Citations

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are increasingly associated with cardiovascular toxicities, including myocarditis and accelerated atherosclerosis. While ICI myocarditis has received substantial attention, thrombotic complications remain underrecognized and may be difficult to distinguish from immune-mediated cardiac inflammation and cancer-related hypercoagulable state. We present a case of non-bacterial thrombotic endocarditis (NBTE) and myocardial microthrombi mimicking ICI myocarditis. Case summary A 76-year-old woman with metastatic adenosquamous lung carcinoma presented with progressive dyspnoea 3 weeks after initiating pembrolizumab. Pulmonary arterial and coronary imaging were unremarkable, but cardiac magnetic resonance imaging (MRI) showed late gadolinium enhancement (LGE) and myocardial oedema suggestive of ICI myocarditis. Chest computed tomography revealed inflammatory lung changes, and empirical corticosteroids were initiated with initial clinical improvement. One week later, brain MRI showed multifocal infarcts, and Doppler ultrasound identified bilateral lower extremity deep vein thromboses. Transoesophageal echocardiography showed thickened mitral and aortic valves with moderate regurgitation. Non-bacterial thrombotic endocarditis with embolic phenomena was suspected. Anticoagulation was escalated from apixaban to therapeutic enoxaparin, followed by warfarin. Despite initial stabilization, the patient died 2 months later. Post-mortem examination revealed fibrin-rich valvular vegetations consistent with NBTE, widespread intramyocardial thrombi, and no histopathologic evidence of myocarditis. Discussion This case underscores how microthrombotic complications of ICI therapy may closely mimic myocarditis on imaging. Nonspecific cardiac MRI findings, such as LGE and T2 signal elevation, can result from thrombotic or ischaemic injury alike. Histopathologic confirmation may be required for accurate diagnosis, as misclassification can lead to suboptimal treatment.

Abstract Introduction Narcolepsy type 2 (NT2) is characterized by excessive daytime sleepiness, heterogeneous symptom severity, and typically normal endogenous orexin levels. The Vibrance-2 phase 2 study evaluated alixorexton, a selective orexin 2 receptor agonist, in patients with NT2. Methods Vibrance-2 was a placebo-controlled, dose-ranging phase 2 study. After a 2-week washout from current narcolepsy medications, adults with NT2 meeting ICSD-3-TR diagnostic criteria were randomized 1:1:1:1 to receive placebo or alixorexton once daily at doses of 10, 14, or 18mg for 8 weeks, followed by an optional 5-week open-label extension. Dual primary endpoints were the change from baseline to week 8 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) and on the Epworth Sleepiness Scale (ESS). Safety evaluation included treatment-emergent adverse events (TEAEs). P-values were adjusted for multiplicity. Results Ninety-three patients were randomized to placebo (n=24) or alixorexton (10mg, n=23; 14mg, n=22; 18mg, n=24); 90 completed double-blind treatment. At baseline, patients had severe symptoms (MWT: 5.6 minutes; ESS: 17.4). The study met its dual primary endpoints. At week 8, MSL on MWT increased 9.3, 6.7, and 6.7 minutes at 10, 14, and 18mg, respectively, from baseline versus placebo, with statistically significant differences observed for the 14 and 18mg doses (adjusted p< 0.05). ESS improved by -2.1, -3.2, and -3.6 points from baseline versus placebo at week 8 for the 10, 14, and 18mg groups, respectively, with statistical significance observed for the 18mg dose (adjusted p< 0.05), where more than 70% of patients achieved normalization. TEAEs in 10% of all alixorexton-treated patients through week 8 were pollakiuria, insomnia, micturition urgency, dizziness, and headache. Most TEAEs were mild-to-moderate with no serious TEAEs. Conclusion Vibrance-2 was the first large clinical trial in patients with NT2 to demonstrate positive results with an orexin 2 receptor agonist. Alixorexton resulted in statistically significant and clinically meaningful improvements in wakefulness and daytime sleepiness at Week 8 and was generally well tolerated. These results support phase 3 clinical development of alixorexton as a treatment for NT2. Support (if any) Alkermes, Inc.

