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Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematological disorder affecting ≈24 per 1,000,000 people in the US. Iptacopan, the first orally administered monotherapy for PNH, received US Food and Drug Administration approval in December 2023. APPRISE-PNH is a data platform designed to capture comprehensive real-world information on iptacopan-treated patients with PNH. The aim of this study was to describe patient profiles and assess treatment patterns and clinical outcomes among iptacopan-treated patients (age ≥18 years) with PNH in the US real-world setting. Methods: The present interim analysis of APPRISE-PNH includes data from patients enrolled between July 2, 2024, and June 13, 2025, with additional data collection expected through 2025. Duration of therapy was measured from the date of iptacopan initiation (index) until discontinuation or data cutoff, whichever occurred first. Treatment adherence was measured using the medication possession ratio (MPR; ratio of the total days' supply to days covered) and the proportion of days covered (PDC; ratio of days with supply to days covered). Clinical outcomes were assessed during follow-up including hemoglobin (Hb; change from pre-index to highest level post index, proportion of patients with Hb increase ≥2 g/dL, and proportion of patients with Hb normalization to ≥12 g/dL), lactate dehydrogenase (LDH) (change from pre-index to lowest level post index and proportion of patients with LDH reduction <1.5× upper limit of normal [ULN]), and number of red blood cell (RBC) transfusions. Results: Among 52 patients enrolled as of June 13, 2025, the median age was 53.7 years, 38% were male, and 60% were covered by commercial insurance. Overall, 25% of patients (n=13) were complement inhibitor (CI) naive at the time of iptacopan initiation, while 75% (n=39) were treatment experienced and had received ≥1 prior CI therapy for PNH (77% ravulizumab, 46% eculizumab, 26% pegcetacoplan). All patients received iptacopan 200 mg twice daily, per the product label; the median (IQR) duration of iptacopan therapy was 9.8 (5.0-12.8) months. At the time of data cutoff, 2 patients discontinued therapy (1 due to provider decision, 1 due to death). The median (IQR) MPR and PDC were 105.2% (100.6%-110.7%) and 97.3% (92.7%-99.5%), respectively. Among the 52 patients enrolled in APPRISE-PNH, 42 patients had medical records available at the time of data cutoff. Of the 23 of 42 patients (55%) with Hb values available pre- and post index at the time of data cutoff, 4 were CI treatment naive (median [IQR] pre-index Hb, 9.9 [9.1-10.2] g/dL) and 19 were CI treatment experienced (median [IQR] pre-index Hg, 10.7 [8.9-12.2] g/dL). The median (IQR) change from pre-index to highest value post-index was similar for both groups (1.6 [0.8-2.3] g/dL and 1.6 [0.6-3.4] g/dL, respectively). However, among the CI treatment–experienced patients, those with pre-index Hb <12 g/dL (n=11) experienced a greater improvement than those with pre-index Hb ≥12 g/dL (n=8), with median (IQR) of 3.3 (2.2-4.5) g/dL vs 0.4 (0.1-1.3) g/dL, respectively. Overall, 12 of 23 patients (52%) achieved a Hb increase ≥2 g/dL, and 17 of 23 (74%) achieved Hb normalization to ≥12 g/dL. Among the 18 of 42 patients (43%) with LDH values available pre- and post index, the median (IQR) change from pre-index to lowest post-index value was −41.5 (−155.8 to 2.5) U/L. Among those with clinical data, most patients (38 of 42; 90%) did not require RBC transfusions during follow-up and 4 had evidence of an RBC transfusion over the follow-up period; 2 of 4 patients requiring transfusions had aplastic anemia and/or myelodysplastic syndrome. At the time of data cutoff, no patients with clinical data available had evidence of a major adverse vascular event (including thrombosis, transient ischemic attack, stroke, and major bleeding) over the follow-up period. Conclusions: These data represent early insights into the real-world use of iptacopan and related Hb response in US patients with PNH. Adherence to iptacopan was high, and iptacopan treatment improved Hb and LDH parameters, providing comprehensive hemolysis control. Enrollment is currently ongoing; data on additional patients with longer follow-up are forthcoming.

