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Abstract BACKGROUND MYCN-amplified spinal ependymoma is a recently classified, rare, and aggressive subtype of spinal cord tumor, first defined by the 2021 WHO CNS5 classification. It predominantly affects adults in their 30s, with a slight female predominance; fewer than 50 cases have been reported worldwide. PURPOSE To characterize the molecular, imaging, and clinical features of MYCN-amplified spinal ependymomas and highlight their distinctiveness to aid in early diagnosis and therapeutic planning. METHODS We retrospectively reviewed institutional cases of MYCN-amplified spinal ependymomas and performed a literature-based analysis. Data on imaging, histopathology, molecular profiles, and clinical outcomes were examined to identify distinguishing diagnostic and prognostic features. RESULTS These tumors are typically present as intradural extramedullary masses, often in the thoracic spine, with intense contrast enhancement and prominent peritumoral edema. A lack of a clear cleavage plane with the spinal cord, early leptomeningeal, and intracranial dissemination are hallmark features. Rare reports of systemic metastases (e.g., to the humerus and paraspinal muscle) exist. Histologically, they are high-grade (WHO grade III) anaplastic ependymomas with a distinct DNA methylation profile. MYCN amplification—commonly seen in medulloblastomas and glioblastomas—drives tumor aggressiveness. Clinically, these tumors are refractory to standard treatments, with high rates of recurrence or progression within 1–2 years post-treatment. The median overall survival is approximately seven years, significantly poorer than conventional spinal ependymomas. CONCLUSION MYCN-amplified spinal ependymomas represent a rare but highly aggressive tumor subtype with unique imaging, histological, and molecular features. Early recognition is critical given rapid progression and poor prognosis. Investigational therapies targeting MYCN—such as HDAC, PARP, Aurora A-kinase, and BET inhibitors—hold promise for improved outcomes.

Abstract Innate immune cells of macrophage family predominate tumor immune microenvironment of CNS malignancies. Although macrophages exhibit myriads of protective functions such as clearance of malignant cells, immune surveillance, inflammation resolution and tissue repair, they are generally linked to immunosuppression in gliomas. To identify anti-glioma myeloid cell effectors, we performed directionally concatenated ligand-receptor (L-R) interactome analyses from dendritic cells (DC) and microglia (MG) to lymphoid (CD4+T, Tregs, CD8+T, NK and NKT) cells identified by single cell transcriptomics analyses of ~145,000 tumor-associated CD45+ leukocytes from tumor brains of eighteen high-grade and low-grade glioma patients. Amongst DC-specific (e.g. adhesion molecules) and MG-specific (e.g. chemokine family) interactomes, we identified LGALS9 encoding Galectin-9 as the most pertinent interactions (e.g. SORL1 encoding sortilin-related receptor 1) in MG of IDH-wild type gliomas. Spectral cytometry, immunohistochemistry and western blotting analyses of MG, macrophage, DC, lymphoid cells and tumor cells confirmed abundant expression of Galectin-9 in glioma-associated MG and not in Nestin+ tumor cells. Furthermore, differential gene enrichment analyses revealed transcripts associated with cellular adhesion (coronin 1A, integrin) and phagocytosis (FcγR, phospholipase D, Rab family proteins etc.) was significantly upregulated in Galectin-9hi compared to Galectin-9lo/- MG and macrophages predicting putative role of Galectin-9 in tumor cell adhesion and phagocytosis. Using glioblastoma relevant patient derived ex vivo primary microglia (pMGs; 707, 2103, 1805) and glioma stem cell (GSC) co-culture model system, we evaluated the functional role of Galectin-9. Confocal imaging analyses of co-cultured pMGs with GSC revealed that siRNA or neutralizing antibody mediated downregulation of Galectin-9 led to significantly impaired adhesion (p<0.001) between pMGs and GSC. Not only adhesion but even phagocytosis of GSC was dramatically attenuated (p<0.0001) across all Galectin-9 silenced or neutralized pMGs. Altogether, our study underscores unappreciated role of Galectin-9 in MG as regulator of glioma cell adhesion and phagocytosis that can be harnessed for glioblastoma immunotherapy.

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 .

