Citations

The role of circulating tumor DNA (ctDNA) in gastroesophageal adenocarcinoma (GEA) has expanded in recent years. In resectable disease, postoperative ctDNA is able to detect patients at highest risk of recurrence months before scans. Tumor-informed assays provide the best sensitivity and emerging methylation assays are useful when tissue is scarce. In metastatic GEA, baseline ctDNA burden correlates with prognosis, and a decrease in ctDNA level after treatment initiation reflects therapeutic response. It can also uncover actionable targets, including ERBB2, FGFR2, and MSI-H, and detect resistance that can arise after starting treatment. Limitations include variable assay performance, low shedding in some tumors, clonal hematopoiesis confounding, and a lack of randomized data showing that ctDNA-guided changes improve outcomes. Ongoing trials are testing MRD-guided escalation/de-escalation and ctDNA-directed biomarker therapy. In this review, we evaluate the role of ctDNA in GEA cancers over recent years.

Objectives Heritable connective tissue disorders (HCTDs), including hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobile spectrum disorder (HSD), have complex clinical manifestations, but the prevalence of left common iliac vein (LCIV) compression in these groups is not well known. This study aimed to compare the prevalence of significant LCIV compression in patients with hEDS, HSD, and healthy controls. Methods This retrospective, IRB-approved, single-center study analyzed 109 patients (25 hEDS, 64 HSD, 20 controls) who underwent contrast-enhanced abdominal and pelvic CT imaging from 2020 to 2023. LCIV compression was measured on axial CT, with >50% luminal narrowing defined as significant. Statistical analyses included chi-square tests, odds ratios, and t -tests. Interrater reliability was evaluated using intraclass correlation coefficients. Results Significant LCIV compression occurred in 68.0% of hEDS, 65.6% of HSD, and 35.0% of controls ( p = 0.034). Both hEDS ( p = 0.027) and HSD ( p = 0.015) groups had significantly higher compression rates than controls, with no statistically significant difference between the two clinical groups ( p = 0.831). Odds of compression were nearly fourfold greater in hEDS (OR 3.95) and HSD (OR 3.54) compared to controls. Conclusion LCIV compression is significantly more prevalent in patients with hEDS and HSD than in healthy controls, warranting further investigation of its clinical significance.

Introduction There is an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygotes for the alpha-1 antitrypsin (AAT) Z allele (PI*MZ), but there is significant variation in outcomes. Matrix metalloproteinases (MMPs) contribute to worse airway disease and emphysema. Given that the AAT protein is an antiprotease, we hypothesised that MMPs play a modifying role among AAT-deficient individuals. Methods We studied PI*MZ (n=39) and PI*ZZ (n=27) individuals from the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study cohort. MMP (MMP3, MMP9, MMP10, MMP12 and MMP15) gene expression was assessed in bronchoalveolar lavage cells and peripheral blood mononuclear cells. Plasma protein MMP (MMP3, MMP9, MMP10 and MMP12) expression was assessed using SomaScan and BAL MMP15 protein using ELISA. MMP values were log-transformed, and linear regression analyses were used to assess lung function, patient-reported outcomes and CT emphysema adjusted for age, body mass index, sex and duration of smoking. Results Alveolar MMP3 and MMP15 were uniquely associated with worse lung function, patient-reported outcomes and emphysema among PI*MZ individuals. MMP10 was associated with less disease severity among PI*MZ individuals. Discussion Our study shows that alveolar MMP3 and MMP15 may uniquely contribute to disease among PI*MZ individuals, raising the possibility that they could serve as biomarkers or therapeutic targets in this highly prevalent COPD phenotype. Furthermore, we show that MMP10 may serve a protective effect. In aggregate, these data support further studies of the MMP pathway among lung-affected PI*MZ individuals, as they may serve as biomarkers or pharmacological targets in future studies.