Introduction Software packages for quantification of CT perfusion parameters allow quick visualization of perfusion deficits to support clinical decision making in acute ischemic stroke (AIS). Several packages are now commercially available for automated quantification of ischemic core, penumbra volumes, and mismatch ratios to indicate eligibility for reperfusion therapies. This study explored the agreement between two software packages, Brainomix 360 e‐CTP and Rapid CTP, in prospective, real‐world use. Methods Consecutive patients scanned for suspected stroke at three comprehensive stroke centers over 90 days from May to July 2024 were included in the study. Eligibility for the current analysis was limited to discharge diagnosis of AIS and CTP imaging processed by both Brainomix and Rapid software. Software processing was conducted in real time after image acquisition. The presence of large vessel occlusion (LVO) was determined from review of electronic medical records. CTP core (CBF<30%) and penumbra (Tmax>6s) volumes from Brainomix and Rapid were recorded for each case. Mismatch ratios were calculated (penumbra÷core volume); positive mismatch was defined according to DEFUSE‐3 criteria (core<70ml, penumbra>15ml, mismatch ratio > 1.8). The correlations and linear regressions between Brainomix and Rapid were computed for core, penumbra and mismatch ratios, and their concordance for mismatch positivity was assessed. Results 137 patients were scanned and received a final diagnosis of AIS. Of these, only 38 had imaging processed by both Brainomix and Rapid. Median age was 69 years (interquartile range: 57‐77.5y); 16 (42%) were female; 13 (34%) had LVO. Linear models between Brainomix and Rapid's outputs for CBF and Tmax volumes are shown in Figure 1a and 1b. The correlation between software outputs for CBF volume was r=0.70 (p<.001), and for Tmax volume was r=0.72 (p<.001). Mismatch ratios were calculated for the 13 cases with LVO (Figure 1c). The linear model between mismatch ratios was not significant, with four Rapid outputs showing infinite mismatch ratios (due to having CBF volumes of 0ml). Concordance between software for mismatch positivity was good; 8/13 cases showed mismatch on both softwares; 1 case showed mismatch on Brainomix only; 1 for Rapid only; and 3 cases showed mismatch on neither software. Conclusion This prospective study, despite limited sample size (N=38), showed good correlations between Brainomix 360 e‐CTP and Rapid CTP for calculation of both core and penumbra volumes. Although mismatch ratios showed less agreement, the categorization of mismatch positivity showed good concordance between software platforms. image

Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for hematological malignancies, yet its potential to drive lymphomagenesis poses significant clinical concerns. In this study, we investigated the mechanisms underlying CAR T-cell–associated lymphomagenesis in the gastrointestinal (GI) tract on a single case, focusing specifically on the role of integrin α4β7 expression and a predisposing somatic SH2B3 mutation. We observed oligoclonal CAR T cells homing to, and clonally expanding in, the GI tract, with the dominant expanded clone harboring both a pathogenic SH2B3 mutation and a CAR transgene integration within a TFCP2 locus. The clonal CAR T cells subsequently transitioned beyond the GI tract into the peripheral blood, suggesting a potential pathway for systemic dissemination. We found clinical, histological, and molecular evidence demonstrating the efficacy of cyclosporine in reducing the expanded malignant clone and achieving durable clinical remission for more than a year. Our findings highlight the complex interplay between CAR T-cell therapy, preexisting genetic vulnerabilities, and the GI microenvironment, emphasizing the need for vigilant monitoring and tailored therapeutic strategies to address the risks associated with CAR T-cell lymphomagenesis.