Abstract Introduction AD109, an investigational oral anti-apneic neuromuscular modulator, combines in one tablet the novel antimuscarinic, aroxybutynin (2.5 mg), with the selective norepinephrine reuptake inhibitor, atomoxetine (75 mg). AD109 significantly improved the apnea-hypopnea index and oxygenation vs placebo (PBO) in two phase 3 clinical trials in OSA. This exploratory analysis evaluated concomitant administration of AD109 with glucagon-like peptide-1 receptor agonists (GLP-1 RA) on weight change in OSA. Methods SynAIRgy (NCT05813275; N=646) and LunAIRo (NCT05811247; N=660) were randomized, double-blinded, PBO-controlled, parallel-arm phase 3 trials of AD109 vs PBO in adults with mild-to-severe OSA (AHI >5) who failed or refused positive airway pressure therapy. Participants must have had a body mass index (BMI) 18.5–40 kg/m2 for males / 18.5–42 kg/m2 for females. Participants receiving GLP-1 RA for diabetes were permitted. Body weight was assessed throughout the trials. Results One-hundred and six participants were enrolled in the phase 3 trials taking a GLP-1 RA for diabetes (PBO+GLP-1 RA: n=48; AD109+GLP-1 RA: n=58). In participants receiving a GLP-1 RA with baseline BMI < 30, AD109 reduced weight by 2.7% (vs PBO: -1.4%, P=0.08) and 0.5% (vs PBO: 2.3%, P=0.60) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI 30 to 34.9, AD109 reduced weight by 0.9% (vs PBO: 1.2%, P=0.84) and 2.5% (vs PBO: 3.3%, P=0.85) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI ≥35, AD109 reduced weight by 5.5% (vs PBO: 0.9%, P=0.02) and 11.5% (vs PBO: 3.8%, P=0.04) at Week 26 and Week 51, respectively. Participants not receiving GLP-1 RA (n=979) showed smaller weight reductions across BMI classes; in participants with BMI ≥35, AD109 reduced weight by 1.4% (vs PBO: 0.2%, P=0.002) and 2.8% (vs PBO: 1.4%, P=0.19) at Week 26 and Week 51, respectively. Conclusion In this exploratory analysis using pooled data from SynAIRgy and LunAIRo, results indicate that participants with a baseline BMI ≥35 receiving AD109+GLP-1 RA experienced progressively greater weight loss over time relative to GLP-1 RA alone. Future studies are needed to further evaluate concomitant administration of AD109+GLP-1 RA in OSA. Support (if any) These studies were supported by Apnimed, Inc.

Abstract Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it’s in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1 -knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload–expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1 -KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

ABSTRACT Macrophages play a central role in determining the outcomes of healing, coordinating regeneration in some injuries and scar formation in others. In both cases, this coordination involves the cross-talk between macrophages and surrounding cells. But what drives the different cross-communication pathways to determine healing outcomes is not well known. In this study, we make use of the mouse digit tip amputation model, in which an amputation through the third phalangeal element (P3) is able to completely regenerate whereas an amputation through the second phalangeal element (P2) forms a scar. We identify a population of macrophages that is specific to the P3 regenerating digit. By integrating single-cell RNAseq, spatial transcriptomics, and metabolomic analyses, we show that this population localizes specifically to the growing bone front, express BMP ligands that drive downstream BMP activation in neighboring osteoblasts and is governed by a two-part metabolic switch involving increased fatty acid oxidation coupled with reduced glycolytic activity. This spatially restricted, BMP-expressing macrophage population is entirely absent in the scar-forming P2 injury, and our data indicate that environmental conditions unique to the regenerating digit are responsible for its emergence. Together these findings identify a regeneration-specific macrophage signaling center for patterned bone formation and suggest that targeting the metabolic conditions that drive this population could improve the efficacy of regenerative therapies.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P =0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04505774.

