Citations

e15713 Background: Fruquintinib demonstrated overall survival benefit in heavily pretreated metastatic colorectal cancer (mCRC) in FRESCO and FRESCO-2. The FDA approved fruquintinib on Nov 8, 2023 for adult patients with mCRC after standard chemotherapy plus anti-VEGF therapy, with anti-EGFR therapy when appropriate (e.g., RAS wild-type). Observed geographic variation in post-approval uptake suggests potential disparities in the delivery of evidence-based medicine across U.S. regions. Methods: We conducted a retrospective cohort study using Epic Cosmos, a database of over 300 million patient records from over 1,500 hospitals nationwide. We identified adults with metastatic colorectal cancer (mCRC) with prior standard systemic therapy exposure and recorded fruquintinib exposure following FDA approval beginning Nov 8, 2023. Fruquintinib uptake was analyzed by U.S. Census region and state, expressed as the proportion of eligible mCRC patients receiving fruquintinib within each geography. Results: Among 116,116 pre-treated mCRC patients, 6,722 (5.79%) had recorded fruquintinib exposure during the post-approval period. Uptake varied nearly five-fold across states (2.27%–11.33%) (Table). High-uptake states were disproportionately concentrated in the central U.S./Midwest, whereas multiple low-uptake states were observed in the West and Northeast, suggesting broader regional variation beyond state-to-state differences. Conclusions: In a large national EHR-derived cohort of pre-treated mCRC patients after U.S. approval, fruquintinib uptake demonstrated substantial geographic variation. These findings raise concern for inequities in delivery of evidence-based later-line therapy and highlight the need to identify modifiable system- and site-level drivers (e.g., access, referral patterns, treatment infrastructure) to promote equitable adoption. Fruquintinib uptake among eligible metastatic colorectal cancer patients by U.S. state. Rank Geography Eligible mCRC (N) Fruquintinib uptake (%) Overall Overall 116,116 5.79 Top 1 Oklahoma 1,236 11.33 2 Kansas 1,312 10.75 3 Indiana 2,448 10.70 4 Missouri 1,521 9.47 5 Connecticut 2,208 9.24 Bottom 1 Washington 1,232 2.27 2 Nevada 441 2.72 3 Rhode Island 476 2.73 4 Tennessee 1490 2.82 5 Maine 614 2.93 Fruquintinib uptake is reported as the proportion of eligible pre-treated metastatic colorectal cancer (mCRC) patients with recorded fruquintinib exposure following U.S. FDA approval. States are ranked by uptake percentage.

10576 Background: Type 2 diabetes mellitus (T2DM) and excess adiposity are independent risk factors for pancreatic cancer. Pancreatic cancer risk within T2DM across body-mass index (BMI) strata is heterogeneous in real-world cohorts and lean T2DM individuals may represent a distinct high risk phenotype. We compared pancreatic cancer incidence and post-diagnosis survival across BMI strata. Methods: We performed a retrospective comparative outcomes analysis using the TriNetX network. Adults with T2DM (HbA1c ≥6.5%) were categorized as obese (BMI ≥30 kg/m²) or lean (BMI <25 kg/m²). The lean cohort additionally excluded any patient with prior BMI of >25 kg/m² to control for cancer associated weight loss. The index event was first T2DM diagnosis, and outcomes were evaluated after a 365-day window. Patients with pancreatic cancer prior to the outcome window were excluded. Propensity score matching was done using the following parameters: age, sex, smoking status, pancreatitis, pancreatic cysts, chronic kidney disease, gallstones, family history of pancreatic cancer, and HbA1c. Outcomes assessed were incident pancreatic cancer over 10 years and all-cause mortality among patients with pancreatic cancer and T2DM. Results: Total number of patients in the obese group was 1,759,075 with mean age of 57 ± 13.4 years and in the lean cohort were 205,193 with a mean age of 61.8 ± 16.6 years. After propensity score matching, there were 204,086 patients in each group. Mean HbA1c levels were 7.4 ± 1.8% in the obese group and 7.9 ± 2.2% in the lean BMI group. The incidence of pancreatic cancer was 0.16% (n = 335) in obese patients as compared to 0.23% in lean (n = 478) patients with a risk difference of 0.07% (p <0.001). Obesity was associated with lower pancreatic cancer risk (RR 0.692, 95% CI 0.603–0.797; p < 0.001). In the subgroup analysis of patients diagnosed with pancreatic cancer, obese patients had longer median survival (1,109 vs 651 days) with HR 0.853 (95% CI 0.793 - 0.918; p <0.001). Conclusions: Lean adults with T2DM had a higher incidence of pancreatic cancer and worse post-diagnosis survival than obese patients. These results identify lean T2DM as a distinct high-risk phenotype and demonstrate that pancreatic cancer risk within T2DM is heterogeneous and not solely attributable to excess adiposity. Further investigation is needed to elucidate the biological mechanisms underlying this association and its implications for clinical risk assessment. Pancreatic cancer incidence and associated risk estimates among obese and lean adults with type 2 diabetes mellitus. Cohort Pancreatic cancer incidence RD RR Obese T2DM(n = 204,086) 0.16% (n = 335) 0.07% (95% CI: 0.04 - 0.10), p < 0.001 1.44 (95% CI: 1.25 - 1.66) Lean T2DM(n = 204,086) 0.23% (n = 478) Abbreviations: CI, confidence interval; RD, risk difference; RR, relative risk; T2DM, type 2 diabetes mellitus.

