Citations

Abstract In radiotherapy, 2D orthogonally projected kV images are used for patient alignment when 3D-on-board imaging(OBI) unavailable. But tumor visibility is constrained due to the projection of patient’s anatomy onto a 2D plane, potentially leading to substantial setup errors. In treatment room with 3D-OBI such as cone beam CT(CBCT), the field of view(FOV) of CBCT is limited with unnecessarily high imaging dose, thus unfavorable for pediatric patients. A solution to this dilemma is to reconstruct 3D CT from kV images obtained at the treatment position. Here, we propose a dual-models framework built with hierarchical ViT blocks. Unlike a proof-of-concept approach, our framework considers kV images as the solo input and can synthesize accurate, full-size 3D CT in real time(within milliseconds). We demonstrate the feasibility of the proposed approach on 10 patients with head and neck(H\&N) cancer using image quality(MAE:<45HU), dosimetric accuracy(Gamma passing rate(2%/2mm/10%):>97%) and patient position uncertainty(shift error:<0.4mm). The proposed framework can generate accurate 3D CT faithfully mirroring real-time patient position, thus significantly improving patient setup accuracy, keeping imaging dose minimum, and maintaining treatment veracity.

This case report describes Osler nodes and Janeway lesions on a man in his 70s.

The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

Abstract Objectives ChatGPT (OpenAI, San Francisco, CA) has shown impressive results across various medical examinations, but its performance in kidney pathology is not yet established. This study evaluated proficiencies of GPT-4 Vision (GPT-4V), an updated version of the platform with the ability to analyze images, on kidney pathology questions and compared its responses with those of nephrology trainees. Methods Thirty-nine questions (19 text-based questions and 20 with various kidney biopsy images) designed specifically for the training of nephrology fellows were employed. Results GPT-4V displayed comparable accuracy rates in the first and second runs (67% and 72%, respectively, P = .50). The aggregated accuracy, however—particularly, the consistent accuracy—of GPT-4V was lower than that of trainees (72% and 67% vs 79%). Both GPT-4V and trainees displayed comparable accuracy in responding to image-based and text-only questions (55% vs 79% and 81% vs 78%, P = .11 and P = .67, respectively). The consistent accuracy in image-based, directly asked questions for GPT-4V was 29%, much lower than its 88% consistency on text-only, directly asked questions (P = .02). In contrast, trainees maintained similar accuracy in directly asked image-based and text-based questions (80% vs 77%, P = .65). Although the aggregated accuracy for correctly interpreting images was 69%, the consistent accuracy across both runs was only 39%. The accuracy of GPT-4V in answering questions with correct image interpretation was significantly higher than for questions with incorrect image interpretation (100% vs 0% and 100% vs 33% for the first and second runs, P = .001 and P = .02, respectively). Conclusions The performance of GPT-4V in handling kidney pathology questions, especially those including images, is limited. There is a notable need for enhancement in GPT-4V proficiency in interpreting images.

AbstractBackgroundWith modern treatment paradigms, olfactory neuroblastoma (ONB) has favorable overall survival (OS); however, the incidence of recurrence remains high. The primary aims of this study were to delineate the prognosis of recurrence of ONB and explore how recurrence subsites are associated with OS, disease‐specific survival (DSS), and further recurrence.MethodsA retrospective chart review of ONB cases from nine academic centers between 2005 and 2021 was completed. Tumor characteristics, recurrence subsites, timelines to recurrence, additional recurrences, and survival estimates were determined using descriptive and time‐to‐event analyses.ResultsA final cohort of 233 patients was identified, with 70 (30.0%) patients recurring within 50.4 (standard deviation ±40.9) months of diagnosis on average, consisting of local (50%), neck (36%), intracranial (9%), and distant (6%) recurrence. Compared with subjects without recurrence, patients with recurrence had significantly different primary American Joint Committee on Cancer T stage (p < 0.001), overall stage (p < 0.001), and modified Kadish scores (p < 0.001). Histopathology identified that dural involvement and positive margins were significantly greater in recurrent cases. First recurrence was significantly associated with worse 5‐year DSS (hazard ratio = 5.62; p = 0.003), and subjects with neck or local recurrence had a significantly better DSS compared to intracranial or distant recurrence.ConclusionsRecurrent cases of ONB have significantly different stages and preoperative imaging factors. Patients with local or neck recurrence, however, have better DSS than those with intracranial or distant recurrence, independent of initial tumor stage or Hyams grade. Identifying specific factors that confer an increased risk of recurrence and DSS is important for patient counseling in addition to surveillance planning.

Abstract In this study, we tested a novel approach of “repurposing” a biomarker typically associated with breast cancer for use in melanoma. HER2/neu is a well characterized biomarker in breast cancer for which effective anti-HER2/neu therapies are readily available. We constructed a lentivirus encoding c-erb-B2 (the animal homolog to HER2/neu). This was used to transfect B16 melanoma in vitro for use in an orthotopic preclinical mouse model, which resulted in expression of c-erb-B2 as a neoantigen target for anti-c-erb-B2 monoclonal antibody (7.16.4). The c-erb-B2-expressing melanoma was designated B16/neu. 7.16.4 produced statistically significant in vivo anti-tumor responses against B16/neu. This effect was mediated by NK-cell antibody-dependent cell-mediated cytotoxicity. To further model human melanoma (which expresses <5% HER2/neu), our c-erb-B2 encoding lentivirus was used to inoculate naïve (wild-type) B16 tumors in vivo, resulting in successful c-erb-B2 expression. When combined with 7.16.4, anti-tumor responses were again demonstrated where approximately 40% of mice treated with c-erb-B2 lentivirus and 7.16.4 achieved complete clinical response and long-term survival. For the first time, we demonstrated a novel strategy to repurpose c-erb-B2 as a neoantigen target for melanoma. Our findings are particularly significant in the contemporary setting where newer anti-HER2/neu antibody-drug candidates have shown increased efficacy.

Importance Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P &amp;lt; .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

Abstract Rationale It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between −600 and −250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97–6.0; and RR per 4 μg ⋅ m−3 PM2.5, 1.43; 95% CI, 0.93–2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0–2.7). Conclusions Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene–environment interactions may influence prevalence of interstitial lung features in COPD.

Objective: Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR. Methods: We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA). Results: We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects. Conclusions: Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals.