Citations

Abstract INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APO E ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOE ε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration : NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.

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 Matrix-producing tumors of the sinonasal region are diagnostically challenging, with a large number of similar-appearing neoplasms having different prognoses, treatment strategies, and genetic syndrome associations. Osteochondromyxoma (OCM) is a very rare tumor known to be associated with Carney complex. Since its initial description in 2001, fewer than 20 cases have been reported, with the sinonasal tract being an apparently favored site. Herein we describe 6 new cases of sinonasal OCM.OCM cases with available slides were retrieved from the surgical pathology files of the authors’ practices. The tumors arose in 4 boys and 2 girls, ranging from 4 to 17 years (mean, 9.5 years). All presented with nasal obstruction and a mass. Radiologically the tumors presented as indolent-appearing, heterogeneous, calcified, expansile masses. Histologically the tumors all consisted of bland, normochromatic spindled to stellate cells in a myxoid to collagenized stroma, with variable amounts of cartilage and bone formation. Mitotic activity was very low and necrosis was absent. All demonstrated complete loss of PRKAR1A expression by immunohistochemistry. Of these 6 cases, 3 had been originally diagnosed as nasal chondromesenchymal hamartomas, and one as osteosarcoma. Treatment and follow up information were available for 5 patients: all were treated with surgery, with one also receiving chemotherapy after an initial osteosarcoma diagnosis. At the time of last clinical follow-up, all 5 patients were alive, one with residual disease. No patient was known to have other stigmata of Carney complex.Although rare, OCM preferentially occurs in the sinonasal tract, and therefore may be encountered by head and neck pathologists. Given their predilection for young patients and overlapping morphologic features, OCM are easily misdiagnosed as other matrix-forming sinonasal tumors, especially nasal chondromesenchymal hamartoma. Immunohistochemical demonstration of PRKAR1A loss is valuable for confirming an OCM diagnosis, which should prompt clinical investigation for the possibility of Carney complex.

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. Here, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared to normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune reactive tumor microenvironment. Mutations in several SWI/SNF subunits were associated with higher rates of outlier retained introns across tumor types in TCGA data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention. Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Further, SWI/SNF localized to genes which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFa and INFb in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to intron retention. Furthermore, T cell activation by novel peptides encoded by these tumor-specific splicing events suggests intron retention could be a source of tumor-associated antigens in SCCOHT. Citation Format: Elizabeth Raupach, Apurva Hegde, Krystine Garcia-Masnfield, Marice Alcantara, David Rose, Rebecca Halperin, Krystal Orlando, Jessica Lang, Ritin Sharma, Victoria David-Dirgo, Salvatore Facista, Rayvon Moore, Rochelle Kofman, Zoe Jensen, Victoria Zismann, Anthony Karnezis, Yemin Wang, Lynda Bennett, Timothy Whitsett, Marcin Kortylewski, William Hendricks, David Huntsman, Lorna Rodriguez-Rodriguez, Bernard Weissman, Jeffrey Trent, Patrick Pirrotte. Loss of SMARCA4 leads to intron retention and generation of tumor-associated antigens in small cell carcinoma of the ovary, hypercalcemic type [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B065.

Abstract Radiological protocol selection is a critical but time-consuming step in clinical workflow, requiring radiologists to match patient indications with the appropriate MRI or CT protocol. Manual selection can be prone to delays or potential errors, and automated approaches must contend with substantial data imbalance, site-specific variation, and evolving nomenclature. We investigated whether a large language model (LLM) can support reliable protocol selection at scale and whether retrieval-augmented generation (RAG) offers operational advantages over direct fine-tuning. Using 498,228 patient reports collected across three Mayo Clinic sites (Arizona, Florida, and Rochester) spanning six radiological divisions, we trained site-specific Llama 3.2 3B models for use with and without retrieval augmentation. Division-scoped Facebook AI Similarity Search (FAISS) indexes constructed from procedure and diagnosis text were used to supply contextual evidence in the RAG framework. Both fine-tuned and RAG-augmented models achieved strong performance across sites, with F1 scores of 0.88–0.90. RAG matched or modestly trailed direct fine-tuning overall but delivered consistent gains in specific divisions (e.g., musculoskeletal imaging). Importantly, the RAG model introduced abstention behavior (Not Enough Information), which concentrated in linguistically diverse divisions and provided an interpretable signal of uncertainty. These findings suggest that RAG-based models are viable for division-scoped protocol selection and offer practical advantages. Retrieval indexes can be refreshed far more easily and with fewer resources than retraining LLMs, enabling continual adaptation to evolving clinical workflows. Future prospective deployment will evaluate real-time accuracy, agreement with practitioners, and the role of abstention as a safety mechanism in clinical decision support.

