Citations

Abstract Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett’s esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett’s esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82–0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86–0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66–0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7–0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett’s esophagus surveillance. Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett’s esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

ABSTRACTSurgical biopsy of brainstem tumors carries a risk of neurological injury. We performed magnetic resonance spectroscopy (MRS) of 2‐hydroxyglutarate (2HG) and glycine in patients with brainstem tumors to assess the feasibility of detecting and quantifying 2HG in the brainstem to obviate the need for a diagnostic biopsy and to establish the clinical significance of glycine MRS in brainstem tumors in vivo. Twenty adult patients with radiographically identified presumed brainstem gliomas were prospectively enrolled in the study. Proton MRS was obtained at 3T with a protocol tailored for detection of 2HG and glycine (TE 97‐ms PRESS). Spectra were fit using LCModel software and in‐house basis signals of metabolites and lipids. The metabolite concentrations were quantified with reference to water and examined with respect to clinical outcomes, including postgadolinium MRI and overall survival time. MRS data from 19 patients were included in subsequent analysis, excluding suboptimal data from one patient. Tumors with elevated 2HG (> 1.9 mM, N = 8) and undetectable 2HG (< 0.3 mM, N = 11) were clearly distinguishable. Tumors with elevated glycine (> 1.5 mM, N = 4) showed rapid progression. Kaplan–Meier survival analyses with metabolite measures demonstrated that tumors with 2HG higher than 1.0 mM were significantly associated with a favorable prognosis (p = 0.01). In contrast, tumors with glycine higher than 2.5 mM showed a strong association with poor survival (p = 0.0005). The data confirm detection of 2HG in brainstem tumors at a concentration that is consistent with an IDH mutation and expected good prognosis, whereas elevated glycine in brainstem tumors portends rapid tumor progression and a worse prognosis.

Abstract Background Delirium is often underdiagnosed in clinical practice and is not routinely coded for billing. While manual chart review can identify delirium, it is labor-intensive and impractical for large-scale studies. Natural language processing (NLP) can analyze unstructured text in electronic health records (EHRs) to extract meaningful clinical information. Methods To support national integration of NLP for EHR-based delirium identification across different institutions, we launched the Delirium Interest Group within the national Evolve to Next-Gen Accrual to Clinical Trials (ENACT) NLP Working Group. This paper outlines our initial efforts to standardize, evaluate, and translate an NLP-based delirium detection model into the i2b2/ENACT platform. Results Multisite contextual inquiry identified several key challenges, including variations in local screening practices (eg, tools used, documentation frequency, and quality control), the need for harmonized definitions in the context of EHRs, and the complexity of modeling temporal logic. Multisite NLP evaluation revealed variable performance degradation driven by differences in delirium screening practices, clinical documentation patterns and semantics, and note syntactic structures. Conclusion Our work represents an important first step toward enabling scalable and standardized NLP-based delirium detection across institutions. By engaging diverse institutions through the ENACT NLP Working Group, we identified shared challenges and site-specific variations that impact model implementation and performance. Our collaborative approach enabled the development of a more robust framework for delirium identification across heterogeneous EHR systems. Future efforts will build on this foundation to enhance the validity, usability, and translational impact of delirium detection.

Abstract Background Increased prevalence of reduced bone mineral density (BMD) is well documented in persons infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or both. This study's purpose was to determine if an association exists between dietary calcium intake and BMD in these patients. Methods Participants were individuals with virologically suppressed HIV or untreated HCV monoinfections, those with HIV/HCV coinfection, and noninfected controls. The Hertzler-Frary dietary calcium questionnaire documented calcium intake with calcium amounts based on the US Department of Agriculture nutrient database. BMD was measured at baseline by dual-energy x-ray absorptiometry, and χ2 tests were used to assess the relationship between BMD and infection status. One-way analysis of covariance was used to compare calcium intake data with the prevalence of normal BMD and osteoporosis by infection group. Adjustments were made for race, age, body mass index, and smoking status. Spearman correlation was used to identify relationships between calcium intake from foods/beverages and BMD. Results A total of 452 men were recruited into the study. Osteoporosis and osteopenia were prevalent, but there was no association between infection group and BMD result (χ2(6) = 6.813; P = .34). Only HCV-infected patients with osteoporosis had lower calcium intake than patients with normal BMD (mean difference, 409 mg/d [95% confidence interval, 35–784 mg/d]; P = .03). Conclusions In this study population, dietary calcium intake was correlated with reduced BMD only in patients with HCV monoinfection.

