Citations

OBJECTIVE Adamantinomatous craniopharyngioma (ACP) is a rare type of brain tumor that affects a wide age range, from children to older adults. Due to the rarity of the disease, existing studies are predominantly limited to single-center or single-surgeon experiences, often lacking statistical power and generalizability. The aim of this study was to address this gap by providing a comprehensive analysis of ACP outcomes based on a large multicenter cohort from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). METHODS This multicenter retrospective cohort study was conducted via the RAPID consortium and assessed patients with histologically confirmed ACP treated surgically between August 2000 and November 2024 at high-volume pituitary centers across the United States. RESULTS Among the 359 patients (206 male, median age at primary surgery of 47 years) included in the analysis, 76% underwent endoscopic transsphenoidal surgery and 22% underwent craniotomy. Gross-total resection was achieved in 45% and subtotal resection in 47%. Notably, 120 of 311 patients (39%) presented with preoperative hypothalamic-pituitary axis dysfunction. Following all treatments, permanent hypothyroidism was reported in 40% of patients, adrenal insufficiency in 33%, and arginine vasopressin deficiency in 19%. Of 263 patients who underwent primary surgery, radiation therapy was administered in 84 (32%). Progression-free survival (PFS) declined from 66% at 1 year to 31% at 6 years. In the multivariable analysis, independent predictors of worse PFS included subtotal resection (HR 0.22, 95% CI 0.11–0.42; p = 0.001), partial resection (HR 0.11, 95% CI 0.04–0.28, p = 0.001), larger tumor size (HR 0.77, 95% CI 0.64–0.94; p = 0.009), and tumor extension beyond the sella and suprasellar regions (HR 0.21, 95% CI 0.06–0.74; p = 0.016). Primary surgery and salvage surgery groups showed comparable PFS. CONCLUSIONS In this large multicenter cohort study, gross-total resection was achieved in fewer than half of patients and was independently associated with improved PFS. Approximately one-third of patients underwent radiation therapy after primary surgery. These findings provide robust evidence supporting the prognostic value of extent of resection and inform contemporary treatment algorithms for ACP. The high incidence of postoperative endocrinopathy underscores the need for individualized multidisciplinary long-term care. While the retrospective design is a limitation, the multicenter approach enhances the generalizability of these results.

OBJECTIVE Protocols for intraoperative mapping during awake craniotomy vary widely. The aim of this study was to evaluate how the number and type of intraoperative neuropsychological paradigms administered via NeuroMapper, a tablet-based platform, during awake glioma surgery affect positive mapping rates, return to work (RTW), and oncological outcomes. Factors associated with the operative duration and early postoperative neurological deficits were of additional interest. METHODS This single-center retrospective study included patients with diffuse low- and high-grade gliomas who underwent awake craniotomy with NeuroMapper-guided mapping between 2018 and 2024. Primary outcomes were RTW, progression-free survival (PFS), and overall survival (OS); operative duration and early postoperative deficits were secondary outcomes. Covariate balancing propensity score (CBPS) analysis was used to address confounding by tumor grade, with all postweighting standardized mean differences < 0.10. A weighted logistic regression model assessed RTW, and CBPS-weighted Cox models assessed PFS and OS. Linear regression was used to analyze intraoperative variables, operative duration, and early postoperative deficits. RESULTS Of 189 patients included in the analysis, 65 had LGG (median age 39 years) and 124 had HGG (median age 56 years). Mapping complexity varied, with 1–6 tasks used (median 4). Weighted multivariate logistic regression analysis identified the following independent predictors of RTW: preoperative Karnofsky Performance Status score ≥ 80 (OR 1.37, p = 0.039), absence of recurrent disease (OR 0.30, p < 0.001), use of 5–6 paradigms (OR 1.54, p = 0.047), positive mapping (OR 2.41, p = 0.017), and subtotal resection (OR 4.43, p = 0.002). Intraoperative seizure, early postoperative deficit, and the resection technique were not significant. IDH mutation status was associated with improved PFS (HR 0.15, p < 0.001), while subtotal resection was associated with worsened PFS (HR 3.00, p < 0.001). Positive mapping was associated with better OS (HR 0.57, p = 0.04). The operative duration was unaffected by mapping variables but was longer in patients with obesity (β = 0.28, p = 0.038). CONCLUSIONS Positive NeuroMapper-guided mapping of more diverse linguistic functions was associated with RTW and longer OS. Additionally, mapping complexity did not prolong surgery times, supporting potential standardization.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Coronary microvascular dysfunction (CMD) has emerged as a crucial contributor to cardiovascular morbidity and mortality, particularly in patients with ischemia and non-obstructive coronary arteries (INOCA). The condition arises from a complex interplay of structural and functional abnormalities within the small coronary vessels, driven by underlying molecular mechanisms including endothelial nitric oxide synthase (eNOS) uncoupling, oxidative stress, and chronic inflammation. Lipid metabolism plays a central role in this pathology, especially in the setting of elevated low-density lipoprotein cholesterol (LDL-C). Furthermore, the protective capacity of high-density lipoprotein (HDL) is increasingly understood to depend on its functionality rather than absolute levels, as it can become dysfunctional and pro-inflammatory in pathological states. Emerging evidence has identified lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins as significant, independent contributors to microvascular injury. Comprehensive clinical assessment of microvascular dysfunction therefore requires integration of advanced lipid profiling, including apolipoprotein B (ApoB), [Lp(a)], and the triglyceride-glucose (TyG) index with invasive and non-invasive measures of coronary flow reserve to more precisely stratify risk. In this narrative review, we synthesize current observational, mechanistic, and early interventional data linking diverse lipid phenotypes to coronary microvascular dysfunction. We propose a concept of lipid-driven CMD endotypes, such as ApoB-/particle overload, dysfunctional HDL, Lp(a)-mediated risk, and metabolic/TyG-high states, and map these to a practical, mechanism-informed management framework. While intensive LDL-C lowering with high-intensity statins and combination therapy remains guideline-directed care for high-risk patients, evidence for dedicated microvascular benefit from newer lipid and cardiometabolic agents is still largely hypothesis-generating. A personalized approach that aligns lipid phenotyping, CMD endotyping, and existing guideline-based therapies may help refine risk assessment and inform future trials.

