Nora Horick

BACKGROUND: Iron deficiency is present in >50% of patients with heart failure with preserved ejection fraction and is associated with reduced exercise capacity and survival. Whether iron repletion improves exercise capacity as objectively measured by peak oxygen uptake ( V ˙ o 2 ) is unknown. The IRONMET-HFpEF trial (Impact of Intravenous Iron Repletion on Mechanisms of Exercise Intolerance in HFpEF) sought to determine whether ferric derisomaltose (FDI) compared with placebo improves peak V ˙ o 2 in heart failure with preserved ejection fraction with iron deficiency. METHODS: This was a double-blind, placebo-controlled randomized clinical trial of patients with heart failure with preserved ejection fraction and iron deficiency, defined as ferritin V ˙ o 2 from baseline to 12 weeks with an analysis of covariance model including terms for treatment group, baseline peak V ˙ o 2 , and sex. Secondary end points included changes in V ˙ o 2 at the anaerobic threshold, 6-minute walk test distance, New York Heart Association class, health status assessed by the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score, and iron biomarkers at 12 weeks. RESULTS: Among 65 randomized participants (median age, 68 years [interquartile range, 58–76 years], 72% women, transferrin saturation 16.0±7.4%, ferritin 57.8±48.9 ng/mL), 64 (98.5%) completed the study. The median baseline peak V ˙ o 2 was 12.7 mL·kg ⁻¹ ·min ⁻¹ (interquartile range, 10.6–15.8 mL·kg ⁻¹ ·min ⁻¹ ) in the FDI group and 12.2 mL·kg ⁻¹ ·min ⁻¹ (11.6–14.6 mL·kg ⁻¹ ·min ⁻¹ ) in the placebo group. At 12 weeks, peak V ˙ o 2 improved by 1.2 mL·kg ⁻¹ ·min ⁻¹ (95% CI, 0.6–1.7) in the FDI group and was unchanged (0.1 mL·kg ⁻¹ ·min ⁻¹ [95% CI, −0.7 to 0.9]) in the placebo group (least-squares mean difference, 1.1 mL·kg ⁻¹ ·min ⁻¹ [95% CI, 0.2–1.9]; P =0.02). V ˙ o 2 at the anaerobic threshold, 6-minute walk test distance, and New York Heart Association class also improved in the FDI compared with the placebo group (all P P =0.20). FDI increased transferrin saturation (9.4% [95% CI, 4.9%–13.9%]) and ferritin (183 ng/mL [95% CI, 128–238]) compared with the placebo group ( P _LSMD <0.001 for both). There were no serious adverse events related to FDI administration. CONCLUSIONS: In the largest trial to date of iron repletion in heart failure with preserved ejection fraction with iron deficiency, FDI improved multiple measures of exercise capacity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04945707

Study Representativeness Table.

Organs at risk dose constraints.

Purpose:Outcomes for grade 2 and 3 meningiomas are poor. A few studies suggest a benefit from radiotherapy dose escalation. This trial evaluates the safety and efficacy of dose escalation with intensity-modulated proton therapy (IMPT) for grade 2 and 3 meningiomas. Patients and Methods:This prospective single-arm phase I trial enrolled patients with grade 2 meningioma with residual disease or recurrence or patients with grade 3 meningioma after gross total resection. Patients underwent dose-escalated IMPT to 66 Gy relative biological effectiveness [Gy(RBE)] for grade 2 gross disease and 63 Gy(RBE) for grade 3 tumor beds. The primary endpoint was acute dose-limiting toxicity (DLT). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and late toxicity. Results:Twenty-one patients with 16 grade 2 and 5 grade 3 meningiomas were enrolled and treated between 2016 and 2023. The median clinical and radiographic follow-up periods were 3.4 and 3.2 years, respectively. No DLT was observed. Five new late grade 3 toxicities occurred in four patients. Three treatment failures were observed in two grade 2 and one grade 3 tumors. Two deaths occurred in patients with grade 2 meningiomas. The 1-, 2-, and 3-year PFS rates were 100%, 95%, and 88.2%, respectively. The corresponding OS rates were 100%, 95%, and 95%, respectively. Conclusions:This first prospective trial investigating dose-escalated IMPT for high-grade meningiomas demonstrated a favorable early safety profile and clinical outcomes. Phase II and III studies are warranted to confirm the superiority of dose escalation for high-grade meningiomas.

