Citations

OBJECTIVES: To develop the first core Critical Care Data Dictionary (C2D2) with common data elements (CDEs) to characterize critical illness and injuries. DESIGN: Group consensus process using modified Delphi approach. SETTING: Electronic surveys and in-person meetings. SUBJECTS: A multidisciplinary workgroup of clinicians and researchers with expertise in the care of the critically ill and injured. INTERVENTIONS: The Delphi process was divided into domain and CDE portions with each composed of two item generation rounds and one item reduction/refinement rounds. Two in-person meetings augmented this process to facilitate review and consideration of the domains and by panel members. The final set of domains and CDEs was then reviewed by the group to meet the competing criteria of utility and feasibility, resulting in the core dataset. MEASUREMENTS AND MAIN RESULTS: The 23-member Delphi panel was provided 1833 candidate variables for potential dataset inclusion. The final dataset includes 226 patient-level CDCs in nine domains, which include anthropometrics and demographics (8), chronic comorbid illnesses (18), advanced directives (1), ICU diagnoses (61), diagnostic tests (42), interventions (27), medications (38), objective assessments (26), and hospital course and outcomes (5). Upon final review, 91% of the panel endorsed the CDCs as meeting criteria for a minimum viable data dictionary. Data elements cross the lifespan of neonate through adult patients. CONCLUSIONS: The resulting C2D2 provides a foundation to facilitate rapid collection, analyses, and dissemination of information necessary for research, quality improvement, and clinical practice to optimize critical care outcomes. Further work is needed to validate the effectiveness of the dataset in a variety of critical care settings.

Abstract The intra- and inter-patient heterogeneity in high-grade glioma (HGG) continues to contribute to its poor prognosis. Clinical biopsies are often harvested from limited regions and typically are not image localized. Thus, they fail to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in tumor development. It is important to gain an understanding of these subpopulation ecologies, their spatial resolution, and interactions between them that may then be exploited for future therapeutic benefit. Further, these may differ by patient characteristics such as sex, age at diagnosis and treatment status. Using an ongoing image-localized biopsy collection protocol, we have so far evaluated the bulk transcriptomics of 202 multi-regional biopsies from 58 patients to characterize HGG heterogeneity. These samples were processed through Monocle, a reverse graph embedding algorithm that groups samples into states and orders them along developmental trajectories. Deconvolution methods were previously used to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample, which we have now overlaid on the Monocle graph. Monocle classified HGG into 4 main states along a three-pronged trajectory. These states reveal distinct population ecologies with associated enriched gene pathways. We also note significant immune pathway enrichments that differ between state and patient-reported sex. Together, these algorithms reveal a simple transcriptomic trajectory that helps us understand the development and evolution of HGG. Characterizing the in vivo diversity within and between high grade gliomas is important for understanding prognosis, stratifying future treatments and ultimately improving patient outcome.

Abstract Magnetic resonance imaging (MRI) is key to clinically managing brain tumor patients, however connecting the biology to imaging remains challenging. We previously developed a two-compartment model of MRI signal intensity to quantitatively estimate relative edema abundance from T2-weighted MRIs. Using this model, we previously identified the fatty acid metabolism (FAM) and oxidative phosphorylation (OxPhos) pathways as sex-distinct, with both pathways amplified for high edema in males and low edema in females. The purpose of this project was to further delineate sex-distinct biology associated with MRI-estimated brain tumor edema abundance. We analyzed 179 multiregional samples (Female: 75; Male: 104) from 55 high grade glioma patients (Female: 21; Male: 34) for bulk RNA-Seq. Patients’ pre-surgical multiparametric MRIs were preprocessed and segmented for abnormal regions and normal tissue. Utilizing the segmentations and preprocessed images we estimated the relative fractions of extracellular and intracellular space based on the edema mathematical model. Samples were characterized by their edema scores, which were analyzed using differential expression for high and low edema, gene set enrichment analysis (GSEA) using MSigDB hallmarks, and leading edge interpretation. Based on transcriptomic leading edge analyses of high and low edema samples from sex-separated cohorts, we identified common and sex-distinct enrichment of the FAM and OxPhos pathways underlying edema patterns. Of the OxPhos pathway leading edge genes, 45 were common, 36 were unique to females, and 66 were unique to males. Of the FAM pathway leading edge genes, 8 were common, 39 were unique to females, and 29 were unique to males. Notably, expression of both IDH1 and IDH2 were increased for males in regions of high edema in the OxPhos pathway. IDH3a was decreased for females in regions of low edema in the OxPhos pathway. These data suggest that there may be sex-distinct metabolism underlying MRI measurable edema formation.

