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Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular-overgrowth disorder within the broader spectrum of PIK3CA -related overgrowth syndromes. Although clinical, radiologic, and orthopedic manifestations are well described, the histologic spectrum of KTS-associated pathology remains under-characterized. Clinicopathologic findings from 21 patients with clinically established KTS were reviewed, including 18 with longitudinal clinical follow-up and 3 consultation cases of rare malignant mesenchymal neoplasms. Cases were identified from institutional pathology and clinical databases, and available hematoxylin and eosin-stained sections and ancillary studies were reviewed. The cohort included 11 males and 10 females. Among the 18 clinically followed patients, 12 had limb length discrepancy or asymmetric limb overgrowth, 9 had documented deep vascular malformations, 4 had intra-articular/synovial malformations, and 10 underwent initial orthopedic evaluation or intervention before age 18. Orthopedic morbidity clustered into mechanical overgrowth-related, vascular malformation-related, and soft tissue/wound-related complications. Histologic findings included superficial and/or deep slow-flow vascular malformations, ulceration and granulation tissue, hemosiderin-laden reactive synovium, and destructive hemorrhagic arthropathy. Intra-articular disease recapitulated a hemophilic arthropathy-like pattern, with hemosiderotic synovitis, papillary synovial hyperplasia, and progressive joint destruction with loss of articular cartilage, exposed subchondral bone destruction and remodeling, all attributable to long-standing intra-articular hemorrhage. Three consultation cases showed malignant mesenchymal neoplasia, including 2 angiosarcomas. Recognition of these patterns is important for pathologists evaluating specimens from patients with known or suspected KTS, particularly when findings mimic hemophilic arthropathy, diffuse-type tenosynovial giant cell tumor, nonsyndromic vascular malformation, and/or end-stage destructive arthropathy.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in type 1 and type 2 diabetes. Although α-cell dysfunction also contributes to disease pathology, α-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas α-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in β-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes. Article Highlights Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.

Background/Objectives: To develop and evaluate a deep learning-based quality control system for Lumbar Spinal Digital Radiographs (LSDR), designed to automate and improve their evaluation and reduce reliance on manual reviews. Methods: This retrospective study utilized a deep learning workflow comprising image segmentation, feature extraction, and a classification model. The dataset, including anteroposterior (AP) and lateral (LAT) X-ray images, was expanded through data augmentation techniques. Four U-Net-based models were assessed: standard U-Net, Swin-UNet, Attention U-Net, and Attention U-Net with the weight map, with the latter selected for its superior performance. Extracted features, such as brightness, contrast, and anatomical positioning, were used in an XGBoost classifier, which was evaluated using mean intersection over union (mIoU), accuracy, sensitivity, specificity, and AUC. Results: The Attention U-Net with weighted attention outperformed the other models, achieving high mIoU scores in both AP and LAT views. The XGBoost classifier achieved the best performance in classifying images as “qualified” or “unqualified,” with an AUC of approximately 0.9, high accuracy, and balanced sensitivity and specificity. This approach effectively addressed class imbalances and improved model accuracy compared to traditional machine learning models such as MLP and SVM. Conclusions: The developed automated quality control system demonstrated potential for enhancing image quality, enhancing diagnostic reliability, and optimizing clinical workflow efficiency.

