Citations

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 >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; <0.0001; <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.

Abstract Background: Melanoma brain metastases (MBM) represent a biologically distinct and clinically aggressive subset of melanoma. Comprehensive molecular characterization focused on intracranial disease remains limited. We aimed to define the genomic landscape of MBM and compare these findings with public melanoma datasets. Methods: We retrospectively identified 166 patients with histologically confirmed MBM across Mayo Clinic tri-sites (2011-2025). Molecular testing was performed in 123 patients (74.1%). Comprehensive next-generation sequencing (NGS; ≥300-gene platforms including Tempus, FoundationOne, Caris, NeoGenomics, and MayoComplete Solid Tumor Panel) was available in 41 patients (24.7%). Intermediate-depth profiling using the MayoComplete Melanoma Panel (17 genes) was performed in 21 patients (12.7%), and a targeted 5-gene melanoma driver panel (BRAF, NRAS, KIT, GNAQ, GNA11) in 52 patients (31.3%). cfDNA-based NGS was available in 12 patients (7.2%). Genomic alterations were summarized and benchmarked against TCGA-SKCM and MSK-IMPACT datasets via cBioPortal. We considered assay heterogeneity, as Mayo panels varied in sequencing depth and CNV coverage, and hybrid-capture platforms often under-detect TERT promoter hotspots. Results: Patients had a median age of 67 years, and 63% were male. BRAF mutations occurred in 48.8% (BRAF V600E/K 41.6%; non-V600 7.2%). Additional MAPK alterations included NRAS (17.5%), KIT (5.4%), GNAQ (1.2%), and GNA11 (0.6%). In the comprehensive NGS subset, tumor-suppressor alterations included CDKN2A (17.5%), PTEN (7.8%), NF1 (9.0%), TP53 (8.4%), and TERT promoter mutations (22.9%). Median TMB was 11.55 mut/Mb (IQR 5.0-25.5). Co-alterations included BRAF+CDKN2A (7.2%), BRAF+PTEN (4.2%), NRAS+CDKN2A (4.2%), NRAS+PTEN (1.2%), and CDKN2A+PTEN (3.6%); overall, 18.1% harbored MAPK driver + tumor-suppressor co-alterations. Compared with TCGA and MSK cohorts, MBM showed similar MAPK driver frequencies but fewer MAPK + tumor-suppressor co-alterations and lower CDKN2A, PTEN, and TP53 disruption, alongside a more prevalent of TERT promoter mutations (22.9% vs 7% and 2.1%), which may partly reflect coverage differences. Conclusion: MBM exhibit a distinct genomic profile characterized by reduced tumor-suppressor loss, fewer MAPK-tumor-suppressor co-alterations, and higher prevalence of TERT promoter mutations. While assay heterogeneity limits direct cross-cohort comparisons, these patterns suggest potentially distinct biological features of intracranial melanoma and underscore the need for harmonized, MBM-specific molecular studies to guide therapeutic development. Citation Format: Dina Elantably, Joseph B. Parker, Jakob Hamilton, Ahmed Abdelhakeem, Oluwatayo Adeoye, Saivaishnavi Kamatham, Winston Tan, Arkadiusz Z. Dudek, Anastasios Dimou, Matthew S. Block, Robert McWilliams, Svetomir Markovic, Mahesh Seetharam, Roxana Dronca, Ruqin Chen. Genomic landscape of melanoma brain metastases: Real-world analysis and comparison with public melanoma cohorts [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 2107.

BACKGROUND: Subtotal cholecystectomy is increasingly recommended as a bailout strategy for the difficult gallbladder, yet its long-term durability and the risk profile of subsequent completion cholecystectomy remain incompletely defined. STUDY DESIGN: We performed a population-based retrospective cohort study of adults undergoing laparoscopic or open subtotal cholecystectomy for acute cholecystitis from 2012 to 2021 using Healthcare Cost and Utilization Project state databases from New York and Florida. The primary endpoint was remnant cholecystitis, defined as a postoperative emergency, inpatient, or outpatient diagnosis of cholecystitis or need for subsequent cholecystectomy. Kaplan–Meier analysis estimated cumulative incidence. Secondary outcomes included completion cholecystectomy and bile duct injury requiring surgical repair. RESULTS: Among 2,682 patients (98.7% laparoscopic), the cumulative incidence of remnant cholecystitis was 13.3% during a median follow-up of 2 years (interquartile range [IQR] 0.7 to 4.1). The median time to developing remnant cholecystitis was 28 days (IQR 13 to 91), with 79.7% occurring within 6 months. Only 70 patients (2.6%) underwent completion cholecystectomy at a median of 103 days (IQR 43 to 202). Completion cholecystectomy was performed via open surgery in 47.1% of patients and was associated with a 7.1% bile duct injury rate and median length of stay of 3 days (IQR 1 to 7), compared with a 0.9% bile duct injury rate for subtotal cholecystectomy overall. CONCLUSIONS: Although remnant cholecystitis occurred in 13.3% of patients after subtotal cholecystectomy, few required completion cholecystectomy. When necessary, completion cholecystectomy was frequently open and associated with a substantially higher bile duct injury rate, supporting referral to experienced hepatobiliary centers for reoperation.