ABSTRACT The Burkholderia cepacia complex (BCC) is comprised of 24 species of Gram-negative bacteria that cause opportunistic infections. While antimicrobial susceptibility testing (AST) has historically been used to guide treatment for BCC infections, recent work highlighting problems with AST for these organisms led the Clinical and Laboratory Sciences Institute (CLSI) to remove disk diffusion (DD) and minimal inhibitory concentration (MIC) breakpoints for BCC from its M100 standards document. Epidemiological cut-off values (ECVs) may be helpful to clinicians in the absence of breakpoints, as they may be used to determine whether an isolate has a wild-type or non-wild-type phenotype. Here we present an analysis of BCC ECVs for ceftazidime (CAZ), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), and trimethoprim-sulfamethoxazole (TMP-SMX). ECVs were calculated using MIC data from 3 previous studies and 3 independent laboratories for 1,896 BCC isolates. ECVs were 16 μg/ml for CAZ, 8 μg/ml for LVX, 16 μg/ml for MEM, and 8 μg/ml for MIN. The ECV for TMP-SMX varied depending on the analysis from 2 μg/ml, 8 μg/ml, and 16 μg/ml and therefore could not be reliably established. Challenges with establishing ECVs for BCC include limitations with the pooled MIC dataset, broad MIC distributions, and high ECVs that are above the obsolete susceptible MIC breakpoints. These challenges limit the clinical utility of ECVs for these organisms and supported removal of ECVs from the CLSI M100 standards document. IMPORTANCE The Burkholderia cepacia complex is a group of bacterial species that cause difficult-to-treat opportunistic infections. Recently, clinical breakpoints, which are used to determine whether organisms are susceptible to certain antimicrobials, were removed from Clinical and Laboratory Standards Institute (CLSI) standards for these organisms due to problems with antimicrobial susceptibility testing performance. Clinicians are now faced with the challenge of how to treat these complex infections without clinical breakpoints. Here we determine epidemiological cut-off values (ECVs) for relevant antimicrobials for the B. cepacia complex. While we established ECVs for four antimicrobials, we encountered significant challenges in our analyses, including limitations with data for these organisms and high ECVs that are not clinically useful. These challenges limit the practical use of these ECVs in helping guide clinicians on treatment and supported the eventual removal of ECVs from the CLSI M100 standards document.

Abstract Chronic low‐grade inflammation characterizes type 2 diabetes mellitus (T2DM) and underlies the development of peripheral neuropathy, symptoms of which include mechanical allodynia and an exaggerated exercise pressor reflex. The purpose of this study was to determine whether mechanical allodynia and/or specific concentrations of inflammatory mediators coincide with the presence of an exaggerated exercise pressor reflex. Haemoglobin A1c was assessed to detect diabetes onset (threshold ≥5.6%) in male University of California Davis (UCD)‐T2DM rats ( n = 18). Age‐matched, healthy Sprague–Dawley rats ( n = 18) served as controls. Monthly measurements assessed mechanical allodynia (via paw withdrawal threshold), insulin and inflammatory mediators (via ELISA and multiplex kits). Paw withdrawal threshold was not different between groups prior to diabetes onset. However, by 8 weeks post‐onset, T2DM rats demonstrated a significant decrease in pain threshold compared to that before diabetes onset, which persisted for 8 weeks. This is the same period in diabetes progression as when the exercise pressor reflex is exaggerated. Prior to diabetes onset, UCD‑T2DM rats had significantly higher circulating levels of IL‑6 and IL‑1β, and these elevations persisted throughout disease progression, with only CRP showing a significant increase at 8 weeks post‑onset. These findings offer a useful foundation for further exploration into the assessments of mechanical allodynia and inflammation to determine when those with T2DM are at an increased risk for experiencing adverse cardiovascular events.

