Citations

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized and overlapping tumor microenvironmental niches. Perivascular, hypoxic, invasive, immunosuppressive, and extracellular matrix-associated niches cooperatively enforce stemness, metabolic adaptability, immune evasion, and phenotypic plasticity, enabling CSC persistence despite maximal surgical resection and standard-of-care therapy. Notably, CSCs extend beyond radiographically defined tumor margins and populate peritumoral regions, providing a biological basis for near-universal recurrence. Advances in multiparametric imaging, stem cell-based ex vivo and in vivo models, and single-cell and spatial profiling have refined insight into CSC heterogeneity, niche dependence, and treatment resistance. Together, these findings reframe therapeutic strategies, highlighting the need for function-preserving maximal resection and multimodal therapies that target both CSC-intrinsic pathways and their supportive microenvironments.

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, Na V 1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

Abstract Background Exercise stress echocardiography (ESE) is recommended in patients with mitral regurgitation (MR) when resting echocardiographic findings and symptoms do not align. However, the role of MR assessment in patients undergoing ESE for any indication remains uncertain. Purpose This study aimed to investigate whether the assessment of MR during ESE provides prognostic value beyond the evaluation of inducible regional wall motion abnormalities (RWMA) in patients undergoing ESE for any clinical indication, including suspected coronary artery disease (CAD). Methods Data were analyzed from a large multicenter and multinational prospective study. Current analysis included patients who underwent ESE for any indication and had MR (from 0= absent, to 3= severe) assessed at rest and peak exercise with an integrated qualitative, semi-quantitative, and (in selected cases) quantitative assessment. The primary endpoint was all-cause mortality. Results Of 1,351 included patients (age 56±16 years; 66% women; 30% with known CAD). MR score increased during exercise (rest=0.74±0.7 vs. peak=0.89±0.8, p<0.001), with severe MR present in 2% of patients at rest and 7% at peak ESE. Patients with severe MR during exercise (n=96, Group 1) compared to those with non-severe MR during exercise (n=1255, Group 2) showed more B-lines, lower left ventricular contractile and chronotropic reserve, and trend (p=0.09) to more frequent decrease in ejection fraction during ESE (Table 1). After a median follow-up of 2.1 years (IQR 1.0–6.9), 99 patients (7%) had died. Severe MR at rest was associated with increased mortality (log-rank p<0.001). Patients with severe MR at peak ESE had a higher risk of death compared to the other patients (log-rank p 0.035) (Figure 1). After adjusting for age, CAD, and inducible RWMA, severe MR with exercise remained strongly associated with an increased risk of death (adjusted-HR: 2.2, 95%CI 1.3-3.8, p=0.002). Similar results were seen with further adjustment for rest MR severity (adjusted-HR:1.9, 95%CI 1.02-3.5, p=0.004). Conclusion Patients, with and without CAD, with severe MR during ESE have greater functional impairment expressed by more pulmonary congestion, blunted heart rate reserve, and lower left ventricular contractile reserve. The assessment of MR during ESE provides significant prognostic information, independent of resting RWMA or inducible ischemia. Incorporating MR evaluation into routine ESE protocols may improve clinical decision-making and patient outcomes.Fig 1 Survival by MR at peak exercise Table 1

