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7023 Background: Axi-cel is an autologous chimeric antigen receptor (CAR) T-cell therapy approved for adults with R/R LBCL after ≥ 1 prior line of therapy (LoT). Adverse events, such as cytokine release syndrome (CRS) and neurologic events (NEs), may deter centers from using axi-cel in an outpatient (OPT) setting, though individual centers have observed comparable safety and effectiveness in OPT and inpatient (IPT) care (Furqan et al. Blood Adv . 2024). Here, we present safety and effectiveness outcomes of axi-cel by intention to treat in OPT and IPT settings in a multicenter real-world dataset. Methods: Pts receiving axi-cel for R/R LBCL in the US from 01/2021-07/2023 with data in the Center for International Blood and Marrow Transplant Research (CIBMTR) registry were eligible for analysis. Pts with prior allogeneic transplant or unknown intended care setting were excluded. Of potential pts, 119 OPT pts were identified from 29 centers where an increasing trend was seen (9.6% of pts in 2021 were OPT, 13.5% in 2022, 22.8% in 2023). Pts were matched to 119 IPT pts by propensity score matching on age, sex, comorbidities, lactate dehydrogenase (LDH), bulky disease, prior LoT, chemosensitivity, and infusion year (see table). Results: OPT pts had median age of 63 y (25% ≥ 70), 66% were male, and 67% had ≥ 1 comorbidity. Half (50%) had elevated LDH and 73% had 1 prior LoT. Bulky disease was reported in 3%, and 60% had chemo-resistant disease. Outcomes were analyzed at median follow-up of 12 mo. Safety and effectiveness outcomes were similar between OPT and IPT pts (see table). In multivariate analyses, no differences were found between intended care setting and CRS (odds ratio [OR] 1.09 [95% CI 0.51-2.35]), CRS Gr ≥ 3 (OR 0.57 [0.12-2.60]), NEs (OR 1.14 [0.65-2.00]), or NEs Gr ≥ 3 (OR 0.98 [0.48-2.00]). Among OPT pts, 24% and 50% did not require hospital admission within 30 d and 3 d, respectively. In pts aged ≥ 70 y, only any Gr NEs were higher in the OPT group. Conclusions: After matching on key factors that may be used to select pts for OPT infusion, outcomes were comparable between intended care settings. These findings corroborate prior results and support the consideration of axi-cel in appropriate OPT care settings. Outcomes between matched pts with R/R LBCL receiving axi-cel intended for OPT or IPT. OPT (n=119) a IPT (n=119) a CRS any Gr / Gr ≥ 3 83 (75−89) / 3 (<1−7) 83 (74−89) / 4 (1−10) NE any Gr / Gr ≥ 3 47 (38−57) / 19 (12−27) 46 (37−56) / 21 (14−30) Overall / complete response rates 78 (69−85) / 68 (59−76) 76 (67−83) / 62 (52-70) Duration of response @ 12 mo 64 (52−74) 69 (58−78) Progression-free survival @ 12 mo 53 (43−62) 53 (43−61) Overall survival @ 12 mo 71 (61−78) 72 (62−79) Non-relapse mortality @ 12 mo 6 (2−11) 4 (1−8) Hospital admission within 30 days of infusion / median duration (range), d 76 (67−83) / 9 (2−53) Not Applicable a Percent (95% CI) unless otherwise specified.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Objectives Generative artificial intelligence (GAI) tools can enhance the quality and efficiency of medical research, but their improper use may result in plagiarism, academic fraud and unreliable findings. Transparent reporting of GAI use is essential, yet existing guidelines from journals and institutions are inconsistent, with no standardised principles. Design and setting International online Delphi study. Participants International experts in medicine and artificial intelligence. Main outcome measures The primary outcome measure is the consensus level of the Delphi expert panel on the items of inclusion criteria for GAMER (Rreporting guideline for the use of Generative Artificial intelligence tools in MEdical Research). Results The development process included a scoping review, two Delphi rounds and virtual meetings. 51 experts from 26 countries participated in the process (44 in the Delphi survey). The final checklist comprises nine reporting items: general declaration, GAI tool specifications, prompting techniques, tool’s role in the study, declaration of new GAI model(s) developed, artificial intelligence-assisted sections in the manuscript, content verification, data privacy and impact on conclusions. Conclusion GAMER provides universal and standardised guideline for GAI use in medical research, ensuring transparency, integrity and quality.

Abstract Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.