Abstract Background Robotic left pancreatectomy (RLP) is increasingly adopted worldwide. Current guidelines suggest a learning curve of 21 cases, yet its impact on major morbidity and oncological quality remains uncertain. Methods A retrospective multicentre international study was undertaken across 10 centres in the UK, Spain, Germany, the USA, and Australia (2014–2025). Consecutive patients undergoing RLP were categorised into competency (first 21 cases per centre) or proficiency phase (>21). The primary outcome was major morbidity (Clavien–Dindo grade ≥ IIIa), and secondary outcome was the R1-margin rate. Mixed-effects logistic regression and risk-adjusted cumulative sum (RA-CUSUM) analyses were performed. Results 521 patients underwent RLP, including 200 (38.4%) in the competency phase and 321 (61.6%) in the proficiency phase. Median age was 63 years (IQR 54–73), and 56.4% were female. Rates of major morbidity were similar between phases (14.5% versus 14.0%, P = 0.981), as were R1 margin rates (21.6% versus 19.7%, P = 0.092). Independent predictors of major morbidity included male sex (OR 1.76, P = 0.037), preoperative pancreatitis (OR 2.23, P = 0.031), and multivisceral resection (OR 2.29, P = 0.034). Among patients with adenocarcinoma (n = 110), prolonged operative time (OR 1.39 per hour, P = 0.004) and nodal positivity (OR 2.62, P = 0.047) predicted R1 resection, while learning phase was not associated with margin status. RA-CUSUM demonstrated no excess morbidity over time in any centre. Conclusions In this first multicentre international analysis, the learning phase of RLP did not increase the risk of major morbidity or compromise oncological quality. These findings support the safe global adoption of RLP with appropriate training and case selection.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

Precis: This retrospective multicentre study of 77 NTG eyes undergoing phacoemulsification and Hydrus implantation showed a sustained reduction in medication burden, while maintaining IOP levels. Complications were rare and nonsight-threatening. Purpose: To evaluate 36-month outcomes of combined phacoemulsification and Hydrus Microstent implantation (Phaco-Hydrus) in eyes with normal tension glaucoma (NTG). Methods: This multicentre retrospective study included 77 NTG eyes from Singapore and Canada that underwent Phaco-Hydrus between 2014 and 2023. Primary outcomes were changes in intraocular pressure (IOP) and medication burden, and cumulative success probabilities from Kaplan-Meier (KM) analyses. Longitudinal changes were analysed using generalized estimating equations. Results: Of 77 eyes, 31 completed 36 months of follow-up. Mean baseline IOP and medications was 13.5±2.5 mm Hg and 1.7±0.9, respectively. No significant reductions in IOP were observed. A sustained reduction in medication use was observed at all follow-up timepoints ( P ≤0.001). At 36 months, medication use decreased by −0.7±0.2 [adjusted mean difference±SE of the mean [SEM]]. Proportion of medication-free eyes increased from 7.8% (n=6/77) at baseline to 45.2% (n=14/31) at 36 months. Cumulative success probabilities varied widely based on definitions. When defined as a decrease in ≥1 medication from baseline without an increase in IOP, or IOP ≤15 mm Hg and reduced ≥20% from baseline while medication-free, and no additional laser or incisional glaucoma surgery, this was 40.7% at 36 months. No visual field mean deviation progression was detected. Adverse events were infrequent and nonsight-threatening. Conclusion: In eyes with NTG, Phaco-Hydrus may offer a greater role in medication reduction or achieving a medication-free status over 36 months, rather than absolute IOP reduction.

Abstract Background High-sensitivity cardiac troponin (hs-cTn) assays are recommended for the diagnosis of acute myocardial infarction. Here, we characterize the analytical performance of a next-generation hs-cTn assay, Elecsys® Troponin T hs Gen 6 (Roche Diagnostics International). Methods Surplus lithium-heparin plasma or serum samples from patients or healthy volunteers were run on Cobas® e 801, e 402, and Pro analyzers. Limits of blank (LoB), limits of detection (LoD), and limits of quantitation (LoQ) were determined according to CLSI EP17-A2, with target values of 1.0 and 1.5 ng/L for LoB/LoD and 3.0 ng/L (10% CV) and 1.5 ng/L (20% CV) for LoQ, respectively. Precision was measured, per CLSI EP17-A2, using 3 QC samples (approximately 4, 30, and 220 ng/L), 12 native samples, and 3 reagent lots. Linearity, per CLSI EP06-Ed2, was determined by diluting samples with cardiac troponin T (cTnT) concentration above the measuring range with a low/blank sample. Interference (per Glick) with endogenous and assay components at 5 cTnT concentrations was assessed. Results Measured values for LoB, LoD, and LoQ at 10% and 20% CV were 0.1 to 0.7 ng/L, 0.3 to 1.4 ng/L, 1.0 to 2.9 ng/L, and 0.4 to 1.2 ng/L, respectively. Repeatability CVs were 1.0 to 5.8% for mean cTnT concentrations of 2.6 to 9230 ng/L in lithium-heparin plasma. High precision was shown across lots, and linearity was observed across the measuring range (1.5 to 9500 ng/L, all Pearson's r = 1.00). No interferences were observed, specified up to ≤1000 mg/dL hemoglobin, ≤50 mg/dL [≤855 µmol/L] icterus/bilirubin, and ≤1200 ng/mL biotin. Conclusions The analytical performance characterization of the assay demonstrated high sensitivity, high precision at the low end and across the measuring range, and resistance to interference.

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.