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background: Coronary microvascular dysfunction (CMD) is a common cause of angina with non-obstructive coronary arteries (ANOCA), but its role in patients with a history of myocardial infarction with non-obstructive coronary arteries (MINOCA) is much less understood. We investigated the incidence of major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing invasive assessment for CMD, divided into patients with MINOCA versus patients with ANOCA. We hypothesized that CMD would be common in both groups. Methods: Serial patients undergoing invasive coronary provocation testing between 2012 and 2022 were divided into MINOCA (n=76) or ANOCA (n=561). Doppler study was performed in the left anterior descending artery. CMD was defined as either coronary flow reserve (CFR) <2.5 with adenosine or <50% increase in flow with acetylcholine. Patients were followed prospectively through 2025. Incidence of MACCE (cardiac death, non-fatal MI, hospitalization for heart failure, urgent revascularization, and stroke) was compared between MINOCA and ANOCA and further analyzed by CMD status. Kaplan-Meier curves were constructed and Cox proportional hazards models were used to estimate hazard ratios (HRs). Results: Among patients with MINOCA, 53 of 76 (70%) had CMD, compared to 363 of 561 (65%) with ANOCA. Invasive provocation testing was performed a median of 163 days (IQR 13 – 255 days) after the MI in the MINOCA group. Patients were then followed for a median of 4.4 years (IQR 3.0 – 6.9 years). MACCE-free survival was significantly lower in patients with MINOCA compared to those with ANOCA (HR = 3.57, p < 0.001; Figure 1). The major contributor to MACCE was non-fatal MI in MINOCA (24%) and heart failure hospitalization in ANOCA (6%). The presence of CMD was associated with worse prognosis in both MINOCA (HR = 3.76, p = 0.02) and ANOCA (HR = 8.35, p < 0.001; Figure 2). Conclusions: Patients with MINOCA experience significantly higher long-term risk of major adverse events compared to those with ANOCA. CMD is common in both groups and is independently associated with worse outcomes. Specifically, patients with CMD had higher rates of MACCE over time, regardless of whether they presented with MINOCA or ANOCA. Invasive assessment of CMD in patients with myocardial infarction and non-obstructive coronary arteries may improve risk stratification and inform management strategies in these understudied populations

Background: Coronary microvascular disease (CMD) may be endothelium-independent (coronary flow reserve, CFR < 2.5) or endothelium-dependent (<50% increase in coronary blood flow in response to acetylcholine). CMD has been implicated in abnormal myocardial relaxation and impaired diastolic function. Wave intensity analysis (WIA) is a hemodynamic method that quantifies the energy of pressure-flow waves driving coronary blood flow. The backward expansion wave (BEW) is the dominant distally originating wave, generated by microvascular suction during ventricular relaxation. Thus, the BEW may offer mechanistic insight into the link between CMD and diastolic dysfunction. Hypothesis: We hypothesized that diastolic dysfunction would be more common in patients with CMD, and that the backward expansion wave (BEW) intensity would be lower in those with diastolic dysfunction compared to those without. Methods: Patients with non-obstructive coronary artery disease undergoing invasive coronary physiology assessment of the left anterior descending artery were included (n = 113). Pressure and Doppler flow were recorded at rest, with adenosine, and with acetylcholine for categorization of CMD as endothelium-independent (CMD-Ei) and/or endothelium-dependent (CMD-Ed). Wave intensity analysis was used to calculate cumulative BEW (J×m -2 ) at rest in CMD, CMD-Ei (endothelium-independent), and CMD-Ed (endothelium-dependent) subgroups. Diastolic dysfunction was diagnosed by transthoracic echocardiogram using the 2016 American Society of Echocardiography (ASE) guidelines. Results: Of the 113 study patients, 88 (77.9%) had CMD and 25 (22.1%) did not. Among those with CMD, 39 patients (44.3%) had diastolic dysfunction (Figure 1). In the patients with CMD, the BEW intensity was significantly lower in patients with diastolic dysfunction compared to those without (6.5 vs. 9.0 × 10 3 W×m -2 ×s -1 , p < 0.05). The same trend was observed for the CMD-Ei (7.2 vs. 9.7 × 10 3 W×m -2 ×s -1 , p < 0.05) and CMD-Ed (6.2 vs. 9.1 × 10 3 W×m -2 ×s -1 , p < 0.05) subtypes. Conclusions: Diastolic dysfunction is frequent in patients with invasively diagnosed CMD. Patients with CMD who have diastolic dysfunction have comparatively lower BEW intensity, regardless of endothelial subtype. Since the BEW is the major driver of coronary flow during diastole, this suggests a mechanism by which CMD may lead to diastolic dysfunction.