Citations

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.

Abstract Aims Inter-atrial shunt device therapy has shown mixed results in clinical trials, with clinical ‘non-responders’ typically showing features of more advanced heart failure. We aimed to analyse the haemodynamic and clinical response of a novel left atrial to coronary sinus (LA-CS) shunt device in patients with higher natriuretic peptide (NP) levels, a marker of disease severity. Methods and results An analysis population (n = 95) of patients from the ALT-FLOW early feasibility study with left ventricular ejection fraction >40% and 1-year follow up was analysed. The cohort was divided into low and high subgroups based on NP levels [b-type natriuretic peptide (BNP) and n-terminal pro BNP (NT-proBNP)]. The mean BNP and NT-proBNP levels for low versus high subgroups were 64.2 ± 34.3 versus 261 ± 103 and 322 ± 269 versus 2050 ± 1070 pg/mL, respectively. Patients in the high NP subgroup had evidence of more advanced disease including worse haemodynamic profiles, lower estimated glomerular filtration rate, and higher percentages of atrial fibrillation. The high NP subgroup experienced significant improvements in KCCQ-OSS and NYHA functional class (P < 0.0001 and P < 0.001, respectively) and to a similar magnitude compared with the low NP subgroup. Compared with pre-implant baseline, workload adjusted pulmonary artery wedge pressure at peak exercise declined in the high NP subgroup (PCWL, 164.1 vs. 96.0 mmHg/W/kg at 6 months, P < 0.003) as well as the low NP subgroup (115.9 vs. 65.9 mmHg/W/keg at 6 months, P < 0.001). Importantly, in both NP subgroups, there was preservation of cardiac index through 6 months as well as right ventricular structure (right ventricular diastolic dimension) and function (tricuspid annular systolic plane excursion) through 1 year. Conclusions The quality-of-life, haemodynamic, and functional class improvements along with stable right heart function seen in ALT-FLOW study of LA-CS shunt remain consistent in the subgroup with highest NP levels. This suggests that shunting location could influence outcomes in symptomatic heart failure patients.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

Abstract Multiple myeloma (MM) is a complex hematological malignancy characterized by genomic changes and transcriptomic dysregulation. Initial exome sequencing approaches have failed to identify any single, frequent (>25%) mutation in the coding genome. However, using whole-genome sequencing, we found that one of the genomic regions most frequently mutated (62% of the patients with MM) was the 5′ untranslated region and/or intron 1 of the BCL7A gene. RNA-sequencing data from a large cohort suggest a loss of BCL7A expression in a large majority of patients with MM as compared with normal plasma cells. BCL7A loss of function in a panel of MM cell lines led to a highly proliferative phenotype in vitro and in vivo, whereas its ectopic expression significantly reduced cell viability, suggesting a tumor suppressor function for BCL7A in MM. We studied the cellular and molecular effects of BCL7A loss and observed that it endows myeloma cells with proliferative potential in cooperation with the plasma cell–defining transcription factor IRF4. BCL7A is involved in a direct protein-protein interaction with IRF4, limiting its DNA-binding activity. Loss of BCL7A thus enhances the expression of IRF4-associated cytokines and reduces mitochondrial metabolism and reactive oxygen species levels. Our study therefore suggests that BCL7A loss provides the necessary molecular change to allow IRF4-mediated transcriptional activity and MM cell growth and survival.