Abstract Objectives Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)‐guided depth leads to provide responsive stimulation to neocortical gray matter. Methods Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti‐responders (≤0%) based on percent seizure reduction at 1 year post‐implant (1‐Y). Pre‐operative T1‐weighted magnetic resonance imaging and post‐operative computed tomography images were merged, and the Euclidean distance between the sEEG epileptic focus (sEEG‐EF) and the nearest RNS System depth lead contacts was calculated. Results A total of 87 depth leads were implanted in 55 patients across neocortical brain regions. The median reduction in clinical seizures improved from 66.7% at 1‐Y to 77.5% at long‐term follow‐up (LTFU: 2.35 ± 0.95 years), with 10 patients (18.2%) achieving complete seizure freedom. Seven patients (12.7%) experienced six serious adverse events. At 1‐Y, shorter Euclidean distance between the sEEG‐EF and RNS System depth leads predicted improved seizure outcome in strong responders ( β = −0.84, p = 0.008) but not in weak responders ( β = 0.21, p = 0.9) or anti‐responders ( β = −20.34, p = 0.11). At LTFU, there was no significant relationship between Euclidean distance and seizure reduction in strong responders ( β = 0.77, p = 0.18), weak responders ( β = 2.05, p = 0.54), or anti‐responders ( β = 0.24, p = 0.99). Exploratory analyses at 1‐Y showed nominal associations between older age ( ρ = 0.32), longer epilepsy duration ( ρ = 0.27), and non‐mesial temporal sEEG‐EFs and greater seizure reduction; however, none survived Bonferroni correction (adjusted α = 0.0027; all post‐correction p > 0.0027), and no associations were observed at LTFU. Significance In this series, neocortical depth leads for RNS therapy had favorable safety and efficacy and proximity to the sEEG‐EF drove initial outcomes for strong responders to RNS therapy. Plain Language Summary In this multi‐center study, patients with difficult‐to‐treat seizures received brain‐responsive stimulation using a device called responsive neurostimulation (RNS), which delivers small electrical pulses to reduce seizures. We focused on patients treated with electrodes placed in the brain's outer regions (the neocortex) and guided by a mapping procedure called sEEG. On average, patients had their seizures cut by two‐thirds after one year and by more than three‐quarters with longer follow‐up, with about one in five becoming seizure‐free. The treatment was safe, and closer electrode placement to the seizure source helped explain early—but not long‐term—improvements.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug‐resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. Methods The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A + DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID‐III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3), Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF‐P), and Pediatric Evaluation of Disability Inventory (PEDI). Results Fifty‐eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age‐appropriate milestones. Mean BSID‐III Cognitive raw scores increased minimally, with age‐equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: –11.0, 95% confidence interval [CI]: −15.3 to −6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF‐P Global Executive Composite T‐scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS‐3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: –9.0, 95% CI: −11.9 to −6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. Significance Infants and young children with SCN1A + DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

ABSTRACT Background Adolescents with youth‐onset type 2 diabetes (YO‐T2D) have an increased risk for cardiometabolic complications. The impact of vertical sleeve gastrectomy (VSG) on fat distribution and cardiac morphology/function in YO‐T2D is unknown. Objectives To evaluate changes in body composition, abdominal and cardiac fat depots, and cardiometabolic health in adolescents with YO‐T2D undergoing VSG. Methods Anthropometrics, labs and imaging were used to assess participants pre‐surgery and 3–12 months post‐surgery. MRI quantified pericardial (PAT), epicardial (EAT), subcutaneous (SAT) and visceral adipose tissue (VAT), hepatic fat fraction (HFF) and cardiac morphology/function. Mixed‐effects models assessed longitudinal changes. Results By 12 months, weight decreased from 134.3 ± 5.1 to 103.3 ± 5.2 kg, VAT 1943 ± 148 to 1248 ± 150 cm 3 , HFF 23.2% ± 2.3% to 5.3% ± 2.3% and PAT and EAT by 27% and 33% (all p < 0.01). Homeostatic model assessment of insulin resistance (HOMA‐IR) improved (7.8 ± 1.2 to 1.7 ± 1.2 [ p < 0.01]). BMI, SAT, resting heart rate (RHR), left ventricular (LV) mass and cardiac output (CO) also decreased (all p < 0.05). VAT decreases correlated with decreases in HFF ( r = 0.70, p = 0.01), HOMA‐IR ( r = 0.60, p = 0.04) and CO ( r = 0.70, p = 0.03). HFF decreases correlated with decreases in BMI ( r = 0.70, p = 0.03), HOMA‐IR ( r = 0.90, p < 0.001), RHR ( r = 0.90, p = 0.002), CO ( r = 0.80, p = 0.007) and LV mass ( r = 0.70, p = 0.02). Conclusions VSG reduces ectopic and regional fat and improves associated insulin sensitivity and cardiac health in adolescents with YO‐T2D.