ImportanceUnderstanding the relationship between patients’ clinical characteristics and outcomes is fundamental to medicine. When critically ill patients die after withdrawal of life-sustaining therapy (WLST), the inability to observe the potential for recovery with continued aggressive care could bias future clinical decisions and research.ObjectiveTo quantify the frequency with which experts consider patients who died after WLST following resuscitated cardiac arrest to have had recovery potential if life-sustaining therapy had been continued.Design, Setting, and ParticipantsThis prospective cohort study included comatose adult patients (aged ≥18 years) treated following resuscitation from cardiac arrest at a single academic medical center between January 1, 2010, and July 31, 2022. Patients with advanced directives limiting critical care or who experienced cardiac arrest of traumatic or neurologic etiology were excluded. An international cohort of experts in post-arrest care based on clinical experience and academic productivity was identified. Experts reviewed the cases between August 24, 2022, and February 11, 2024.ExposurePatients who died after WLST.Main Outcome and MeasuresThree or more experts independently estimated recovery potential for each patient had life-sustaining treatment been continued, using a 7-point numerical ordinal scale. In the primary analysis, which involved the patient cases with death after WLST, a 1% or greater estimated recovery potential was considered to be clinically meaningful. In secondary analyses, thresholds of 5% and 10% estimated recovery probability were explored.ResultsA total of 2391 patients (median [IQR] age, 59 [48-69] years; 1455 men [60.9%]) were included, of whom 714 (29.9%) survived to discharge. Cases of uncertain outcome (1431 patients [59.8%]) in which WLST preceded death were reviewed by 38 experts who rendered 4381 estimates of recovery potential. In 518 cases (36.2%; 95% CI, 33.7%-38.7%), all experts believed that recovery potential was less than 1% if life-sustaining therapies had been continued. In the remaining 913 cases (63.8%; 95% CI, 61.3%-66.3%), at least 1 expert believed that recovery potential was at least 1%. In 227 cases (15.9%; 95% CI, 14.0%-17.9%), all experts agreed that recovery potential was at least 1%, and in 686 cases (47.9%; 95% CI, 45.3%-50.6%), expert estimates differed at this threshold.Conclusions and RelevanceIn this cohort study of comatose patients resuscitated from cardiac arrest, most who died after WLST were considered by experts to have had recovery potential. These findings suggest that novel solutions to avoiding deaths based on biased prognostication or incomplete information are needed.

Abstract Background Neuro-oncology education in American neurology departments is highly variable, with no clear guidelines on appropriate practices. To better understand its current state, we focus on the perspective of departmental Grand Rounds (GR), views of adult neurology residency program directors (ANRPD), neuro-oncologists, and residents. Methods First, we obtained GR series from academic years 2017–2018 and 2018–2019 via an online search and direct emails to neurology residency programs. Second, two online surveys were dispensed to ANRPD and neuro-oncologists. Third, a cohort of neurology residents completed surveys with pre/post-didactic tests. Results Neuro-oncology consisted of 7% (28/ 411) GR in 2017–2018 and 6% (29/463) in 2018–2019; approximately 20% of institutions had no neuro-oncology GR. Twenty neuro-oncologists and 25 of the 175 ANRPDs completed the surveys. Respondents thought 1-to-4 GR annually was adequate. Thirty-five residents completed the survey. Residents might consider neuro-oncology with more exposure (77%, 27/35) and a stronger knowledge base (57%, 20/35). After 8-hours of didactics, residents demonstrated significant (P = .019) pre-/post-test improvement. Conclusions Here, we begin to define the status of several aspects of neuro-oncology education: 1 in 5 academic institutions do not have any neuro-oncology GR lectures annually, and both ANRPDs and neuro-oncologists agree that 1-to-4 lectures annually are adequate. Residents overwhelmingly stated they would be more interested in neuro-oncology with more exposure, and a pilot study of 8 hours of didactic did show knowledge improvement. While these initial datasets require confirmation in larger studies, it suggests that small changes to the current state at some institutions could have a meaningful impact.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (&amp;lt;60 years vs ≥60 years) and disease duration (&amp;lt;6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (&amp;lt;60 years or ≥60 years) and disease duration (recent [&amp;lt;6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P &amp;gt;.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

BACKGROUND: Catheter ablation of ventricular arrhythmias, one of the most rapidly growing procedures in cardiac electrophysiology, is associated with magnetic resonance imaging–detected brain lesions in more than half of cases. Although a retrograde aortic approach is conventional, modern tools enable entry through a transseptal approach that may avoid embolization of debris from the arterial system. We sought to test the hypothesis that a transseptal puncture would mitigate brain injury compared with a retrograde aortic approach. METHODS: The TRAVERSE trial (Transseptal Versus Retrograde Aortic Ventricular Entry to Reduce Systemic Emboli) was a multicenter randomized controlled comparative effectiveness trial. Patients with left ventricular arrhythmias undergoing catheter ablation procedures were randomly assigned to a transseptal puncture approach compared (1:1) with a retrograde aortic approach. The primary outcome was the presence of an acute brain lesion detected by magnetic resonance imaging. Secondary outcomes included clinically manifest complications, procedural efficacy, and 6-month neurocognitive assessments. RESULTS: Among the 62 patients randomly assigned to a retrograde aortic approach with postoperative brain magnetic resonance imaging, 28 (45%) exhibited an acute brain lesion compared with 19 of the 69 (28%) of those randomized to a transseptal puncture ( P =0.036). No differences in clinically manifest complications or procedural efficacy were observed. More patients in the retrograde aortic arm were categorized as having a high likelihood of cognitive impairment at 6 months (33% compared with 19% of those in the transseptal arm), but substantial loss to follow-up was present. CONCLUSIONS: Among patients undergoing left ventricular catheter ablation procedures, a transseptal approach reduced the risk of acute brain lesions by nearly half compared with a retrograde aortic approach without sacrificing safety or efficacy. Given a likely embolic pathogenesis, the brain magnetic resonance imaging findings may reflect a propensity to other organ damage; these findings may extend to other procedures requiring left ventricular entry. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03946072.