Citations

Abstract Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score >= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p< 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.

Abstract Background Catheter ablation of ventricular tachycardia (VT) may be performed under general anesthesia (GA) or monitored anesthesia care (MAC). There is a paucity of data studying these two sedation strategies with respect to intraprocedural characteristics, and outcomes of VT ablation. Purpose The purpose of this study was to assess the effects of anesthesia techniques on VT inducibility and outcomes. Methods A single-center, retrospective study of patients undergoing catheter ablation for scar-related VT, from 2016-2022, was conducted. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, echocardiograms, detailed procedural characteristics, and outcomes. Results One hundred sixty-eight patients who underwent a total of 200 VT ablation procedures were included. The patients undergoing GA had a greater burden of comorbidities including congestive heart failure (77.2% vs. 60.9%), hypertension (66.9% vs. 60.0%), atrial arrhythmias (50.7% vs. 43.8%), diabetes mellitus (21.3% vs. 9.4%), chronic kidney disease (44.1% vs. 31.3%), prior stroke (11.8% vs. 10.9%), myocardial infarction (31.6% vs. 29.7%), pre-existing implantable cardioverter-defibrillator (86.8% vs. 71.9%) and had a higher median number of antiarrhythmic drugs at baseline (2 vs. 1) [Figure 1]. There was a greater percentage of patients with non-ischemic cardiomyopathy (58.1% vs. 51.6%) in the GA cohort. The mean left ventricular ejection fraction was not different among the two groups (39.3 ± 13.9 vs. 42.5 ± 15.3). The GA group had more hemodynamic instability at baseline (p < 0.01), and during VT induction (p < 0.01). There was no significant difference in the number of VT induced, or tachycardia cycle length, in each group. Despite higher radiofrequency energy delivery time in the GA group as compared to the MAC group, the GA group had higher VT inducibility post-procedure and were more likely to be discharged on antiarrhythmic drugs. Even though the recurrence of VT was higher in the GA group compared to the MAC group (41.9% vs. 31.3%), the VT-free survival curves were not significantly different by Kaplan-Meier analysis (p=0.19) [Figure 2]. In a multivariate regression analysis, the sedation strategy was not an independent predictor of VT recurrence (p=NS). However, baseline hemodynamic instability was an independent predictor of VT recurrence after accounting for all intraprocedural characteristics (p=0.008). Conclusion Patients undergoing VT ablation under GA have more comorbidities and tend to be on more antiarrhythmic drugs. The GA group had more hemodynamic instability during the procedure and had greater overall VT recurrence, however, not significant in a time-based analysis. The greater overall recurrence in the GA group could be because they represent a sicker population, or the hemodynamics during the procedure preclude adequate ablation of the VT circuit elements.Figure 1Figure 2

Abstract Background Catheter ablation of ventricular tachycardia (VT) has emerged as the mainstay of management for these sick patients. There is a lack of long-term data studying the characteristics and outcomes of VT ablation in females and the comparison with males. Purpose The purpose of the study was to assess the impact of sex on outcomes of catheter ablation for ventricular tachycardia. Methods A single-center retrospective study of 200 procedures in 168 patients undergoing catheter ablation for scar-related VT under GA or MAC sedation was conducted. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, structural data including echocardiograms and cardiac magnetic resonance imaging, detailed procedural characteristics, and outcomes. Results Females undergoing VT ablation were younger (49.4 ± 15.6 vs. 65.5 ± 12.2 years) [Figure 1]. Females had a lower burden of comorbidities, including congestive heart failure (30.0 % vs. 82.5%), hypertension (27.5% vs. 74.4%), atrial arrhythmias (20.0% vs. 55.6%), chronic kidney disease (25.0% vs. 43.8%), prior myocardial infarction (15.0% & 35.0%), and coronary artery bypass graft surgery (0.0% & 23.8%). Females were on fewer antiarrhythmic drugs at baseline. During the procedure, males had a greater likelihood of undergoing general anesthesia (72.5% vs. 50.0%) and associated hemodynamic instability at baseline (30.0% vs. 12.5%). It was more likely for VT to be induced in males, and females required more induction medications. There was no difference in complication rates between males and females. A greater proportion of males were discharged and maintained on antiarrhythmic drugs after the procedure. There was no significant difference in VT recurrence or long-term mortality. Using Kaplan-Meier analysis, no difference was seen in long-term VT-free survival by sex (p=0.20) [Figure 2]. In a multivariate regression model, female sex had no bearing on the VT-free survival. Conclusion Females undergoing catheter ablation for VT are younger and have fewer comorbidities. They tend to be on fewer antiarrhythmic drugs at baseline, and after ablation. Interestingly, despite a healthier baseline profile, females do not experience less VT recurrence or mortality compared to males. Further study would be needed to investigate this association.Figure 1Figure 2