Abstract Background Inducible ST-segment depression during stress echocardiography (SE) is associated with a higher risk in patients with inducible regional wall motion abnormality (RWMA). Objective To assess ST segment elevation's prevalence and functional correlates during SE. Methods ECG response was analyzed in 1712 patients (age 63±12 years; 1011 men, 59%) undergoing SE for chronic coronary syndromes (CCS) prospectively recruited at 39 laboratories. Among the patients analyzed, 1286 (75%) performed SE with exercise, 306 (18%) with dobutamine and 120 (7%) with a vasodilator. ECG response was considered abnormal in case of ST-segment shift >1.0 mm from baseline at 80 ms from the J point developed in ≥2 contiguous leads during SE. The stress to rest (∆) change in the wall motion score index (WMSI) was assessed in all patients. Coronary angiography was available in 765 patients. Major adverse cardiac events (MACE) were the outcome measure in 746 patients with follow-up information. Results No significant ST segment shift was observed in 1000 patients (58%, Group 1), ST-segment depression occurred in 609 patients (35.5%, Group 2), and ST-segment elevation in 103 patients (6%, Group 3). ST-segment elevation occurred in 66/1286 patients (5.2%) with exercise, 30/306 with dobutamine (10%), and 7/120 with vasodilators (6%, p = ns vs. exercise and p<0.01 vs. dobutamine). The prevalence of stress-induced RMWA was higher in Group 2 (38.1%) compared to Group 3 (33%) and Group 1 (11.9%. P< 0.001 vs. Groups 2 and 3); however, the ΔWMSI was more pronounced in Group 3 compared to Group 2 and Group 1 (p = ns vs. Group 2 and p<0.001 vs. Group 1). (Figure, left panel). Non-significant CAD (defined as coronary stenosis <50% on coronary angiography) was more prevalent in Group 1 (36%) and 3 (40%) compared to Group 2 (17.5%, p<0.01 vs. Group 1 and 3). . During a median follow-up of 387 days (IQ range 314-603 days), 150 events occurred in 112 patients: 14 all-cause deaths, 39 acute myocardial infarctions, 19 atrial fibrillations, 34 late coronary revascularizations, and 44 acute heart failure hospitalizations. The exposure-adjusted event rate was the lowest in Group 1 compared to Groups 2 and 3 (Figure, right panel). Conclusion In all-comers with CCS, the electrocardiographic pattern of ST-segment elevation is not rare, more frequent with dobutamine, associated with more stress-to-rest change in RWMA and more events despite less extensive underlying anatomic CAD. The paradox of more ischemia with less coronary stenosis is consistent with a coronary vasospastic origin as an important yet frequently overlooked cause of stress-induced ST segment elevation.Figure

Abstract Background Obese patients often exhibit a clustering of cardiovascular risk factors and are frequently referred for noninvasive cardiac imaging. Coronary microvascular dysfunction (CMD) represents an early indicator of cardiovascular disease that can be noninvasively diagnosed using coronary flow velocity reserve (CFVR) measurements obtained during stress echocardiography (SE) in patients without evidence of obstructive coronary artery disease (CAD). Purpose This study aimed to evaluate the prognostic significance of CFVR in overweight and obese patients within a prospective multicenter cohort. Methods 2273 patients (mean age 65 ± 11 years; 51% women) classified as overweight or obese (for definition see Table) were included in 27 sites from 11 countries. All patients had normal left ventricular ejection fraction (EF ≥ 50%), no prior history of CAD, and underwent exercise or pharmacological SE, which was negative for inducible ischemia. CFVR of the left anterior descending coronary artery was assessed, with CMD defined as CFVR >2.0. Patients were divided into two groups based on the presence (Group 1) or absence (Group 2) of CMD. The primary endpoint was overall mortality. Results CMD was identified in 492 patients (22%), with a mean CFVR of 2.3 ± 0.5 across the study population. Group 1 patients (CMD) were older, with a greater prevalence of diabetes and metabolic syndrome compared to group 2 (no CMD) (Table). During a median follow-up period of 2.1 years (IQR: 1.2-3.7 years), 103 patients (5%) died. Patients with CMD had significantly worse late survival compared to those without CMD (3-year survival: 96 ± 1% vs. 96 ± 1%, p=ns; 6-year survival: 79 ± 4% vs. 93 ± 1%, p < 0.0001): see Figure. Multivariate analysis adjusting for age, sex, EF, body mass index, smoking habits, diabetes, dyslipidemia, arterial hypertension, and type of stress confirmed CMD as an independent predictor of mortality (hazard ratio: 1.8 [95% CI: 1.1–2.8], p = 0.01). Conclusions CMD, assessed via CFVR during SE, was a robust and independent prognostic marker of long-term mortality in obese patients with preserved EF and no evidence of inducible ischemia. These findings underscore the pivotal role of noninvasive assessment of CMD in refining risk stratification and guiding clinical decision-making in this high-risk population.