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Abstract Background Obesity is strongly associated with the development of heart failure (HF) with preserved ejection fraction (HFpEF). Beyond increased body mass index (BMI), an abundance of epicardial adipose tissue (EAT) may play a role in its pathophysiology. Purpose To study the associations between increased EAT, functional status and invasive exercise hemodynamics in a large cohort of HFpEF patients. Methods This is a sub-analysis from a large randomized clinical trial that investigated an atrial shunt device in patients with HF with left ventricular ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25mmHg. At baseline, all patients underwent echocardiography, 6-minute walk distance (6-MWD) test, Kansas City Cardiomyopathy Questionnaire (KCCQ) and invasive hemodynamic assessment at rest and during supine ergometry. EAT thickness was measured on the free wall of the right ventricle on echocardiography, expressed in mm and patients were divided according to EAT tertiles. Results In total, 566 patients were examined. Their mean age was 72±8 years, 62% were women, mean BMI was 33±6 kg/m2 and mean EAT thickness was 6.0±2.4 mm, ranging from 1.7 to 17.2 mm. With increasing EAT thickness tertiles, 6-MWD and KCCQ overall summary score were significantly lower (320 vs. 315 vs. 287m, p=.01; 51 vs. 45 vs. 41, p=.003; respectively, Figure 1A-B). The association between increased EAT and lower KCCQ score was independent of BMI (p=.004, β: -2.6), whereas the association with lower 6-MWD was not independent of BMI (p=.1, β: -6.9). At rest, invasive hemodynamics were not different across EAT tertiles. At peak exercise, patients in the highest EAT thickness tertile had higher PCWP and PCWP to right atrial pressure gradient, as compared to patients in the first and second EAT thickness tertiles (36±8 vs. 34±8 mmHg, p=.009; 18±7 vs. 16±7 mmHg, p=.002, respectively, Figure 1C). Conclusion Excess EAT is common in patients with HFpEF and is associated with lower functional status and with higher left-sided filling pressures at peak exercise. These data suggest that EAT plays a significant role in functional status and exercise hemodynamics in HFpEF.Figure 1

BACKGROUND Predictive biomarkers to guide chemotherapy decisions for metastatic castration–resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS The CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA 50 response rate were assessed. RESULTS High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52–3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01–2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSION This preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION ClinicalTrials.gov number NCT02485691. FUNDING Funded by Sanofi and Epic Sciences.

Background: Cuffless blood pressure (BP) monitoring devices with the ability to continuously and noninvasively collect data could transform the screening and management of hypertension. While some wearable devices can estimate BP, their accuracy and reliability remain limited. Objective: To evaluate the feasibility of using a wrist-worn photoplethysmography (PPG) device (Lifeleaf®) in combination with a supervised learning algorithm to infer clinically useful BP measurements. Methods: A total of 87 patients undergoing electrophysiology procedures were enrolled (Table 1). Time-synchronized BP data from an intra-arterial line served as the reference. These data were divided into (1) a training set to develop a convolutional neural network (CNN) and (2) a testing set to assess the algorithm’s predictive performance. Data from 60 patients were used to train the model, and the remaining 27 patients were used for validation. Results: Data from 81 of 87 patients were included in the final analysis. The mean age was 63.6 ± 10.5 years, and 69.1% were male. A total of 6,977 paired PPG and arterial BP readings were analyzed. The mean absolute deviation for systolic BP was 13.08 ± 17.22 mm Hg, and for diastolic BP, 8.42 ± 10.56 mm Hg. Subgroup analysis revealed reduced correlation in patients with BP >140/90 mm Hg, likely due to fewer training samples in this range. Conclusion: This study demonstrates the feasibility of extracting clinically meaningful BP measurements from a PPG device using a supervised learning algorithm. The use of arterial line BP as the reference standard adds methodological rigor. Future work will focus on enhancing model performance, particularly in the hypertensive cohort.

