Citations

Objectives/Goals: Our study’s objective is to evaluate RadOnc-GPT, a GPT-4o powered LLM, in generating responses to in-basket messages related to prostate cancer treatment in the Radiation Oncology department. By integrating it with electronic health record (EHR) systems, the goal is to assess its impact on clinician workload, response quality, and efficiency in healthcare communication. Methods/Study Population: RadOnc-GPT was integrated with patient EHRs from both hospital-wide and radiation-oncology-specific databases. The study examined 158 pre-recorded in-basket message interactions from 90 non-metastatic prostate cancer patients. Quantitative natural language processing analysis and two randomized single-blinded grading studies, involving four clinicians and four nurses, were conducted to evaluate RadOnc-GPT’s response quality in completeness, correctness, clarity, empathy, and estimated editing time. Response times were measured to estimate the time saved for clinicians and nurses. The study population included patient messages across all phases of care (pre-, during, and post-treatment) for those undergoing radiotherapy. Results/Anticipated Results: In the single-blinded grader study, clinician graders evaluated 316 responses (158 from human care teams and 158 from RadOnc-GPT). Results showed RadOnc-GPT outperformed human responses in empathy and clarity, while humans excelled in completeness and correctness. Sentiment analyses using TextBlob and VADER revealed RadOnc-GPT responses had a positive mean score of 0.25, whereas human responses clustered around neutral. VADER analysis indicated a high median score for RadOnc-GPT, nearing 1.0, reflecting predominantly positive sentiment, while human responses displayed a broader sentiment range, indicating sensitivity to context. Clinicians averaged 3.60 minutes (SD 1.44) to respond, compared to 6.39 minutes (SD 4.05) for nurses, highlighting RadOnc-GPT’s efficiency in generating timely responses. Discussion/Significance of Impact: RadOnc-GPT effectively generated responses to individualized patient in-basket messages, comparable to those from radiation oncologists and nurses. While human oversight is still necessary to avoid errors, RadOnc-GPT can speed up response times and reduce pressure on care teams, shifting their role from drafting to reviewing responses.

Diagnosing pulmonary rheumatoid nodules (RN) is challenging because they are rare and share clinical, radiologic, and histopathologic features with other necrotizing granulomatous diseases such as infectious granulomas (IG) and granulomatosis with polyangiitis (GPA). Herein, we revisit the histopathologic features of RN and the findings in the adjacent lung tissue, in comparison with IG and GPA, to identify distinguishing features. Twenty-eight cases with surgically resected RN evaluated at our institution (1991 to 2024), 33 IG (10 mycobacterial infection, 10 histoplasmosis, 13 coccidiomycosis), and 10 GPA cases were included in the study. All available slides with H&E and special stains were reviewed for various histologic parameters within the nodules and in surrounding lung tissue. Many histopathologic features of RN overlap with the necrotizing granulomas seen in infections and GPA. However, some findings in the adjacent lung tissue showed significant differences. The lack of airspace granulomas/non-necrotizing granuloma and the absence of necrotizing vasculitis in the setting of RN can help to differentiate between infection cases and GPA, respectively. Given their considerable overlap, correlation with clinical context, serologic and microbiologic studies, as well as careful evaluation of special stains is crucial in the diagnosis of RN.

Abstract Background In breast cancer patients treated with pencil‐beam scanning proton therapy (PBS), the increased linear energy transfer (LET) near the end of the proton range can affect nearby ribs. This may associate with a higher risk of rib fractures. Purpose To study the effect of LET on rib fracture in breast cancer patients treated with PBS using a novel tool of dose‐LET volume histogram (DLVH). Methods From a prospective registry of patients treated with post‐mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients who did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. The DLVH index, V (d, l), defined as volume( V ) of the structure with at least dose(d) and dose‐averaged LET (l) (LETd), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V (d, l) and the observed fracture at each combination of d and l . The p ‐value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p ‐value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5–14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p ‐value map demonstrated larger V (0–36 Gy[RBE], 4.0–5.0 keV/µm) in patients experiencing fracture ( p < 0.1). For example, the p ‐value for V (30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusion In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LETd may result in an increased risk of rib fracture.