Abstract Background Ischemic mitral regurgitation (IMR) is a common complication of coronary artery disease (CAD), often occurring after myocardial infarction (MI). Even when moderate in severity, IMR is associated with adverse outcomes, including a twofold increase in mortality rates. Aim To assess the functional correlates of resting IMR during stress echocardiography (SE) in patients with CAD. Methods This prospective multicenter study included 192 patients with CAD (143 males; mean age 65 ± 10 years) from eight cardiology institutions. Exclusion criteria included a history of coronary artery bypass surgery, more than moderate IMR, and other significant valvular diseases. Patients were divided into two groups based on semiquantitative- quantitative assessment at rest based on EACVI-ASE criteria: Group 1: Patients with moderate IMR, Group 2: Patients without IMR or with trivial IMR. All patients underwent stress echocardiography (SE) using the ABCE protocol. Patients underwent exercise tests, if execise echocardiography was not possible, dobutamine stress tests were performed. At rest and peak SE, we assessed: Left atrial volume index (LAVi), Left ventricular end-diastolic (LV EDV) and end-systolic volumes (LV ESV), ejection fraction (EF), wall motion score index (WMSI), global longitudinal strain (GLS), B-lines (4-site simplified scan), tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (SPAP), LV contractile reserve (LVCR) and heart rate reserve (HRR). Results Despite similar EF at rest, Group 1 patients showed more pronounced functional impairment at rest, which increased during stress. Stress-induced functional worsening affected indices of MR (more frequently becoming severe), ischemic burden (WMSI), diastolic function (LAVI and LVEDV dilation), LV systolic function (LVCR), pulmonary congestion (B-lines), cardiac sympathetic reserve (reduced HRR) and right ventricular/pulmonary artery coupling (reduced TAPSE/SPAP): table 1. Conclusion Compared to CAD patients with absent-to-trivial resting IMR, patients with moderate IMR at rest show a constellation of functional vulnerabilities during SE involving more frequent exercise-induced worsening of MR, blunted LV diastolic and systolic reserve, more pulmonary congestion, impaired cardiac autonomic reserve, and worse right ventricular-pulmonary artery coupling. The individual patient's functional response heterogeneity can be identified with comprehensive exercise SE, possibly a roadmap to personalized and targeted therapeutic interventions.

Abstract INTRODUCTION Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy. METHODS Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety‐six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and −, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using 11 C‐ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages. RESULTS TSPO was upregulated in human microglia under AD‐like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions. DISCUSSION These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation. Highlights TSPO expression increases in human microglia under AD‐like inflammation. 11 C‐ER176 PET shows stage‐dependent neuroinflammation across the AD spectrum. Neuroinflammation overlaps with tau and is more widespread in amyloid‐positive individuals. Activity peaks in MCI, stabilizes later, and relates to vascular and neurodegenerative changes.

Objective: To establish international benchmark values for relevant outcome parameters in robotic Whipple. Summary Background Data: For safe adoption of surgical innovation, robust quality control is essential. Benchmarking is a validated tool for assessing surgical performance. Recent international consensus identified establishing benchmark values for robotic Whipple as top priority. Methods: We analyzed consecutive patients undergoing robotic Whipple between 2020-2023 with a minimum one-year follow-up. Reference centers were required to perform ≥15 cases/year, be scientifically active in the field, and maintain a prospective database. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Benchmarks were established for 13 outcome parameters. Result: The benchmark cohort comprised 418 patients from 12 centers across four continents. Benchmark values were: conversion rate ≤4.3%, transfusion rate ≤2.1%, 6-month mortality ≤2.2%, major complications ≤23.2%, and CCI® ≤20.9. Clinically relevant pancreatic fistula (grade B/C) and hemorrhage (grade B/C) rates were ≤23.6% and ≤12.7%, respectively. For pancreatic ductal adenocarcinoma (n=123), the benchmark for lymph node yield was ≥20. Higher surgical difficulty was associated with increased overall postoperative morbidity (R 2 =0.38, P =0.019), higher center caseload with reduced pancreas-specific complications (R 2 =0.28, P =0.044). Independent POPF predictors included duct diameter ≤4 mm (OR 1.37, 95% CI: 1.03, 1.82), anticoagulation (OR 2.45, 95% CI: 1.47, 3.99), and indication other than PDAC (OR 2.33, 95% CI: 1.68, 3.27). Conclusions: This study establishes the first international benchmarks for robotic Whipple, demonstrating oncologic outcomes and morbidity comparable to open surgery with the benefits of minimally invasive surgery.