Objective: Pulmonary air trapping is critical for diagnosing and prognostication of various lung diseases. Expiratory CT imaging serves as an accessible method to assess air trapping, which correlates with small airway disease outcomes. Air trapping manifests as mosaic attenuation on inspiratory chest CT that is difficult for visual estimation. The primary aim of this study was to develop an automated tool to quantify mosaic attenuation on inspiratory CT and air trapping on paired expiratory CT. Secondary aims included comparing CT-derived parameters with PFT measurements and dyspnea scores. Methods: This retrospective analysis of noncontrast chest CTs from 2 academic hospitals was conducted between January 1, 2018, and December 31, 2019. Patients with paired inspiratory and expiratory CT chest scans and PFTs performed on the same day were included. A chest radiologist manually annotated lung parenchyma in a reference cohort. Several histogram-based metrics were computed from lung parenchymal CT values, with the maximum peak position showing the strongest correlation with manually determined thresholds. This threshold, derived from the histogram peak, was applied in the adaptive thresholding process to quantify mosaic attenuation and air trapping. Results: We analyzed 267 patients (65.5% female, median age 68). Most exhibited normal physiological patterns (44.0%). Patients with elevated residual volume (RV) by PFTs (28.1%) had significantly higher inspiratory CT mosaic attenuation (1629.6 vs. 1311.5 mL, P <0.01) and expiratory CT air trapping volumes (1413.7 vs. 886.2 mL, P <0.01). Correlation analyses demonstrated strong relationships between CT-derived mosaic attenuation and air trapping measures and RV. The correlation with PFT parameters was even stronger in subgroup analyses in patients with obstructive PFT patterns. These models had good predictive ability for an abnormal RV (AUC of 0.92, sensitivity of 72.4%, and specificity of 92.0%) and clinical utility based on good correlation with the mMRC dyspnea score ( r =0.71; 95% CI: 0.65-0.77). Conclusions: This automated adaptive thresholding on inspiratory and expiratory chest CT scans showed a high correlation of lung volume and air trapping parameters with PFTs, revealing that measures of lung function have a complex interplay with air trapping.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Objective To update, synthesise and provide meta-analytical evidence of the associations between domain-specific physical activity (PA) and mental health and mental ill-health outcomes. Design Systematic review and multilevel meta-analysis. Data sources In March 2024, we systematically searched five databases. Eligibility criteria Methods employed replicated those of a previous review in 2017. All studies examining associations between domain-specific PA and specified mental health outcomes were included. Results 372 studies met inclusion criteria and 361 were included in the meta-analysis. Across the 372 studies (combined sample size of 3 323 711), 338 examined leisure-time PA, 54 work-related PA, 72 transport-related PA, 44 household PA, 5 school sport and 8 physical education. Multilevel meta-analyses showed that leisure-time PA (r=0.205, 95% CI 0.157 to 0.253), transport-related PA (r=0.138, 95% CI 0.042 to 0.231) and household PA (r=0.096, 95% CI 0.025 to 0.165) were positively associated with mental health . Leisure-time PA (r=−0.149, 95% CI −0.189 to –0.11) and school sport (r=−0.096, 95% CI −0.115 to –0.077) were inversely associated with mental ill health . However, work-related PA (r=0.134 95% CI 0.069 to 0.199) was positively associated with mental ill health . Conclusion The direction of the association between PA and mental health/mental ill health is dependent on the domain in which PA occurs. Promoting PA for leisure purposes is likely to yield the greatest benefits for both promoting mental health and preventing mental ill health. As such, leisure-time PA should be prioritised in messaging, guidelines and interventions/programmes designed to support mental health through PA. PROSPERO registration number CRD42024510303.