Citations

Abstract Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

The systemic impairment that accompanies liver cirrhosis is known to carry a significant burden on death and postoperative complications in cardiovascular interventions. This review analyzes the impact of liver cirrhosis on short‐ and long‐term outcomes after cardiac surgery and percutaneous procedures, providing an evidence‐based guidance in the decision‐making process and perioperative management of these patients. Several parameters should be considered by the heart teams when assessing eligibility, indications for intervention, and perioperative management of these patients. Life expectancy, long‐term procedural outcomes, Child–Pugh or the Model for End‐Stage Liver Disease score, presence of gastroesophageal varices and hepatic venous pressure gradient were extrapolated as the main determinants in decision making in patients with cirrhosis. Assessment and treatment of gastroesophageal varices is mandatory. Hepatic venous pressure gradient values >20 mm Hg preclude patients from a surgical approach. Considering the poor prognosis of advanced liver cirrhosis, futile treatments should be avoided. A multidimensional heart team approach involving surgical, cardiologic, anesthesiologic, hepatological, and medical considerations is recommended.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Abstract Background Despite the high precision of deep learning models on internal tests on CT, their effectiveness often drops on external validation due to artifacts caused by patient motion and implants like metal or silicone that were not accounted for in the carefully curated training data. Potential wide categories of “unknown” anomalies within a CT exam makes training a supervised model for out‐of‐distribution (OOD) identification impractical, especially when considering unseen external data. Purpose To develop an artificial intelligence (AI) model to detect and identify anomalies/OOD data in abdominal–pelvis CT exams for the purpose of improving the performance of downstream applications. Methods Our proposed 2D and 3D generative architecture receives the third lumbar vertebra (L3) slice (slice‐level model) or all the slices from the series (series‐level model), generates a reconstruction and the secondary part of our architecture—anomaly score computation block, computes the anomalies pixels/voxels (slice‐level/series‐level) to identify anomalous L3‐slices/volumes (slice‐level/series‐level). We trained on data from over 2850 abdominal–pelvis CT volumes from adults over age 50 years collected throughout multiple Mayo Clinic campuses (60% female; mean age: 66.9, 92.4% non‐Hispanic White) and tested on a prospective test set of 544 CTs from July 2024 (47.3% female; mean age: 70.9, 94% non‐Hispanic White) as well as an external test set. Results We found that while traditional methods show moderate success, our generative models—Vector Quantized Variational Autoencoder (VQVAE) and Vision Transformer‐Masked Autoencoder (VIT‐MAE)—deliver excellent results with negligible false positives (FPs) and are also superior in identifying varied types of OOD samples. Prospective analysis showed the model was able to handle the under‐documentation of anomaly in radiology reports with 86.11% true positive (TP) rate. We also performed external validation using the publicly available AbdominalCT‐1k dataset, which contains 1062 CT scans compiled from several existing benchmark datasets. The model achieved a 75.26% TP rate, while the 24.7% FP rate was primarily triggered by anomalies located outside the body. Conclusions The proposed method can be leveraged to detect both intra‐ and interclass OOD data from abdominal CT images and can assess the quality of CT datasets to provide actionable insights. This workflow is particularly valuable for nonshareable healthcare collaborations, where it can be deployed as a service within local firewalls for automated dataset curation without prior knowledge about the OOD types. The implementation of the algorithm is available in the GitHub: https://github.com/gokul‐ramasamy/implant_detection.git .

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, Na V 1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

BACKGROUND AND OBJECTIVES: En bloc spondylectomies are essential for controlling malignant spinal tumors, but existing classification systems are often complex and impractical. This study introduces the Column, Line-of-Sight, Margins, Ring (CLiMR) framework, a novel system simplifying and standardizing en bloc spondylectomy planning and classification. METHODS: A retrospective review of patients who underwent single- or multistage en bloc spinal tumor resections was conducted at a single academic center (October 2019-December 2024). The CLiMR framework assigns scores to 4 components: Column (osteotomies/diskectomies for tumor release), Line-of-Sight (approach for circumferential access), Margin (adjacent structures sacrificed), and Ring (size of the vertebral ring window for safe delivery of neural tissue). Scores were applied using operative notes and imaging. RESULTS: Column scores ranged from 0.5 to 4.5. Of the patients included, 40.9% underwent sagittal split osteotomies, 22.7% radical diskectomies, 18.2% horizontal osteotomies, and the remaining 18.2% combinations of previous osteotomies . A posterior-only approach (Line-of-Sight score = 1) was used in 45.4% of cases, whereas 45.4% required a multistage approach (score = 2). Margin scores reflected increasing morbidity: 31.8% (n = 7) involving chest wall/pleura resection (grade 3), 40.9% (n = 9) requiring eloquent nerve sacrifice (grade 6), and 9.1% (n = 2) necessitating limb sacrifice (grade 7). The majority (86.4%, n = 19) of ring scores were grade 1, requiring laminectomies/facetectomies. The mean CLiMR score was 9.36 ± 2.43, with higher scores correlating with longer hospital stays (R = 0.64, P = .0012), longer case durations (R = 0.61, P = .0023), and increased blood loss (R = 0.40, P = .067). Patients with local recurrence, positive margins, or complications trended toward greater CLiMR scores. CONCLUSION: The CLiMR framework provides a novel, user-friendly method for planning and communicating en bloc spondylectomies. By addressing technical complexities and morbidity, CLiMR enables standardized assessment, facilitates surgical decision-making, and supports future research. This study demonstrates feasibility and lays the foundation for future validation studies.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.