Citations

INTRODUCTION: Treatment of celiac disease (CeD) requires a strict gluten-free diet (GFD). Adherence is difficult to assess and influenced by many factors. Identification of potential gluten exposures is essential, but no validated screening measures exist in pediatrics. The aim of this study was to develop and validate a measure screening for gluten exposure risk in pediatric patients with CeD. METHODS: The Gluten Exposure Risk Assessment (GERA) was developed in 3 phases. First, items were generated and refined by a modified Delphi process. Next, psychometrics, factor structure, and validity were examined in a sample of caregivers of pediatric patients younger than 18 years with CeD at 12 pediatric celiac centers. Finally, the final measure was tested on an independent sample population using confirmatory factor analysis and test-retest data. RESULTS: A total of 134 items were generated representing up to 6 domains, with 36 items selected for initial testing. Based on psychometrics and confirmatory factor analysis data from 484 caregivers, the final measure included a total of a single screening question and 9 validated items representing 2 domains (Home, Outside). Repeat testing on a separate sample (N = 369) confirmed factor structure and validity of the final measure (Comparative Fit Index = 0.96, Tucker–Lewis index = 0.95, root mean square error of approximation = 0.06). DISCUSSION: The GERA is a valid screening measure, completed by caregivers, for assessment of gluten exposure in children and adolescents with CeD following a GFD. GERA is a useful tool for evaluating the potential of risk of gluten exposure and potential need for intervention.

Clonus is a disabling symptom of upper motor neuron dysfunction in patients with multiple sclerosis (MS). We report immediate termination of mechanically evoked clonus by epidural lumbosacral spinal cord stimulation (ES) in a 58-year-old man with secondary progressive MS. This observation was captured during training using video and skin surface electromyography of soleus muscle activity. ES immediately reduced mechanically evoked clonus duration and cycle count compared to trials without stimulation, as determined by a Kruskal–Wallis test ( p < 0.05, n = 2–3 trials), and reverted to baseline status when stimulation was off.

ABSTRACT This study aimed to distinguish between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre‐PMF) using routine blood tests, with a focus on white blood cell (WBC) and platelet (PLT) levels. We evaluated the predicted probability of a pre‐PMF diagnosis based on the interaction between WBC and PLT levels using data from a logistic regression model involving 891 patients with ET and 180 patients with pre‐PMF. Patients were divided into four groups based on whether their WBC and PLT values were below or above the respective thresholds of 8.85 × 10 9 /L and 793 × 10 9 /L. The results showed that patients with low levels of both WBCs and PLTs had the lowest predicted probability of pre‐PMF (6%), indicating a profile more typical of ET. When either WBC or PLT levels were elevated, the probability increased to approximately 18%–19%, indicating a potential shift toward pre‐PMF features. Notably, patients with elevated levels of both WBCs and PLTs had the highest probability of a pre‐PMF diagnosis (26%), which was more than four times higher than that of the low–low group. The association between combined WBC/PLT levels and a pre‐PMF diagnosis remained significant ( p < 0.001), even when adjusting for serum lactate dehydrogenase (LDH) and splenomegaly. These findings suggest that elevated WBC and PLT levels together can serve as a practical and accessible diagnostic tool for supporting the differential diagnosis of ET or pre‐PMF in cases of uncertainty, and for deferring bone marrow biopsy in cases of early disease presenting with isolated thrombocytosis.

Abstract The roles of nucleoplasm-residing nucleoporins (NUP) in solid tumors, including prostate cancer, remain unknown. In this study, we reveal the clinical significance and mechanistic role of the off-pore NUP, soluble POM121 (sPOM121), as a crucial transcriptional regulator that enhances the aggressiveness of metastatic prostate cancer. Using orthogonal methodologies in human samples, sPOM121 was identified as the predominantly expressed nucleoplasmic NUP in prostate cancer. Unbiased proteomic and epigenomic studies demonstrate that sPOM121, through its C-terminus, interacts with the chromatin remodeler SMARCA5 at gene promoter sites and localizes at nuclear condensates, reprogramming gene expression. Indeed, sPOM121 regulates a distinct oncogenic gene network, including β-catenin, leading to prostate cancer progression and immune evasion. Importantly, targeting the sPOM121/β-catenin axis in patient-derived preclinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances antitumor immunity. Taken together, these findings reveal previously unknown actionable reprogramming functions of off-pore NUPs in solid tumors. Significance: This study uncovers how oncogenic signaling programs are transcriptionally heightened by the NUP sPOM121 in metastatic prostate cancer. Localization of sPOM121 at active transcriptional nuclear condensates propels disease progression and immune evasion, offering novel anticancer therapeutic opportunities.