Abstract Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdcscid Il2rgtm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1+CD4+ peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh- like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. Tfh/Tph cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies and lymphopenia-induced proliferation (LIP) have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

ABSTRACTBackgroundWe investigated mental health diagnoses (MHDs) in mycosis fungoides (MF) patients compared to the general population, evaluated risk factors, and studied survival outcomes in a large population database.MethodsMF patients from the Utah Cancer Registry diagnosed from 2001 to 2014 were matched with up to five general population individuals from the Utah Population Database. MHDs were retrospectively tracked in both populations (median follow‐up = 6.67 years). Risk factors for new MHDs among MF patients were studied using the Cox proportional hazards model. Overall survival (OS) and disease‐specific survival (DSS) were assessed using Kaplan–Meier analysis.ResultsThe incidence of anxiety disorders (HR = 1.99, 95% CI [1.16, 3.42]) and delirium/dementia disorders (HR = 2.43, 95% CI [1.05, 5.63]) was higher among MF patients than the matched general population. Among MF patients, Charlson Comorbidity Index (CCI) ≥ 2 and BMI < 18 kg/m2 were risk factors for new anxiety disorders. Radiation therapy, CCI ≥ 2, and female gender were risk factors for new delirium/dementia disorders. The 15‐year OS was worse for MF patients with versus without an MHD (36% vs. 81%, HR 2.62, 95%CI [1.24, 5.65]). The 15‐year DSS also worsened for MF patients with versus without an MHD (63% vs. 97%, HR 6.55, 95%CI [1.64, 26.2]).ConclusionsMF patients developed anxiety and delirium/dementia disorders at rates above the general population, and MHDs correlated with worse DSS and OS. Careful mental health monitoring may be an actionable step towards improving health‐related quality of life in this population.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium amplifies circadian rhythms and is neuroprotective, indicating mechanistic overlap across cellular systems. We examined the role of neuroprotection in determining lithium response and how circadian clock genes regulate apoptosis. In stem‐cell‐derived neuronal progenitor cells (NPCs) from BD patients, and in immortalized mouse hippocampal neurons, lithium was neuroprotective against staurosporine (STS)‐induced apoptosis. However, neuroprotection did not distinguish lithium‐responders (Li‐Rs) from nonresponders (Li‐NRs). Disruption of selected clock genes—period circadian regulator 1 ( PER1 ), basic helix–loop–helix ARNT like 1 ( ARNTL , also known as BMAL1 ), and nuclear receptor subfamily 1 group D member 1 ( NR1D1 ; also known as REV‐ERBα )—with small interfering RNA (siRNA) had distinct effects on apoptosis in mouse neurons and human NPCs. In BD patient NPCs, reduced expression of PER1 and BMAL1 increased apoptosis more in Li‐NR NPCs vs. Li‐R NPCs. Reduced expression of REV‐ERBα caused more extensive apoptosis in BD vs. control NPCs, but did not distinguish Li‐Rs vs. Li‐NRs. The REV‐ERB agonist GSK4112 was neuroprotective in mouse neurons and control NPCs, but did not reduce apoptosis in BD NPCs. Simultaneous treatment of NPCs with STS and GSK4112 revealed BD‐ and Li‐R‐associated differences in apoptosis‐related gene expression. In summary, the pharmacological effects of lithium in promoting neuroprotection are not sufficient to distinguish between Li‐Rs and Li‐NRs. However, genetic and pharmacological manipulations of the circadian clock reveal distinct roles in apoptosis in BD patient NPCs, some of which do distinguish Li‐Rs and Li‐NRs. We conclude that genetic disruption of cellular circadian clocks may predispose neurons to apoptosis preferentially in BD and/or Li‐NR. These findings imply that differences in BD between Li‐Rs/Li‐NRs primarily arise from defining biological characteristics of patient subgroups, not from distinct pharmacodynamic factors following lithium treatment.

