Coordinates: 33°47′30″N 84°19′11.7″W / 33.79167°N 84.319917°W / 33.79167; -84.319917Emory University Hospital is a 733-bed facility in Atlanta, Georgia, specializing in the care of acutely ill adults. Emory University Hospital is staffed exclusively by Emory University School of Medicine faculty who also are members of The Emory Clinic. The hospital is renowned as one of the nation's leaders in cardiology and cardiac surgery, oncology, transplantation, ophthalmology, and the neurosciences.
Well-differentiated neuroendocrine tumors, grade 3 (NETs G3) of the digestive system are high-grade neuroendocrine neoplasms characterized by well-differentiated neuroendocrine morphology and high proliferative activity. Their molecular identity and therapeutic vulnerabilities remain incompletely defined. We performed a transcriptomic analysis and a comprehensive genomic profiling of 40 cases, including 26 NETs G3, 8 NETs G1/G2, and 6 neuroendocrine carcinomas (NECs). Targeted sequencing assessed alterations at both the DNA and RNA level, and gene expression profiling was conducted using a targeted immune-oncology panel. NETs G3 retained recurrent alterations in chromatin-regulatory genes characteristic of well-differentiated tumors and largely lacked the consistent TP53 and RB1 inactivation typical of NECs. Transcriptomic and genomic analysis demonstrated separation of NECs from NETs, with NETs G3 partially overlapping with NETs G1/G2 supporting a model of molecular relatedness. However, when compared with NETs G1/G2, NETs G3 showed upregulation of extracellular matrix remodeling, metabolic reprogramming, and cytokine signaling pathways. NETs G3 were heterogeneous in terms of number of genomic alterations per case and involved genes. A distinctive genomic feature was the predominance of large-segment copy-number losses, frequently involving chromatin-regulatory regions on chromosomes X and 10. Potentially targetable alterations were detected in up to 25% of NETs G3. Analysis of immune microenvironment supported a poorly inflamed tumor status, with individual cases harboring microsatellite instability or enrichment in tumor-infiltrating lymphocytes potentially amenable to immunotherapy.
There are few prospective studies of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) for pediatric lupus nephritis (pLN) and none evaluating rituximab (RTX). The Prospective Pediatric Lupus Nephritis Registry (ProPeL-R) enrolled patients < 21 years within 4 weeks of an initial kidney biopsy diagnostic of pLN. Demographic, clinical, and laboratory data were collected prospectively at enrollment, 3 months, 6 months, and then every 6 months thereafter for up to 5 years of follow-up. For this study, we compared patients receiving initial therapy with corticosteroids (CS) and either MMF (n = 33) vs. CYC (n = 18), and those treated with CS, either MMF or CYC, with RTX (n = 20) vs. without RTX (n = 51). Histology consisted of 18
To compare venous thromboembolism (VTE) events in patients undergoing open reduction and internal fixation (ORIF) of acetabular fractures who did and did not receive weight-based dosing of prophylactic enoxaparin. This retrospective cohort study included patients with acetabular fractures treated with ORIF between 2013 and 2020 at a single level-1 trauma center. Patients with pre-existing VTE, allergy, no enoxaparin use, or receipt of other prophylactic agents were excluded. Patients were categorized as having received appropriate or inappropriate weight-based enoxaparin dosing based on institutional BMI-tiered protocol. The primary outcome was incidence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Group comparisons were performed with Pearson’s Chi-square, and binomial logistic regression was used to adjust for additional VTE risk factors. Among 363 patients, 198 (54.5
BACKGROUND:For patients with atrial fibrillation, the use of oral anticoagulant therapy to prevent stroke is limited by the risk of bleeding. Left atrial appendage closure is considered for patients who are unsuitable candidates for long-term anticoagulation, but its role in patients who are eligible for anticoagulants has not been established. METHODS:In this ongoing, prospective, international, randomized trial involving patients with atrial fibrillation who were suitable candidates for anticoagulation, we randomly assigned patients in a 1:1 ratio to receive either device-based left atrial appendage closure (device group) or non-vitamin K antagonist oral anticoagulant (NOAC) therapy (anticoagulation group). The primary efficacy end point - a composite of death from cardiovascular causes, stroke, or systemic embolism - was tested for noninferiority (noninferiority margin, 4.8 percentage points) after 3 years of follow-up. The primary safety end point, non-procedure-related bleeding, was tested for superiority. RESULTS:Of the 3000 patients who underwent randomization, 1499 were assigned to the device group and 1501 to the anticoagulation group. The mean (±SD) age of the patients was 71.7±7.5 years, 31.9% of the patients were women, and the mean CHA2DS2-VASc score was 3.5±1.3. At 3 years, a primary efficacy end-point event had occurred in 81 patients (Kaplan-Meier estimate, 5.7%) in the device group and in 65 patients (Kaplan-Meier estimate, 4.8%) in the anticoagulation group (difference, 0.9 percentage points; 95% confidence interval [CI], -0.8 to 2.6; P<0.001 for noninferiority). Non-procedure-related bleeding occurred in 154 patients (Kaplan-Meier estimate, 10.9%) in the device group and in 260 patients (Kaplan-Meier estimate, 19.0%) in the anticoagulation group (hazard ratio, 0.55; 95% CI, 0.45 to 0.67; P<0.001 for superiority). CONCLUSIONS:Among patients with atrial fibrillation who were candidates for anticoagulation, device-based left atrial appendage closure was noninferior to NOAC therapy with respect to a composite of death from cardiovascular causes, stroke, or systemic embolism and was superior to NOAC therapy for non-procedure-related bleeding at 3 years. (Funded by Boston Scientific; CHAMPION-AF ClinicalTrials.gov number, NCT04394546.).
Background Ki-67 proliferation index (PI) is essential for grading well-differentiated neuroendocrine tumors (WD-NETs). Pathologists traditionally assess Ki-67 PI by identifying hotspots and manually counting the positive cells among negative cells, which is expressed as a percentage. We developed an algorithm to objectively determine Ki-67 hotspots and calculate PI in WD-NETs, comparing its results with pathologists' selected hotspots to assess reliability. Methods Hotspots for gastroenteropancreatic WD-NETs (n = 20) were manually annotated on whole-slide images (WSIs) by six pathologists and compared with algorithm-selected areas. Ki-67 (DAKO, MIB-1 clone, and prediluted) scoring was performed using QuPath's custom object classification algorithm. Pathologists identified hotspots on WSI, captured images, and submitted them for PI determination using the same algorithm. Ki-67 PI was translated to grade per WHO classification (G1: <3%, G2: 3–20%, G3: >20%). A pathologist's consensus grade was determined based on majority pathologist grading (>3/6) for each case. Fleiss's Kappa was used to assess inter-pathologist agreement, Cohen's Kappa was used to evaluate the agreement between pathologists and the algorithm, and Friedman test was used for hotspot area variability analysis. Results Pathologists showed moderate agreement (Fleiss's Kappa = 0.42, 80% agreement), whereas pathologist–algorithm agreement was fair (Cohen's Kappa = 0.32, 58.9% agreement). Among cases with pathologist consensus grade (n = 19), the algorithm assigned a higher grade in 8 cases (42%). In 60% of cases, hotspots overlapped between methods. There was significant hotspot area variability (Friedman statistic: 95.97, p < 0.001). Conclusion Manual Ki-67 hotspot assessment is subjective, leading to grading variability. Algorithm-based assessment enhances reproducibility, though this occasionally leads to tumor upgrading, highlighting the need for standardization and further validation.