Abstract Background Catheter ablation has emerged as the first-line therapy for management of ventricular tachycardia (VT) over the last decade. There is a reluctance for older patients to be referred for catheter ablation with concerns for complications and poor outcomes. Purpose The purpose of the study was to assess the safety and outcomes of catheter ablation for VT in patients more than 74 years of age in comparison to younger patients. Methods A single-center retrospective study of 200 procedures in 168 patients undergoing catheter ablation for scar-related VT was conducted. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, Holter, device electrograms, structural data including echocardiograms and cardiac magnetic resonance imaging, detailed procedural characteristics, and outcomes. Results The mean age in the older cohort was 77.7 ± 3.7 years compared to 57.6 ± 13.1 years in the younger group (p < 0.01) [Figure 1]. The geriatric patients had more males (93.6% vs. 75.8%) and had greater proportion of comorbidities including congestive heart failure (89.4% vs. 66.7%), hypertension (91.5% & 56.9%), atrial arrhythmias (66.0% vs. 43.1%), chronic kidney disease (68.1% vs. 31.4%), prior myocardial infarction (53.2% vs. 24.2%), and stroke (21.3% vs. 8.5%). The older patients were on more antiarrhythmic drugs at baseline. During the procedure, the number of cases with VT induction and hemodynamic stability was similar in older and younger groups. In cases where VT was induced, the older patients had a greater number of VTs induced (2.7 ± 3.0 vs. 1.9 ± 1.8), with slower cycle lengths (454.9 ± 122.6 vs. 379.3 ± 108.1 milliseconds). There was no difference noted in the procedural complications between the two groups. Older patients were more likely to be discharged on antiarrhythmic medications (87.2% vs. 71.2%) and had higher long-term mortality (29.8% vs. 7.8%). The older group was less likely to have a repeat ablation procedure (8.5% vs 24.2%). There was no difference in long-term VT-free survival rates among the two groups [Figure 2]. Conclusion Patients more than 74 years of age undergoing catheter ablation for structural VT have a greater comorbidity burden but demonstrate similar procedural complications and VT-free survival rates, when compared to the younger cohort.Figure 1Figure 2

Abstract Background Premature ventricular contractions (PVCs) are the most common arrhythmia affecting the ventricle. Frequent PVCs are associated with the development of PVC-cardiomyopathy (CM). It is known that the PVC burden has a direct correlation to the severity of left ventricular (LV) dysfunction. However, only 5% of patients with frequent PVCs (>10,000 per day) have associated PVC-CM. Thus, selecting patients for therapy options with drugs or catheter ablation is challenging, especially, when patients are asymptomatic with the PVCs. Purpose To train a deep learning model to predict the probability of low LV ejection fraction (LVEF) in patients with PVCs on a 12-lead electrocardiogram (ECG). Methods Using 69,440 paired 12-lead ECGs (containing at least one PVC), and echocardiogram data, including the left ventricular ejection fraction at Mayo Clinic, we trained a convolutional neural network to identify patients with ventricular dysfunction, defined as ejection fraction ≤35%, using the ECG data alone. ECGs were acquired at a sampling rate of 500 Hz using a Marquette ECG machine (GE Healthcare) and stored using the MUSE data management system for later retrieval. Comprehensive 2-D or 3-D and Doppler echocardiography were available for all patients. We trained a convolutional neural network using the Keras framework with TensorFlow (Google). The ECG-echocardiogram pairs were divided into a 60:20:20 training:validation:test split. Results The mean age of the patients used to train the model was 69.9 ± 13.0 years, and 65.2 percent of patients were male. The mean LVEF for this population was 52 ± 14.9 %, and the proportion of patients with low LVEF was 16.8 percent. The model yielded values for area under the curve, sensitivity, specificity, and accuracy of 0.897, 0.830, 0.813, and 0.816, respectively (Figure 1). A representative example of model prediction of normal LVEF and low LVEF is shown in Figure 2. Conclusion Using large-scale data, we have trained a highly accurate convolutional neural network with excellent predictive accuracy for LV systolic dysfunction using the surface ECG. Such a tool would be invaluable for cardiologists when risk-stratifying patients with frequent PVCs, especially those that are asymptomatic. Patients at risk will benefit from early referral to electrophysiologists for drug therapy and catheter ablation to mitigate the risk of PVC-CM.Figure 1Figure 2

Abstract The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

SummaryBackgroundAlpha‐1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha‐1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.AimsTo characterise patients with AATD Pi*ZZ and liver disease (AATD‐LD‐Pi*ZZ) with or without lung disease and describe liver disease‐related clinical events longitudinally.MethodsThis was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow‐up. Clinical events associated with liver disease progression were assessed.ResultsAATD‐LD‐Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease‐related clinical events (8.5 years and not reached, respectively). AATD‐LD‐Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.ConclusionIn patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.

AbstractIntroductionPalliative care is a critical component of pediatric oncology care. Embedded pediatric palliative care (PPC) is relatively new in pediatric hematology/oncology (PHO) and may improve access, utilization, and quality of PPC. In June 2020, the Mayo Clinic PPC service transitioned from an afternoon, physically independent clinic to an all‐day clinic embedded within PHO.MethodsRetrospective chart review was used to quantify consultation rates from PHO to PPC in 12‐month study periods before and after establishment of an embedded clinic. Changes in descriptive statistics and consult patterns were calculated. Study periods were compared using either chi‐square or Fisher's exact tests for categorical variables and Wilcox rank sum tests for continuous variables.ResultsThere was an 89% increase in consultations from PHO to PPC after initiation of an embedded clinic (n = 20 vs. n = 38 per 12 months). The absolute number of completed outpatient consults increased from three (15% of visits) pre‐embedment to fourteen (37%) post‐embedment (p = .082). The median number of days from first oncology visit to PPC assessment was unchanged after embedment (36 vs. 47 days, p = .98). Consults for solid tumors increased from 22% (n = 4) pre‐embedment to 60% (n = 18) post‐embedment (p < .05). Consults for symptom management increased from 60% (n = 12) to 87% (n = 33) (p < .05).ConclusionsEmbedment of PPC into a PHO workspace was associated with an increased number of total consults, outpatient consults, solid tumor consults, and consults for symptom management. Our “partial‐PPO” model allowed for provision of PPC in the outpatient oncology setting in a clinic where there is not enough volume to support a full‐time oncology‐focused clinician team.