Background: Tricuspid regurgitation (TR) can lead to right ventricular failure (RVF) and poor clinical outcomes. The TriClip™ G4 transcatheter edge-to-edge repair (TEER) system has shown improved outcomes in TR patients and received FDA approval on April 2, 2024. The FDA’s Manufacturer and User Facility Device Experience (MAUDE) database collects mandatory manufacturer reports and voluntary provider reports on device-related complications. Methods: We retrieved all TriClip™-related adverse events from the MAUDE database post-FDA approval, excluding duplicate entries and literature reviews. After removing 47 literature reviews and 36 duplicate reports, 443 unique adverse event reports from 407 procedures (some with multiple events) were analyzed between April 2, 2024, and January 31, 2025. Results: SLDA (Single Leaflet Device Attachment) was the most frequent complication, occurring in 204 cases (Figure 1). Detached leaflets included septal (105 cases), anterior (46), posterior (27), lateral (3), multiple (2), and unreported. Contributing factors included poor imaging, tethered leaflet, clip-clip interaction, dense chordae, large right atrium (RA) or gap size, pacer lead, or prior valve intervention. Persistent TR was a common consequence. SLDA was addressed with additional clips in 77 cases (18 requiring multiple clips), no intervention in 55 cases (13 with significant residual TR), repeat TriClip procedures in 16 cases, and surgical repair in 4 cases. Other complications included partial SLDA (23 cases), clip deployment or gripper malfunctions (68), chordal entanglement (41), leaflet entanglement (3), and clip migration/embolization (6). Migrated clips were found in the RA, right atrial appendage, cardiac vein, or pulmonary artery; three required snare retrieval, and three were left in place. Triclip Steerable Guide Catheter (TSGC) malfunctions, such as leaks, loss of column support, and blockages, were reported in 29 cases, with 27 requiring replacement. Miscellaneous events included residual TR, leaflet grasping issues, F-knob malfunction, lock line jams, and TSGC entanglement. Clip opening during Establishing Final Arm Angle (EFAA) occurred in 25 cases, and leaflet puncture in 15 cases, with one requiring surgical intervention. Conclusion: SLDA was the most frequently reported complication following TriClip™ approval, with some cases leading to severe outcomes. Continued surveillance is crucial to assess long-term safety and optimize procedural strategies.

Background: Patients with repaired Tetralogy of Fallot (TOF) undergoing pulmonary valve replacement (PVR) are at increased risk of major adverse ventricular arrhythmias and related events (MAREs). Perioperative electrophysiological study (EPS) has been used for risk stratification and guiding future management, but these studies are limited by small sample size. Objectives: To perform a systematic review of outcomes of pre-PVR EPS in TOF patients with PVR. Methods: A comprehensive search of PubMed, Embase, Scopus and Google scholar databases was performed per PRISMA 2020 guidelines. Studies on patients with repaired TOF undergoing PVR with perioperative EPS were included. Data were extracted on study design, sample size, EPS outcomes and MAREs during follow-up. Results: A total of 1,528 patients (age: 35.5±3.8 y; 57% male; LVEF: 57.1±1.5%, RVEF: 42.6±1.5%) were included from 12 studies. EPS was performed in 1212/1528 (79.3%), with sustained VT inducibility in 404 (33.3%)-monomorphic VT in 258 (63.8%), while 808 (66.6%) were non- inducible. 8/12 studies reported the type of PVR (transcatheter-36.8%). 174/293 (59.3%) inducible patients had an ablation (9 studies), while ICD (6 studies) was implanted in 70/263 (26.6%). Follow-up EPS (6 studies) showed 35/230 (15.2%) remained inducible. Overall,113 (9.3%) patients experienced MAREs over a median follow-up ranging from 6 months to 6.7 years. Sustained VT (11/12 studies) occurred in 70/1092 (6.4%), appropriate ICD therapy (7/12 studies) in 13/622 (2.1%) and sudden cardiac death (10/12 studies) in 30/906 (3.3%). Five studies provided MARE data stratified by VT inducibility. 12/164 (7.3%) inducible patients experienced MAREs, compared to 2/318 (0.6%) non-inducible patients. Reported risk factors for MAREs included older age at initial repair and PVR, QRS duration (>180ms), LVEF <45%, RVEF <35%, history of syncope, prior palliative shunts and atrial arrhythmias. Some studies identified MRI-derived scar burden, pulmonary annulus size, and RV/LV volume ratios as additional predictors. Conclusion: TOF patients remain at high risk of VA after PVR with 1/10 patients experiencing MAREs. People with inducible VT had a 12-fold greater risk than people who were non-inducible. EPS identifies a subset of TOF patients at higher arrhythmic risk during PVR and supports tailored ablation and ICD strategies. Prospective multicentre studies are needed to optimize integration of EPS and clinical risk models.