Among patients with treatment-naive hepatocellular carcinoma, glass microsphere radiation segmentectomy before liver transplant achieved high rates of complete pathologic necrosis, which was positively associated with the number of optimized treatment parameter thresholds.

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Abstract INTRODUCTION Sleep and circadian rest–activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS‐associated AD continuum remain uncharacterized. METHODS We analyzed 7‐day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group‐specific associations. RESULTS DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

Abstract Transcriptional condensates (TCs) are dynamic, membrane-less assemblies of proteins and nucleic acids that form at specific genomic loci to control gene expression. The primary drivers of TC formation and function are long stretches of polypeptide chains that lack well-defined tertiary structure, known as the intrinsically disordered regions (IDRs) of Transcription Factors (TFs). However, the role of well-structured domains such as the DNA-binding domain (DBD) in condensate formation and downstream regulation remains poorly understood. Here, we investigated whether the DBD of the Progesterone Receptor (PR), a model TF regulated by hormone binding, contributes to the formation of PR TCs. By combining Single Particle Tracking (SPT) with deep-learning-based single-trajectory analysis, we demonstrated that both the IDR and the DBD are required for the formation of PR condensates. Furthermore, transcriptomic analysis showed that mutations of either of the two domains result in the expression of a distinct set of genes, with functional assays corroborating these findings and linking domain-specific transcription to differential effects on cell proliferation and migration. Together, our results show that domains beyond IDRs also play a role in TC formation and function and uncover domain-specific regulation of transcriptional and oncogenic programs.

Abstract Context Incidental thyroid findings (ITFs) are increasingly detected on imaging performed for non-thyroid indications. Their prevalence, features, and consequences remain undefined. Objective To develop, validate, and deploy a natural language processing (NLP) pipeline to identify ITFs in radiology reports and assess their prevalence, features, and clinical outcomes. Design Retrospective cohort study. Setting Mayo Clinic sites (Rochester, Arizona, Florida, Mayo Clinic Health System). Participants Adults without prior thyroid disease undergoing thyroid-capturing imaging from July 1, 2017, to September 30, 2023. A transformer-based NLP pipeline identified ITFs and extracted nodule characteristics from image reports from multiple modalities and body regions. Outcomes ITF prevalence, downstream thyroid ultrasound, biopsy, thyroidectomy, and cancer diagnosis. Logistic regression identified demographic and imaging-related factors. Results Among 115 683 patients (mean age, 56.8 [SD 17.2]; 52.9% women), 9077 (7.8%) had an ITF (92.9% nodular). ITFs were more likely in women, older adults, higher BMI, and in imaging ordered by specialties different from Emergency Medicine. Compared with chest CT, ITFs were more likely via neck CT, PET, and nuclear medicine scans. Nodule characteristics were poorly documented, with size reported in 44% and other features in fewer than 15%. Compared with patients without ITFs, those with ITFs had higher odds of thyroid nodule diagnosis (OR 45, 95%CI 41.1-49.3), biopsy (OR 46.8, 95%CI 39.0-56.2) thyroidectomy (OR 55.8, 95%CI 31.3-99.3), and thyroid cancer diagnosis (OR 61.7, 95%CI 38.6-98.5). Most cancers were papillary (88.5%) and larger when detected after ITFs (2 cm SD 1.4) vs no ITF (1.3 cm SD 0.8). Conclusion ITFs were common and strongly associated with cascades leading to the detection of small, low-risk cancers, highlighting their role in overdiagnosis and the need for standardized reporting and more selective follow-up.