ABSTRACT Introduction Donation after circulatory death (DCD) allografts are underutilized in liver transplantation (LT) due to increased risk of complications. These risks stem from ischemic injury sustained during the total donor warm ischemia time (tDWIT), historically limited to 30 min. Normothermic machine perfusion (NMP) can mitigate these risks and facilitate LT of DCD grafts with extended tDWIT. We aimed to compare outcomes of DCD allografts with extended tDWIT preserved on NMP versus static cold storage (SCS). Methods This single‐center study included adult DCD LT with tDWIT ≥ 30 from 2019 to 2023. Outcomes of NMP and SCS were compared including EAD, IC, graft survival, and patient survival. Results Among 68 DCD LT with tDWIT ≥ 30, 64.7% ( n = 44) were preserved with NMP and 35.3% ( n = 24) with SCS. No differences in donor or recipient demographics were observed. The median tDWIT was 33 min for NMP and 30.5 min for SCS ( p < 0.01). Despite longer tDWIT, the NMP group had lower rates of EAD (4.5% vs. 66.7%, p < 0.01) and IC (2.3% vs. 29.2%, p < 0.01). One‐year graft survival was higher in NMP ( p < 0.01), and 1‐year patient survival was comparable between groups ( p = 0.18). Conclusion NMP challenges traditional tDWIT constraints and can increase the pool of viable DCD allografts for transplantation.

ABSTRACT Metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) incidence is rapidly rising worldwide. Lipid metabolic reprogramming is a hallmark of solid tumors to satisfy cancer high metabolic demand. However, it may confer sensitivity to ferroptosis, a cell death mode driven by iron-dependent lipid peroxidation. In this report, we describe the lipid metabolic landscape in MASH-HCC and characterize long chain acyl-CoA synthetases (ACSLs), a family of enzymes involved in synthesis of cellular lipids. Bulk RNA-sequencing, single-cell RNA-sequencing, spatial transcriptomics and immunohistochemistry analyses of human MASH-HCC were integrated to identify differentially expressed lipid metabolism genes. Ferroptosis in vitro was assessed in human HCC cell lines. A characterization of ACSLs was also conducted at the single-cell level in a diet-induced experimental murine model of MASH-HCC. Our analysis revealed that in human MASH-HCC, ACSLs exhibit a heterogeneous expression, with ACSL4 notably enriched in tumor tissues, contrasting with ACSL5 upregulation in non-cancerous MASH. We identified a unique lipid metabolic gene signature of MASH-HCC, which included genes associated with ferroptosis vulnerability. In vitro , ACSL4 upregulation was associated with increased ferroptosis sensitivity in human HCC cell lines. Lastly, single-cell RNA-sequencing revealed elevated ACSL4 expression in immune cells in a murine MASH-HCC model, suggesting a role of ACSL4 in shaping the tumor immune microenvironment. Overall, this report offers new insights into lipid metabolic landscape and ferroptosis sensitivity for novel MASH-HCC treatments. GRAPHICAL ABSTRACT

Abstract Objectives To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies. Methods Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension). Results Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19–5.82; P = 0.9472) for the QD, and 0.39 (0.07–2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo. Conclusion Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.

AbstractMetabolic syndrome (MetS) is a prevalent comorbidity in patients with chronic pain conditions. Emerging evidence suggests that the relationship between MetS and chronic pain is bidirectional. This interplay involves complex mechanisms, including proinflammatory mediators in nociceptive modulation and pain‐induced lifestyle changes affecting metabolic function. This scoping review examines the association between MetS and chronic pain. We conducted a scoping review, including 28 studies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses Extension for Scoping Reviews guidelines. We included observational studies (cross‐sectional, case–control, and cohort studies) from the following databases: Ovid MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus. We identified studies on migraine (n = 9), spinal pain (n = 8), general chronic pain (n = 4), fibromyalgia syndrome (n = 3), carpal tunnel syndrome (n = 1), osteoarthritis (n = 1), shoulder pain (n = 1), and neuropathic pain (n = 1). Most studies used a cross‐sectional design and standard criteria to define MetS, with some exceptions. Individuals with MetS and spinal pain, fibromyalgia, or general chronic pain showed higher pain scores and increased functional limitations. MetS was common in patients with migraine, but its effect on pain severity was inconclusive. The relationship between MetS and other pain conditions requires further investigation to clarify the association and potential mechanisms. MetS is prevalent in patients with chronic pain and is associated with worse pain and functional outcomes. Health care providers should acknowledge the wide spectrum of MetS beyond obesity. This understanding may help identify those at risk for more severe chronic pain.