Abstract Objective The goal of this study was to examine if differing platelet counts in platelet‐rich plasma (PRP) formulations affected overall pain and function outcomes when compared to hyaluronic acid or placebo control saline injections. Design/Methods We conducted a systematic review and meta‐analysis (International Prospective Register of Systematic Reviews CRD42022340057) evaluating randomized controlled trials comparing injections of PRP to hyaluronic acid (HA) or saline (NS) control in patients with mild or moderate knee osteoarthritis. All studies used a validated outcome measure that examined pain, function, or overall patient global assessment. Study PRP interventions were subclassified as investigating the total number of platelets delivered in a low dose (1–5 billion total deliverable platelets), moderate dose (5–10 billion total deliverable platelets), or high dose (greater than 10 billion total deliverable platelets) injected into the joint. Results A total of 32 trials met inclusion criteria. All three PRP groups had significant improvements in validated patient‐reported outcomes when compared to HA. Both the “low” and “high” platelet count groups resulted in a moderate effect size, respectively (standardized mean difference [SMD] = .47; 95% confidence interval [CI] .05–0.89, p < .01; SMD = .68; 95% CI .26–1.09, p < .01). Only the “moderate” (SMD = 1.48; 95% CI .71–2.58 p < .01) platelet count group resulted in large effect size on validated patient‐reported outcomes. When compared to NS, all three PRP groups resulted in significant large effect sizes when examining pain reduction. Conclusions When compared to HA, PRP with platelet counts between 1 and 10 billion total deliverable platelets may result in a larger decrease in pain symptoms when compared to platelet counts greater than 10 billion at 6 months. In addition, platelet counts between 5 and 10 billion total deliverable platelets may be associated with greater improvement in functional outcomes.

Abstract Objectives Hepatic steatosis impacts the quality of grafts, affecting transplant outcomes. Rising obesity rates and subsequent donor graft steatosis further influence the organ shortage crisis in pediatric liver transplantation (LT). Our study aimed to evaluate how donor steatosis modulates the outcomes of pediatric LT. Methods We analyzed the United Network of Organ Sharing database for transplanted donor grafts from January 01, 2004, to April 30, 2024. We stratified pediatric (≤18 years) LT recipients into steatotic grafts, subdivided into <30% and ≥30%. Graft failure was assessed using Kaplan–Meier curves, and Cox proportional hazards models, with Lasso regression identifying key predictive variables. Gradient‐boosting decision tree was used to assess the level of likelihood importance for post‐LT survival. Results Five hundred and ninety‐five pediatric LT recipients were included; 62 (10.4%) received donors with steatosis levels ≥30%. Survival rates for steatotic grafts ≥30% were 93.5% at 1 year, 89.9% at 5 years, and 84.4% at 10 years, compared to 94.7%, 89.5%, and 85.2% respectively, among steatotic grafts <30% ( p = 0.72, p = 0.92, and p = 0.92). Donor age (adjusted hazard ratio [aHR]: 1.01, 95% confidence interval [CI]: 1.01–1.03), donation after cardiac death (DCD) (aHR: 10.68, 95% CI: 3.27–34.86), and recipient life support (aHR: 1.95, 95% CI: 1.19–3.20) were associated with an increased risk of mortality. Conclusion Steatotic grafts in pediatric patients had acceptable outcomes. Predictors of mortality in steatotic grafts, including donor age, DCD, and recipient life support, underscore the complex interplay of multiple factors in post‐LT outcomes.

Objectives To develop an internationally validated, structured robot‐assisted radical nephroureterectomy (RARNU) training programme through expert consensus. Materials and Methods A RARNU‐specific questionnaire was developed/adapted from previously published, validated questionnaires for robot‐assisted urological procedures. This included five key domains and 11 surgical steps. In all, 30 upper tract urothelial carcinoma experts were invited to participate. A two‐stage modified Delphi approach was employed. Consensus was defined as ≥80% agreement. Modifications and additional statements were proposed during the second round following qualitative/quantitative feedback from the initial round. Results Response rates for the first and second Delphi rounds were 80% (24/30) and 92% (22/24), respectively. All agreed that adoption of a standardised training curriculum can improve clinical outcomes during the RARNU learning curve. There was ≥92% agreement on all proposed RARNU steps. Five RARNU clinical modules of increasing complexity were defined using individual step difficulty and number of prior RARNU cases required, with ≥96% agreement among respondents. Respondents unanimously agreed that the final assessment should be based on a procedure‐specific scale focusing on the hilar dissection, ureteric dissection, and bladder cuff excision steps. No consensus was reached for the annual minimum RARNU volume required for eligibility as a RARNU curriculum host centre. Conclusion This is the first structured training curriculum for RARNU using international expert consensus. This will help guide surgical educators and trainees toward independent completion of a full RARNU.