Citations

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) arises predominantly from activating KRAS mutations, yet individual genetic variants differ markedly in signaling output and clinical impact. G12D, the most prevalent variant, strongly drives oncogenic programs, whereas G12R signals less efficiently through the AKT and ERK pathways and is associated with longer patient survival than G12D-driven PDAC. Methods: To elucidate how these differences influence early cellular transformation, we expressed a panel of KRAS mutants in non-cancerous pancreatic ductal epithelial cells as a model of early PDAC initiation and profiled transcriptional and phospho-proteomic responses. We next examined whether epigenetic differences translate into mutation-specific changes in nuclear organization using quantitative imaging of G12D- and G12R-expressing nuclei at 24 and 48 h. Results: Each variant established a unique regulatory program enriched for chromatin remodelers, histone modifiers, and nuclear structural factors, indicating that variant-specific KRAS signaling rapidly develops divergent epigenetic states. Integrated transcriptomic and phospho-proteomic analyses identified G12D and G12R as the most divergent variants. G12D induced pronounced nuclear remodeling, including increased nuclear size, irregular morphology, and reorganization of the nucleolus and spliceosome, consistent with extensive chromatin and transcriptional reprogramming. In contrast, G12R elicited a weaker response, with minimal or delayed structural changes. Conclusions: Together, these findings demonstrate that KRAS mutational context in pancreatic ductal epithelial cells shapes early transcriptional reprogramming that actively remodels nuclear architecture and nuclear sub-compartments. This work establishes nuclear structural remodeling as a structural state of KRAS-driven epigenetic dysregulation during PDAC initiation.

Abstract Objectives Diagnosing adult T-cell leukemia/lymphoma (ATLL) remains challenging due to its clinical and histopathologic heterogeneity. While HTLV-1 serology is a key diagnostic criterion, it is often unavailable at the time of diagnosis and does not confirm viral integration in tumor cells. The HTLV-1–encoded HBZ RNA is a reliable diagnostic biomarker for ATLL. We evaluated the diagnostic performance of RNAscope in situ hybridization (ISH) for HBZ RNA in formalin-fixed, paraffin-embedded (FFPE) tissues to distinguish ATLL from other T-cell lymphomas. Methods HBZ ISH was evaluated in 72 cases, including 52 ATLLs and 20 non-ATLL T-cell lymphomas, to determine diagnostic sensitivity and specificity, interobserver agreement, interlaboratory reproducibility, and comparison with digital gene expression. Results This assay demonstrated 86.5% sensitivity and 100% specificity, with sensitivity improving to 97% when excluding bone marrow clot sections and FFPE blocks older than 5 years. Interobserver agreement among 3 pathologists was excellent (κ = 0.92, percent agreement: 94%). Interlaboratory reproducibility of HBZ ISH was high, with 93% to 95% concordance across these Clinical Laboratory Improvement Amendments–certified laboratories. HBZ RNA ISH–positive cases demonstrated significantly higher HBZ gene expression levels by digital gene expression profiling. Conclusions We established HBZ ISH as a reliable tissue-based surrogate for HTLV-1 infection in ATLL. This assay will enhance diagnostic accuracy, expedite definitive diagnosis, and improve patient selection for targeted therapies and clinical trials, particularly in regions with a high prevalence of HTLV-1.

Abstract Context Osteoanabolic therapy for osteoporosis should be followed by antiresorptive treatment (“consolidation”) to preserve bone mass. Although osteoanabolic therapy is increasingly endorsed for primary fracture prevention, real-world implementation of consolidation remains unknown. Objective To assess patterns and predictors of timely consolidation after osteoanabolic therapy for primary fracture prevention. Methods We conducted a retrospective cohort study using US commercial, Medicare Advantage, and traditional Medicare claims data. Adults aged ≥50 years who initiated romosozumab, teriparatide, or abaloparatide between 2011 and 2022 were included. The primary outcome was timely consolidation, defined as initiation of an antiresorptive medication within 3 months after osteoanabolic therapy. Secondary outcomes included delayed consolidation (initiation >3 months after completion), osteoanabolic restart following a treatment gap, and no consolidation therapy. We further distinguished participants who completed the full osteoanabolic course, defined as ≥12 months for romosozumab and ≥18 months for teriparatide or abaloparatide. Multivariable logistic regression models were used to identify predictors of consolidation patterns. Results Among 15 389 patients (mean age 70.6 years; 89% women; 85% White), 30% completed osteoanabolic therapy (median, 12.9 months for romosozumab; 23.4 months for teriparatide/abaloparatide). Overall, 25% had timely consolidation, 24% delayed consolidation, 12% restarted osteoanabolics, and 40% had no consolidation; only 12% completed therapy with timely consolidation. Timely consolidation was more likely with endocrinology (OR 1.31; 95% CI, 1.17-1.48) or rheumatology (OR 1.45; 1.30-1.62) vs primary care, and less likely among patients aged 50-64 years (OR 0.67; 0.58-0.77) vs 65-74, those enrolled in Medicare Advantage (OR 0.85; 0.74-0.98) vs traditional Medicare, or those recently hospitalized (OR 0.88; 0.80-0.97). Odds increased over time (OR 4.27; 3.63-5.05 for 2021 vs 2011 starts). Conclusion Only 1 in 4 patients received timely consolidation therapy after osteoanabolic treatment, and 1 in 8 completed the full sequence. Strategies to improve consolidation in primary fracture prevention are needed.

Abstract Background Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. Methods The Neuroendocrine Tumors–Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record–based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. Results Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P < .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). Conclusions This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.