ABSTRACT Background Large vegetations in cardiac implantable electronic devices (CIEDs) are associated with high mortality due to risks of major pulmonary artery obstruction. The rising incidence of CIEDs infections has complicated management, particularly in patients with delayed diagnoses. Current guidelines recommend open‐heart surgery for vegetations > 2.5 cm, but this approach poses significant risks for high‐morbidity patients. This study evaluates the feasibility and outcomes of percutaneous vacuum‐assisted aspiration using the AngioVac system in managing giant vegetations (≥ 4.0 cm) in patients unsuitable for open surgery. Materials and Methods Fourteen patients with giant vegetations (≥ 4.0 cm), undergoing transvenous lead extraction, were treated with the AngioVac system. The procedure involved large‐bore central venous cannulation and extracorporeal aspiration of vegetations. Outcomes assessed included procedural success, embolization management, and post‐extraction microbiological findings. Results The cohort included 64% males with a median age of 73 years. Vegetation sizes ranged from 4.0 to ≥ 7.0 cm. Most patients (79%) presented with advanced heart failure symptoms (NYHA class III/IV). Despite pulmonary embolism in 29% of cases, all were successfully managed with mechanical aspiration. The procedure achieved 100% complete removal of all leads and vegetations, with no perioperative mortality, and all patients were discharged alive. Conclusion Percutaneous aspiration using the AngioVac system is a safe and effective alternative to open‐heart surgery for high‐risk patients with giant vegetations. This minimally invasive approach demonstrates potential for broader application in managing high‐risk CIEDs infections, warranting further investigation in larger studies.

ABSTRACT Background Transvenous lead removal (TLR) in patients with a history of mediastinal radiation poses unique challenges due to potential radiation‐induced fibrosis, vascular changes, and anatomical distortion, which may increase procedural complexity and complication risk. However, contemporary data on clinical outcomes in this population remain limited. Methods We analyzed the National Readmissions Database (2016–2021) to identify adults (≥ 18 years) undergoing TLR. Patients were stratified by prior mediastinal radiation. Baseline characteristics were compared using standard statistical tests. Multivariable logistic regression was used to evaluate the association between prior mediastinal radiation and in‐hospital outcomes, 30‐day mortality, and 30‐day readmissions after adjustment for demographics and comorbidities. Results A total of 48,985 patients underwent TLR, of whom 735 (1.5%) had a history of mediastinal radiation. Compared with patients without radiation, those with prior radiation were older (70.1 vs. 66.2 years, p < 0.01), were more frequently females (38.2% vs. 31.6%, p < 0.01), and had higher rates of valvular heart disease, atrial fibrillation, and peripheral vascular disease. Adjusted analyses demonstrated no increased risk of in‐hospital mortality (2.3% vs. 3.4%; adjusted odds ratio [aOR] 0.65, 95% confidence interval [CI] 0.41–1.18, p = 0.29) or major complications, including cardiac arrest, pericardial complications, vascular injury, pulmonary complications, or embolic events. Similarly, (3.6% vs. 5.3%; aOR 0.76, 95% CI 0.48–1.43, p = 0.35) and 30‐day all‐cause readmissions (8.7% vs. 9.1%; aOR 0.81, 95% CI 0.64–1.28, p = 0.70) were not significantly different between groups. Subgroup analyses by indication for TLR (infection vs. mechanical complication) revealed no differences in outcomes. Conclusion Despite theoretical concerns, prior mediastinal radiation was not associated with excess procedural risk or worse short‐term outcomes after TLR. These findings may inform procedural planning and risk counseling in clinical practice.