e12644 Background: Standard neoadjuvant therapy for HER2-positive early breast cancer combines multi-agent chemotherapy with HER2-targeted antibodies and is associated with substantial toxicity. HER2-directed antibody–drug conjugates (ADCs) may enable de-escalation. We compared efficacy and toxicity of neoadjuvant ADC-based regimens given without concurrent chemotherapy versus standard chemotherapy-based regimens, including by platinum use in the control arm. Methods: We searched PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science through December 18, 2024 for randomized controlled trials in early/locally advanced HER2-positive breast cancer. Eligible trials compared neoadjuvant ADC-based regimens without concurrent chemotherapy versus standard chemotherapy-based regimens. Outcomes were pathologic complete response (pCR; per trial definition), grade ≥3 adverse events (AEs), and treatment discontinuation. Odds ratios (ORs) were pooled and heterogeneity was summarized with I². Results: Nine randomized trials (n = 2,021; mean age 50.7±13.7) were included. There was no significant difference in pCR between groups (OR 0.93, 95% CI 0.62–1.40; I² = 59.8%). ADC-based regimens were associated with fewer grade ≥3 AEs (OR 0.30, 95% CI 0.11–0.84; I² = 91.5%). Treatment discontinuation did not differ (OR 1.10, 95% CI 0.39–3.12; I² = 85.8%). Findings were consistent when stratified by platinum use in the control regimen. Conclusions: In HER2-positive early breast cancer, neoadjuvant ADC-based regimens without concurrent chemotherapy achieve pCR comparable to standard chemotherapy while substantially reducing severe toxicity without increasing discontinuation, independent of platinum use. Confirmation in phase III trials with mature survival endpoints is needed.

3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .

ABSTRACT Background In chronic liver disease, fat and fibroinflammatory changes often coexist. However, their biomarkers, proton density fat fraction (PDFF) and T 1 , are typically assessed separately. Their reproducibility under mutual confounding remains unclear. Purpose To assess multicenter, multi‐vendor reproducibility of confounder‐corrected chemical shift‐encoded (CSE)‐MRI‐based PDFF mapping and MOLLI‐based T 1 mapping using a combined PDFF‐T 1 phantom. Study Type Prospective phantom study. Phantom Commercial PDFF‐T 1 Phantom (Model 725) with varying PDFF (0%–30%) and T 1 (200–1400 ms) values. Field Strength/Sequence 1.5 T and 3 T multi‐echo, three‐dimensional spoiled‐gradient‐echo (SGRE) sequence for PDFF mapping, and MOLLI sequence (5(3)3 acquisition scheme) using two‐dimensional SGRE readouts for T 1 mapping across four centers and vendors. Assessment PDFF and T 1 maps were acquired using standardized protocols. PDFF maps were reconstructed locally, while T 1 maps were generated using a centralized algorithm. All maps were quantitatively analyzed by a single radiologist using standardized region‐of‐interest placement. Phantom temporal stability was assessed at one center across five sessions over 9 months (baseline, retest, 1 week, 6 and 9 months). Statistical Tests Intraclass correlation coefficients (ICC), reproducibility coefficients (RDC), and linear regression analysis were used. A p value < 0.05 was considered statistically significant. Results PDFF showed overall excellent reproducibility (ICC = 0.987, RDC = 3.7%), with increased variability at higher T 1 values (RDC up to 7.9% at T 1 = 1400 ms). T 1 mapping showed good reproducibility in the absence of fat (RDC 16–161 ms at PDFF = 0%), but moderate to poor reproducibility in the presence of fat, with RDC increasing up to 1553 ms at PDFF 30%. Temporal stability was excellent ICC ≥ 0.998 for both PDFF and T 1 , and RDC of 1.1%–1.3% for PDFF and 52–57 ms for T 1 . Data Conclusion This phantom study demonstrated high reproducibility of PDFF, whereas T 1 reproducibility deteriorated at higher fat and T 1 levels, underscoring the need for fat‐corrected T 1 mapping for reliable assessment of fibroinflammatory changes. Evidence Level N/A. Technical Efficacy Stage 1.

ABSTRACT Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid neoplasms shaped by genetic lesions and immune dysregulation, both of which contribute to disease progression and poor outcomes. Existing prognostic systems, such as IPSS‐R and IPSS‐M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi‐center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia‐free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS‐R, IPSS‐M, and bi‐allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time‐dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS‐high cases demonstrated reduced cytotoxic T‐cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS‐high cases to multikinase and NF‐κB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction. Trial Registration: #201709072RINC, #202109078RINB, #202207050RINB