Multi-listing (ML) increases the odds of transplantation compared with single-center listing. However, not all patients have equivalent access to ML. The recent allocation policy change prioritized distance from the donor hospital in an attempt to decrease geographic disparities. This study assessed access to liver transplant (LT) given ML practices before and after the acuity circles policy change. United Network for Organ Sharing data were queried for LTs between January 1, 2016, and November 1, 2024. Patients were grouped by listing at one versus multiple centers and by acuity circle era (ACE). Cohort characteristics and comparisons were described using chi-square and Wilcoxon rank tests. Multivariable logistic regressions and propensity score match (PSM) were performed to assess associations between ML and LT. The final cohort consisted of 105,030 patients; 4084 (3.9%) were multi-listed. Racial/ethnic minority groups, less educated, and publicly insured candidates were less often multi-listed. ML was positively associated with LT in all analyses (overall: OR=1.180, p <0.001; PSM: OR=1.164, p =0.001; pre-ACE: OR=1.127, p =0.015; post-ACE: OR=1.218, p <0.001). Education, race/ethnicity, and insurance type were also associated with LT across all analyses. ML patients were more often transplanted at their primary center with a significant increase in primary center LT post-ACE (53.4% vs. 63.4%, p <0.001). ML and LT had a positive correlation. There was a negative association between minority groups and ML as well as LT. Although acuity circles decreased geographic disparities, they did not change ML accessibility across candidates.

Background: Little is known about how silicone metacarpophalangeal (MCP) arthroplasty outcomes compare between rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Methods: Using our single institutional data from 2000 to 2022, we propensity matched 46 primary silicone MCP arthroplasties in 33 OA patients 1:2 to 92 arthroplasties in 54 RA patients based on age, sex, body mass index, operative digit, and if the surgery was on the dominant hand. We used Kaplan-Meier estimates and cluster-robust Cox proportional hazard models to compare survival free from revision, all-cause reoperation, and development of coronal plane deviation >10°. Results: There was comparable 10-year survival free of revision (94% OA, 91% RA) and all-cause reoperation (91% OA, 87% RA), with no difference in risk for each outcome between groups. Revision in OA patients occurred early (mean 0.6 years) for recurrent deformity (n = 2) and periprosthetic joint infection (n = 1). Revision in the RA cohort occurred later (mean 6.3 years postoperatively) for recurrent deformity (n = 3) and dislocation (n = 1). Osteoarthritis patients had less coronal plane deviation at the final radiographic follow-up (6.5° vs 16.2°, P < .001), higher 10-year survival free from coronal deviation > 10° (79% vs 17%), and lower risk of progressive coronal deformity (hazard ratio 0.15, P < .001). Conclusions: Silicone MCP arthroplasty remains a durable option with low reoperation rates for RA and OA. Osteoarthritis patients experience less coronal deviation and late reoperation for deformity than RA patients, likely due to their more robust soft-tissue stabilizers and noninflammatory disease process.

Abstract Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used “gray-white-CSF” models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center (ADRC) are presented.

Abstract Chimeric antigen receptor (CAR) T-cell therapy achieves high response rates in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, yet only 40% of patients achieve durable remission. Identifying biological programs linked to long-term response remains critical. As metabolic fitness underlies T-cell persistence and effector function, we profiled metabolic pathways associated with clinical outcomes following commercial CD19 CAR T-cell therapy. Single-cell RNA sequencing of peripheral blood mononuclear cells collected at baseline (BL), peak CAR-T expansion (PK), and one-month post-infusion (M1) was analyzed using CellRanger v7.0.1, immunopipe. Seurat v4.3.0 was applied for unsupervised clustering to delineate cell subsets based on top differentially expressed genes. Patients were categorized as durable complete remission (CR ≥6 months; n = 16), primary refractory (PD1; n = 4), or relapse after initial response (PD2; n = 12). Gene-set enrichment analysis defined metabolic pathway activity across T-cell, monocyte, dendritic cell (DC), and natural killer (NK) subsets. Oxidative phosphorylation (OXPHOS) emerged as the dominant metabolic program distinguishing clinical outcomes. At BL and PK, OXPHOS was consistently enriched in PD1 relative to CR across T-cell, monocyte, and DC subsets, suggesting early oxidative activation in non-responders. By M1, this pattern inverted, with higher OXPHOS activity in CR. PD2 largely paralleled PD1, but several subsets including CD8 T central memory, classical monocytes TGFβ, intermediate monocytes CD38, monocytic myeloid-derived suppressor cell (mMDSC) HIF1A, and mMDSC SIRPA, showed OXPHOS enrichment in CR at BL and/or PK that persisted through M1. In contrast, DC and NK subsets exhibited the opposite pattern: OXPHOS was enriched in CR at PK (conventional DC 2 (cDC2), plasmacytoid DC (pDC), NK, proliferating NK), but shifted toward enrichment in PD2 at M1 (cDC2, NK, NK CD56bright). Glycolysis (GLY) followed a similar trajectory in monocytes and NK cells, with enrichment in PD1/PD2 at BL and PK, followed by enrichment in CR at M1. In T-cells, PD1 maintained GLY enrichment from BL through PK, with no significant differences observed at M1. The inositol-phosphate metabolism pathway showed a more static pattern and was consistently enriched in multiple PD2 effector and memory T-cell subsets without reversal at M1. Taken together, these data reveal distinct, lineage-specific metabolic signatures that differentiate durable remission from early and late progression. Dynamic OXPHOS and GLY programming, characterized by lower activity early and enhanced activity at M1 in CR, may reflect adaptive metabolic programming that supports sustained antitumor immunity. Immune-metabolic profiling may therefore serve as a biomarker of response and highlight actionable metabolic pathways to enhance CAR T-cell durability. Citation Format: Melinda S.Y. Tan, Panwen Wang, Patrizia Mondello, Jacqueline Turner, Andre de Menezes Silva Corraes, Chen Wu, Zuoyi Shao, Kevin Regan, Ma Audrey, Arushi Khurana, Nora N. Benanni, Yucai Wang, Paul Hampel, Jonas Paludo, Saad J. Kenderian, Urshila Durani, Patrick B. Johnston, Jose Caetano Villasboas, Stephen M. Ansell, Ying Li, Haidong Dong, Hu Zeng, Yi Lin. Metabolic pathway signatures defining response to CD19 CAR T-Cell therapy in aggressive B-cell non-hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3278.

