between volume-derived LVEF, LVESDi, and LVESVi and all-cause death (ACD). The secondary outcome was the association of these LV indexes with cardiovascular death (CVD). Clinical and echocardiographic data were analyzed retrospectively. A de novo disk-summation method was used to derive LV volumes and volume-derived LVEF.ResultsOf 1259 patients (mean [SD] age, 64 [17] years; 934 [74%] male), 515 (41%) were Japanese and 744 (59%) were Taiwanese. The median follow-up was 4.1 years (IQR, 1.56-7.24 years). The mean (SD) body surface area was 1.67 (0.21) m2; LVEF, 55% (11%); LVESDi, 24.7 (5.7) mm/m2; LVESVi, 50.1 (28.0) mL/m2; and indexed mid–ascending aorta size, 24.7 (5.5) mm/m2. Aortic valve surgery occurred in 483 patients (38%); 240 patients (19%) died during follow-up. Overall mean (SD) 8-year survival was 74% (2%). Separate multivariate models adjusted for covariates demonstrated independent associations of LVEF, LVESDi, and LVESVi with ACD (LVEF: hazard ratio [HR] per 10%, 0.80; 95% CI, 0.70-0.92; P = .002; LVESDi: HR, 1.04; 95% CI, 1.01-1.06; P = .002; LVESVi: HR per 10 mL/m2, 1.11; 95% CI, 1.05-1.17; P &amp;lt; .001) and CVD (LVEF: HR per 10%, 0.69; 95% CI, 0.56-0.85; P &amp;lt; .001; LVESDi: HR, 1.05; 95% CI, 1.01-1.09; P = .01; LVESVi per 10 mL/m2: HR, 1.15; 95% CI, 1.06-1.24; P &amp;lt; .001). In the total cohort, spline curves showed that mortality started to increase for an LVEF of 53% or less, LVESDi of 22 mm/m2 or greater, and LVESVi of 46 mL/m2 or greater for both ACD and CVD. Early surgery was beneficial in 3 strata of LVESDi (&amp;lt;20, 20 to &amp;lt;25, and ≥25 mm/m2) and 2 strata of LVESVi (&amp;lt;46 and ≥46 mL/m2).Conclusions and RelevanceThis multicenter cohort study of Asian patients with hemodynamically significant AR found cutoff values of LVEF, LVESDi, and LVESVi that were associated with increased risk of death. These findings suggest that Western guidelines seem applicable in Asian patients and, most importantly, that indexed LV parameters with a lower cutoff could be used in discriminating patients with excess mortality risk.