Overall survival. A: Complete cohort. B: Stratified by WHO grading. C: Stratified by treatment indication.

Local failure rates, progression-free survival, and overall survival.

Germline variants influence immune checkpoint inhibitor responses, but their role in engineered immune cell therapies, such as chimeric antigen receptor T cells (CAR T cells), remains unclear. We integrated whole germline sequencing from patients with lymphoma treated with axicabtagene ciloleucel CAR T cell products in the ZUMA-1 and ZUMA-7 clinical trials with detailed biomarker and functional analyses to identify variants influencing clinical toxicity and pharmacokinetics. Putative deleterious variants in STXBP2 ( syntaxin binding protein 2 ) were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically, STXBP2- deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in ADAMTSL3 , a TGFβ (transforming growth factor–β) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in PTPN22 , a negative regulator of T cell receptor signaling, strongly associated with enhanced CAR T cell expansion, a key determinant of efficacy. Together, these findings demonstrate that germline genetics shape the safety and activity of engineered immune cell therapies, affecting future design and patient management.

Compare the direct antiglobulin test (DAT) versus end-tidal carbon monoxide (ETCOc) to predict significant hyperbilirubinemia. Prospective review of a convenience sample of 151 newborns admitted to the newborn nursery who had ETCOc testing in addition to standard of care (including DAT for those with ABO incompatibility). The optimal ETCOc cutoff to predict a serum bilirubin meeting the neurotoxicity risk phototherapy threshold was 2.1 ppm. DAT had a sensitivity of 13% with specificity of 89% and ETCOc ≥ 2.1 ppm had a sensitivity of 88% with specificity of 68% to predict this outcome. Use of ETCOc ≥ 2.1 ppm rather than DAT to determine neurotoxicity risk increased indications for serum bilirubin testing (25% versus 18%) and phototherapy (8% versus 1%). ETCOc ≥ 2.1 ppm had higher sensitivity but lower specificity than DAT to predict hyperbilirubinemia and resulted in increased indications for serum bilirubin testing and phototherapy.

Background: The financial impact of chronic liver disease among adults undergoing liver transplant (LT) evaluation remains understudied. We performed a cross-sectional multicenter study to explore high financial burden, defined as medical out-of-pocket expenses ≥10% of income (per prior literature), among adult LT candidates. We aimed to identify associations between high financial burden and (1) work productivity impairment; (2) financial distress (material, behavioral, and psychological consequences of financial burden); (3) financial toxicity (health-related quality of life, HRQOL). Methods: From May 2023 to April 2024, 453 patients from 13 United States transplant centers were included. Patients completed questionnaires assessing financial burden, financial distress, financial toxicity (EuroQol EQ-5D-5L instrument), and work productivity and impairment (Work Productivity and Activity Impairment Questionnaire: Specific Health Problem Version). Results: Among LT candidates, 23.3% reported a high financial burden, and only 27.6% were employed. High financial burden was associated with a higher rate of absenteeism from work (34.1% vs. 16.9%, p =0.018) among employed participants. In adjusted models, high financial burden was significantly associated with inability to pay for basic necessities (aOR 4.76, 95% CI: 2.34–9.67), delayed or foregone medical care (aOR 4.02, 95% CI: 2.30–7.02), and psychological distress (aOR 4.63, 95% CI: 1.95–10.98) but was not associated with HRQOL (EQ-5D β: −0.04, 95% CI: −0.08 to 0.00; EQ-5D-VAS β: −4.53, 95% CI: −10.1 to 1.02). Conclusion: These results highlight the critical importance of implementing routine screening for financial burden in this high-risk population and developing strategies to mitigate associated adverse outcomes.