Citations

Abstract Purpose: Circulating tumor fraction estimate (ctFE) is a machine learning–derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre-treatment and early on-treatment ctFE could robustly risk-stratify patients with locally advanced (LA) and oligometastatic non–small cell lung cancer (NSCLC) treated with radiotherapy (RT). Experimental Design: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB to IIIC NSCLC received magnetic resonance (MR)-guided hypofractionated chemoradiotherapy (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (days 10–14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: LA NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with RT (OM-RW; n = 309). Results: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), outperforming Max VAF and ctFE detectability. The baseline ctFE was prognostic for OS (HR 5.93, P = 0.005) and PFS (HR 11.08, P < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both P < 0.001). Early ctFE dynamics defined three molecular response groups with OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; P < 0.001). ctFE remained associated with survival in both validation cohorts. Conclusions: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in LA and oligometastatic NSCLC treated with RT, supporting its use as a practical biomarker for precision treatment adaptation.

Abstract We present chromosome-level, phased diploid genome assemblies of two widely used human fibroblast cell lines: BJ (46,XY) and IMR-90 (46,XX). Using Oxford Nanopore, PacBio HiFi, and Hi-C sequencing data, we generated assemblies spanning 5.9 and 6.0 Gbp with diploid quality values exceeding QV 60. To validate structural integrity, we developed KaryoScope, an alignment-free tool for generating computational karyograms from k-mer feature databases. We identify >50 000 structural variants relative to T2T-CHM13v2.0, the majority of which are heterozygous and cell-line-specific. Combining reference-based and de novo gene annotation, we uncover a previously unreported 1 Mbp homozygous duplication at the 16p11.2 locus in BJ, demonstrating that even karyotypically normal cell lines can harbor clinically relevant submicroscopic rearrangements. We show that mapping publicly available short-read, RNA-seq, and ChIP-seq data to sample-matched diploid assemblies substantially improves read alignment and enables haplotype phasing of 23%–28% of short reads. The BJ and IMR-90 assemblies and associated variant calls are publicly available as a resource for the research community.

ABSTRACT Complete esophageal obstruction is a rare but serious complication of endoscopic variceal band ligation (EVBL). We present the case of a 75-year-old man with cirrhosis and esophageal varices who developed acute esophageal obstruction following EVBL, which was successfully managed with a combination of endoscopic scissors to cut the band and through-the-scope balloon dilation, restoring luminal patency and recanalization of the esophagus. This case highlights the importance of prevention, early recognition, and timely management of this rare but important complication of EVBL. Key management options addressed include preventive, conservative, and interventional strategies to improve patient outcomes.

ABSTRACT Background Older adults experience age‐related physiological changes that alter the pharmacokinetics and pharmacodynamics of certain medications, which may necessitate reduced dosing. Our objective was to assess emergency department (ED) and hospital outcomes of older patients administered opioids by emergency medical services (EMS) clinicians. Methods Retrospective cohort study of adults ≥ 65 years who received an opioid between 2019 and 2024 within a health system‐affiliated EMS agency. We excluded patients with an advanced airway and those with no documented weight. Maximum single and cumulative weight‐based opioid dosages were classified as low, therapeutic, or high. Outcomes were measured in the ED/hospital and compared using Poisson regression with Huber/White standard errors, adjusted for age, sex, vitals, Glascow Coma Scale, emergency severity index, and chief concern. Results were reported as adjusted risk ratios (aRRs). Results A total of 6406 patients, including 747 (11.7%, 95% CI: 10.9–12.5) with a high opioid dose, 3663 (57.2%, 95% CI: 56.0–58.4) with a therapeutic dose, and 1996 (31.2%, 95% CI: 30.0–32.3) with a low dose, were included. Receipt of a high maximum single opioid dose versus a low/therapeutic dose (excluding patients receiving a concomitant sedative) was associated with increased risk of altered responsiveness (aRR = 1.28, 95% CI: 1.03–1.58) and delirium (aRR = 2.43, 95% CI: 1.08–5.45) in the ED/hospital setting. When 311 (4.9%) patients who received a concomitant sedative were included, patients who received a high opioid dose similarly had an increased risk of altered responsiveness (aRR = 1.28, 95% CI: 1.06–1.56) and delirium (RR = 2.65, 95% CI: 1.25–5.59), compared to a low/therapeutic dose. There was no difference in outcomes of hypoxia, death within 30 days, or ED length of stay between dose groups. Conclusion Prehospital administration of high opioid doses to older patients was associated with increased rates of altered responsiveness and delirium. These findings highlight how out‐of‐hospital care can impact a patient's ED and hospital course.

The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ–producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c + KLRG1 + effector CD8 T cells (CD11c + T E ) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c + T E cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ–producing CD11c + T E cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions.

Objective This study aims to identify factors associated with patient global assessment (PtGA) and physician global assessment (PhGA) and discordance between them in systemic sclerosis (SSc). Methods Data from adults with early SSc (<5 years) from the Collaborative National Quality and Efficacy Registry were included. PtGA and PhGA (0–10 scale), clinical evaluations, and patient‐reported outcomes (PROs) were collected every six months. Multivariable mixed‐effects linear regression identified factors associated with PtGA and PhGA using (1) clinical variables and (2) clinical variables plus PROs. Relative weight analysis (RWA) determined the relative importance of each variable. Discordance (≥2 points between PtGA and PhGA) was assessed using multinomial mixed‐effects logistic regression. Results Among 956 patients (83% women, 33% limited disease), mean PtGA and PhGA at enrollment were 4.2 (SD 2.6) and 3.4 (SD 2.0), respectively ( P < 0.001). RWA of clinical variables identified modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class as most influential for both global assessments. After including PROs, PtGA was most influenced by measures of pain, skin symptoms, and physical function. Discordance occurred in 53% of patients (35% PtGA worse, 18% PhGA worse). Worse PtGA was associated with higher overall pain and discomfort. Worse PhGA was associated with higher mRSS, worse NYHA class, higher pain interference, and lower diffusing capacity of the lung. Conclusion Discordance between PtGA and PhGA occurs commonly, highlighting the need for comprehensive symptom management and measurement of disease burden in this complex disease. In SSc, differences in PtGA and PhGA reflect dissimilar weighting of data elements.

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.