Study Design. Subanalysis of a prospective, multicenter, observational study at 72 US adult, pediatric, and mixed trauma centers. Objective. We investigated trauma-related risk factors and patient-level factors associated with multiregional spinal column injury, defined as cervical spine injury (CSI) requiring treatment and thoracolumbar injury (TLI). Summary of Background Data. Traumatic spinal injury causes morbidity and mortality in pediatric patients. Injuries to multiple spinal column regions require early identification and thoughtful management. Methods. All children <18 years undergoing cervical spine evaluation after blunt multisystem trauma were prospectively identified and enrolled. Clinically significant CSI was defined by cervical spine surgery or halo placement. TLI incidence and management was recorded. The primary outcome was multiregional spinal column injury (CSI+TLI). Results. Of 19,651 enrolled patients, 1484 children (7.5%) experienced a TLI, 159 (0.81%) had CSI requiring treatment, and 30 (0.15%) had CSI+TLI. Multivariate analysis revealed that the trauma-related factors mechanism of injury ( P <0.001), rib fractures (odds ratio (OR) 2.8 [2.3-3.4]), hemothorax/pneumothorax (OR 2.0 [1.7-2.4]), bowel injury (OR 4.0 [2.9-5.4]), pelvic fracture (OR 1.5 [1.2-1.9]), and clinically significant CSI (OR 1.9 [1.2-2.9]) were independently associated with TLI. Of the 159 children with clinically significant CSI, 30 also experienced TLI (19%). Multivariate analysis identified prehospitalization intubation (OR 3.1 [1.1-8.4]) and rib fractures (OR 3.9 [1.2-12.8]) as independent associations with CSI+TLI. Conclusions. Of children with CSI requiring treatment, 19% experienced TLI. MOI and various trauma-related injuries were independently associated with TLI, whereas prehospitalization intubation and rib fractures were independent risk factors for CSI+TLI. These factors should trigger screening for multiregional spinal column injury in pediatric trauma patients. Furthermore, if there is known TLI, the cervical spine should be evaluated, and if there is significant CSI, then dedicated imaging of the thoracic and lumbar spine is indicated. Level of Evidence. III

Background Carotid artery calcification represents a common feature of atherosclerotic plaques. However, the geometric relationships of calcific clusters have not been systematically investigated. This study aimed to develop a geometry-based atlas, independent of symptom status, characterizing the three-dimensional properties of calcium clusters within carotid plaques and quantifying population-level distributions and data-driven couplings between size, shape, and density. Methods Standardized three-dimensional calcium masks of clinical CT scans were analyzed using connected-component labeling. Extracted features included cluster volume, aspect ratio, eccentricity, compactness, and CT attenuation values (mean μ, standard deviation σ). Associations between cluster features were assessed using Spearman correlations with Benjamini–Hochberg false discovery rate correction. Independent associations were determined using partial Spearman correlation and restricted cubic spline regression. Results Among 107 plaques, 149 distinct clusters were identified, most frequently presenting as a single elongated cluster (aspect ratio = 2.23). Independent associations (all p < 0.001) were identified for: eccentricity with μ (ρ = −0.39), volume with μ (ρ = 0.47), compactness with μ (ρ = 0.39), and volume with eccentricity (ρ = 0.82). Multi-cluster plaques exhibited smaller mean cluster volume (76.1 vs 359.5 mm 3 ; p < 0.001) and lower eccentricity (0.5 vs 1.6; p < 0.001) compared with single-cluster plaques. Conclusion Carotid calcification most frequently manifests as a single elongated cluster, with robust couplings between cluster size, shape, and density. These geometric archetypes provide a quantifiable framework for future biomechanical and biological studies of plaque vulnerability.