Abstract Introduction: Therapeutic outcomes in B-cell non-Hodgkin’s lymphoma (B-NHL) have substantially improved with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy. Yet, persistent immune dysfunction and underlying metabolic dysregulation remain major obstacles to achieving durable clinical responses in B-NHL. We hypothesize that mitochondrial pathways play a critical role in mediating anti-tumor immunity during CAR-T therapy. Methods: Peripheral blood mononuclear cells were collected from healthy controls (CNTRL, n=5) and patients with advanced stage lymphoma (LYM) who received FDA approved CAR-T (n=32). Samples were collected before lymphodepletion (BL), at peak CAR-T expansion (PK) and one-month post-infusion (M1). Single-cell RNA sequencing was used to interrogate differential mitochondrial gene expression. Samples were obtained from LYM patients with complete remission for &gt;6 months (CR), primary refractory (PD1), or relapsed (PD2) disease. Results: Compared to CNTRLs, LYM patients exhibited reduced expression of cytochrome c oxidase. At BL, CR patients demonstrated broader mitochondrial differential gene expression across all T-cell subsets relative to PD1 and PD2 and showed higher expression of MT-ATP-6, MT-ATP-8, and MT-CO3. Following CAR-T infusion, global mitochondrial gene expression increased across patients corresponding with expansion of CD8 effector T cells (Tem tumor circulating) and activated peripheral memory T cells (Tpm). Certain mitochondrial genes, such as MT-CO1, were durably expressed across LYM patients at BL, PK, and M1 in peripheral and central memory T cells (Tpm, Tcm). At PK, cytochrome c oxidase and ATP synthase genes were upregulated in CR Tpm and Tcm. At M1, MT-ATP-6, MT-ATP-8, MT-CO3 were significantly upregulated in CD8 memory precursor effector T-cells (MPECs) of CR patients compared to both PD1 and PD2. While CR and PD2 patients appeared clinically responsive at M1, CR samples maintained significantly higher MT-ATP-8 expression across T cell subsets (CD8 MPECS, Tpm, Tcm) compared to PD2 (p values 0.008; &lt;0.0001; &lt;0.0001). Conclusions: We report a temporal shift in immunometabolism with CAR-T therapy in LYM. Clinical responders exhibited sustained mitochondrial activity characterized by persistent expression of ATP synthase in CD8 MPECs and cytochrome c oxidase in Tpm and Tcm. In sum, mitochondrial programming may distinguish effective versus dysfunctional T cells and identify targets for therapeutic development. Citation Format: Jacqueline Turner, Panwen Wang, Patrizia Mondello, Melinda Tan, Christoph Schaefers, Chen Wu, Andre de Menezes Silva Corraes, Kevin Regan, Zuoyi Shao, Ma Audrey, Arushi Khurana, Nora N. Benanni, Yucai Wang, Paul Hampel, Saad J. Kenderian, Jonas Paludo, Urshila Durani, Patrick B. Johnston, Jose Caetano Villasboas, Stephen M. Ansell, Haidong Dong, Ying Li, Zeng Hu, Yi Lin. Mitochondrial transcriptome profiles associated with clinical responses to CAR-T therapy in aggressive lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1213.