Abstract Trigeminal neuralgia (TN) is characterized by excruciating facial pain usually caused by neurovascular compression of the trigeminal nerve roots. TN can be treated medically or invasively. Microvascular decompression is the procedure of choice and usually results in complete symptom relief. During surgical decompression, Teflon can be placed between the offending vessel and the nerve root entry zone. In some cases, chronic Teflon-related inflammation can cause recurrent TN, which might lead to additional surgical intervention. We present imaging and histopathological correlation of a patient presenting with intractable recurrent TN approximately 2 years after microvascular decompression with Teflon implant.

Abstract BACKGROUND Leptomeningeal disease (LMD) carries poor prognosis with an average survival of 3-6 months after diagnosis. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for delivery of intrathecal chemotherapy (IC) and disease monitoring but are not widely used. Intraventricular administration of chemotherapy may be associated with superior efficacy and improved patient comfort. The purpose of this study was to assess safety and efficacy of IC and disease monitoring via OR in routine clinical practice. MATERIAL AND METHODS Patients who received at least one administration of IC via OR for LMD between 2017 and 2022 were included. Demographics, treatment type, complications and outcomes were recorded. RESULTS We identified 22 patients (17 females, 5 males) with mean age 50.9 ± 14.8 years. The primary tumors were: breast (12), leukemia (3), ovarian carcinoma (3), CNS lymphoma (1), urothelial carcinoma (1), spinal melanocytoma (1), and high-grade glioma (1). A total of 208 OR injections were performed [median was 9 OR injections per patient, interquartile range (IQR) (5, 13)]. Five patients (23%) experienced mild adverse events of grade 2 or lower by Common Terminology Criteria for Adverse Events. Overall risk of adverse event from injection was 3.4% (7/208). Eight patients (36.3%) converted into negative CSF cytology (median 1 month following first injection), and 18 patients (82%) had clinical or radiological progression of their LMD (median 2 months following first injection). Eleven patients (50%) died of their LMD during follow-up. Median OS and PFS from the first injection were 5.3 months [95% CI 4.8-NE (not estimable)] and 4.3 months [95% CI 1.8-16.0], respectively. CONCLUSION Use of OR in routine clinical practice is a safe and feasible option and should be strongly considered for treatment and frequent disease monitoring of patients with LMD, especially in the era of circulating tumor cells analysis. The median OS in our cohort is comparable to prior published series.

Abstract Background Our institution is facing increasing demand for oncology testing that requires high quality DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. The current DNA extraction workflow involves a time and labor-intensive manual process that limits our ability to accommodate increasing downstream clinical testing volumes. We evaluated the KingFisher (KF) Flex utilizing Autolys M Tubes and the MagMAX FFPE DNA/RNA Ultra Kit as a possible high-throughput, automated DNA isolation workflow option that would decrease hands-on time and be conducive to volume growth without the need for additional staff. Methods DNA from 52 FFPE tissue samples (n=24 unique cases previously extracted by the current “manual method”) were extracted using Autolys M tubes, the MagMAX FFPE DNA/RNA Ultra Kit, and the KF Flex (Thermo Fisher Scientific Waltham, MA) over 4 “automated method” runs. Method modifications to the published procedure were introduced over the runs to determine any effects on DNA quality/quantity. Timings were taken during each run to compare hands-on and total run time against that of the manual method. Precision experiments were performed by extracting 4 replicates of sample on a single run (intra-assay precision) and 2 samples from 2 cases over 2 runs (inter-assay precision). Three cases were processed using varying tissue input levels to assess input-yield correlation. DNA yield was measured using HS dsDNA Qubit (Thermo Fisher Scientific, Waltham, MA). A subset of samples was tested by digital droplet PCR (ddPCR) (n=10), chromosomal microsomal microarray (CMA) (n=1), and next-generation sequencing (NGS) (n=3). Variants and QC metrics of the KF DNA were compared to those of the manual method DNA. Results The average total DNA yield was 3% lower from samples extracted following the manufacturer recommended KF procedure compared to matched samples extracted using the manual method (n=28 samples from 23 unique cases). A CV of 2.8% was observed in an intra-assay experiment (n=4 replicates from 1 case) and 3.0% in an average inter-assay experiment (n=2 replicates from 2 cases). There was a direct correlation between the tissue input amount (4 amounts of varied tissue input) and the total DNA yield (n=3 samples). We observed concordant fractional abundance values for ddPCR samples and concordant variant detection for NGS and CMA samples. We did not see a significant difference in the quality metrics tracked for any of the downstream testing assays. Conclusions This evaluation demonstrated that, as compared to our manual method, the automated method resulted in comparable DNA yields and downstream assay results. The incorporation of this automation would significantly increase our FFPE DNA extraction capacity without requiring additional staff while reducing hands-on time per run by about six hours. We would also be able to reduce ergonomic hazards related to tube cap manipulation, eliminate use of hazardous reagents, and leverage the plate format to better integrate extracted DNA into our clinical sample preparation workflows. These operational benefits highlight the value of automating high-throughput workflows.