Abstract Introduction COVID-19, a global health crisis, prompted rapid vaccine development. Bivalent vaccines by Pfizer-BioNTech and Moderna target both original and Omicron strains. Despite vaccination efforts, the persistence of adverse events underscores the importance of ongoing safety monitoring. Method We collected COVID-19 bivalent vaccine adverse event reports from the Vaccine Adverse Event Reporting System (VAERS) (September 15, 2022, to September 1, 2023). The Medical Dictionary for Regulatory Activities (MedDRA) categorized reported symptoms into corresponding concepts. Statistical analyses included zero-truncated Poisson regression for estimating symptom rates, logistic regression for identifying risk factors, and Spearman correlation for assessing non-parametric relationships between adverse events in different System Organ Classes (SOCs). Results Our analysis of COVID-19 bivalent vaccine adverse events identified significant correlations between SOCs. Notably, a positive correlation (ρ = 0.3) linked Infections (SOC 1) with Respiratory disorders (SOC 13), while a negative correlation (ρ=-0.3) connected Investigations (SOC 23) with Injury (SOC 24). Zero-truncated Poisson modeling estimated an average of 6.179 symptoms per individual, varying by age, gender, and vaccine. Gender and age significantly influence reported adverse events associated with COVID-19 bivalent vaccines. Females generally experienced higher odds for most SOCs compared to males, except for cardiac and product-related issues. Older adults showed a higher likelihood of symptoms across various SOCs, while children and adolescents had distinct susceptibility patterns. Additionally, Moderna and Pfizer vaccines were associated with different SOCs, with Moderna linked mainly to immune and skin disorders and Pfizer associated primarily with cardiac and metabolic issues. Conclusion In conclusion, our study aligned self-reported items with widely-accepted medical terminology and rigorously analyzed adverse events following COVID-19 bivalent vaccine using advanced statistical methods. The significant findings provide crucial insights, guiding evidence-based strategies and interventions for vaccine safety.

Abstract Gallium-68-DOTA-Tyr3-Octreotate (Ga-68-DOTATATE) positron emission tomography/computed tomography (PET/CT) has recently been shown to have utility for the localization of phosphaturic mesenchymal tumors (PMT) that cause tumor-induced osteomalacia (TIO), a rare renal phosphate-wasting disorder. The aim of this study was to evaluate the accuracy of Ga-68-DOTATATE PET/CT in localizing PMTs causing TIO and to compare its performance with other functional imaging modalities. Prospective recruitment and retrospective chart review of 30 patients with suspected TIO and evaluation with Ga-68-DOTATATE PET/CT between 2017 and 2023 were conducted at a tertiary medical center. True positive (TP) lesions were defined by histological confirmation of PMT. There were 22 TP lesions identified among 18 patients, with a mean SUVmax of 16.8 (±10.9). Sensitivity, specificity, and accuracy of Ga-68-DOTATATE PET/CT were 85.7%, 77.8%, and 83.3% on patient-based analysis, and 84.6%, 56.3%, and 73.8% on lesion-based analysis. Lesions such as subacute fractures, parathyroid adenomas, thymus uptake, vertebral hemangiomas, bone enchondromas, liver hemangiomas, and avascular necrosis were some of the pitfalls in interpretation. Ga-68-DOTATATE PET/CT led to a significant impact on clinical management in 24 (80%) of patients. The presence of DOTATATE-avid fractures was significantly associated with a localizing scan on univariable (OR 15.0, 95% CI 2.80-110, p = .001) and multivariable analysis (OR 9.45, 95% CI 1.33-98.4, p = .003). Ga-68-DOTATATE PET/CT has good accuracy for the localization of TIO, with superior sensitivity compared to F-18-FDG PET/CT. This significantly impacted clinical treatment decisions. Although DOTATATE-avid fractures may be a source of false positives, they may also indicate a higher probability of a localizing study.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.