Abstract Endoscopic mucosal resection (EMR) techniques for large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) have expanded with the introduction of ablation and cold EMR. This study assessed adverse events (AEs) for the newer EMR techniques, including cold EMR, compared with hot EMR. We conducted a secondary analysis of four prospective multicenter studies of consecutive patients with LNPCPs undergoing EMR from 2019 to 2024. The primary outcome was serious AEs (SAEs) with cold and hot EMR. Secondary outcomes included SAEs in the hot EMR subgroups (no ablation [hEMR], margin ablation [hEMR-m], margin and base ablation [hEMR-mb]). 1762 patients (mean age 65.8; 1890 LNPCPs) were included: 522 cold and 1368 hot EMRs (368 hEMR, 770 hEMR-m, 230 hEMR-mb). SAEs were higher with hot EMR (4.7%, 95%CI 3.6%–5.9%) vs. cold EMR (1.9%, 95%CI 0.9%–3.5%), also for the subgroups of hEMR (6.0%, 95%CI 3.8%–8.9%), hEMR-m (3.9%, 95%CI 2.6%–5.5%), and hEMR-mb (5.2%, 95%CI 2.7%–8.9%). Serious postendoscopic bleeding (PEB) was numerically higher with hot EMR (2.3%, 95%CI 1.6%–3.3%) vs. cold EMR (1.3%, 95%CI 0.5%–2.7%), also for the subgroups of hEMR (3.0%, 95%CI 1.5%–5.3%), hEMR-m (1.9%, 95%CI 1.1%–3.2%), and hEMR-mb (2.6%, 95%CI 1.0%–5.6%). Perforation, intraprocedural and post-procedural, was numerically higher with hot EMR (1.2%, 95%CI 0.7%–2.0%) vs. cold EMR (0.2%, 95%CI 0.0%–1.1%). hEMR-m and hEMR-mb with clipping had lower rates of serious and overall PEB than no clipping. Cold EMR demonstrated lower rates of SAEs, serious PEB, and perforation compared with hot EMR. Perforation and mortality occurred almost exclusively after hot EMR. Hot EMR with margin +/− base ablation did not increase SAEs compared with hot EMR without ablation.

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients undergoing elective cardiac surgery with implementation of cardiopulmonary bypass had their serum isolated at baseline, 24 h, seven days, and three months postoperatively to assess serum concentrations of IGFALS and insulin growth factor 1 (IGF-1). Markers of perioperative injury included troponin I (TnI), high-mobility group box 1 (HMGB-1), and heat shock protein 60 (Hsp-60). Inflammatory status was assessed via interleukin-6 (IL-6) and interleukin-8 (IL-8). Additionally, we measured in vitro cytokine production to viral stimulation of whole blood and monocytes. Surrogates of neuronal distress included neurofilament light chain (NF-L), total tau (τ), phosphorylated tau at threonine 181 (τp181), and amyloid β40 and β42. Renal impairment was defined by RIFLE criteria. Cardiac dysfunction was denoted by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Serum IGFALS levels declined significantly after surgery and remained depressed even at 3 months. Administration of acetaminophen and acetylsalicylic acid differentiated IGFALS levels at the 24 h postoperatively. Serum IGFALS 24 h post-operatively correlated with production of cytokines by leukocytes after in vitro viral stimulation. Serum amyloid-β1-42 was significantly associated with IGFALS at baseline and 24 h post-surgery Patients discharged home had higher IGFALS levels at 28 days and 3 months than those discharged to healthcare facilities or who died. These findings suggest that IGFALS may serve as a prognostic biomarker for recovery trajectory and postoperative outcomes in cardiac surgery patients.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.