Citations

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.

AbstractPurposeTo systematically review the literature regarding machine learning in leg length discrepancy (LLD) and to provide insight into the most relevant manuscripts on this topic in order to highlight the importance and future clinical implications of machine learning in the diagnosis and treatment of LLD.MethodsA systematic electronic search was conducted using PubMed, OVID/Medline and Cochrane libraries in accordance with Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. Two observers independently screened the abstracts and titles of potential articles.ResultsA total of six studies were identified in the search. All measurements were calculated using standardized anterior‐posterior long‐leg radiographs. Five (83.3%) of the studies used measurements of the femoral length, tibial length and leg length to assess LLD, whereas one (16.6%) study used the iliac crest height difference to quantify LLD. The deep learning models showed excellent reliability in predicting all length measurements with intraclass correlation coefficients ranging from 0.98 to 1.0 and mean absolute error (MAE) values ranging from 0.11 to 0.45 cm. Three studies reported measurements of LLD, and the convolutional neural network model showed the lowest MAE of 0.13 cm in predicting LLD.ConclusionsMachine learning models are effective and efficient in determining LLD. Implementation of these models may reduce cost, improve efficiency and lead to better overall patient outcomes.Clinical RelevanceThis review highlights the potential of deep learning (DL) algorithms for accurate and reliable measurement of lower limb length and leg length discrepancy (LLD) on long‐leg radiographs. The reported mean absolute error and intraclass correlation coefficient values indicate that the performance of the DL models was comparable to that of radiologists, suggesting that DL‐based assessments could potentially be used to automate the measurement of lower limb length and LLD in clinical practice.Level of EvidenceLevel IV.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

Abstract Background Non-bacterial thrombotic endocarditis (NBTE) is a non-infectious condition characterized by thrombotic and/or inflammatory depositions involving the cardiac valves. It is a challenging diagnosis of exclusion. Purpose This study aimed to better characterize patients with pathologically proven NBTE and assess its clinical, echocardiographic characteristics and prognostic implications. Methods We retrospectively identified patients with pathology-proven NBTE at a single center. Patients with positive preoperative blood cultures, a history of active or treated infective endocarditis, or identification of valvular organisms by special stains were excluded from the study. Patients with pathology reports of valve perforation or chordal rupture were also excluded because of the high likelihood of an infectious etiology for these lesions. Results A total of 53 patients with NBTE (median age 57 years; 61% females) were identified. In this cohort, 22% had a history of malignancy, 30% had connective tissue disease, 32% had coronary artery disease, and 11% prior history of NBTE. Neurological events accounted for 18 (34%) of the presenting symptoms (TIA n=17, CVA n=9), while new valvular dysfunction in 7 (13%) and fever in 8 (15%) of patients. Five patients (9%) had NBTE involving more than one valve. NBTE involved the mitral valve in 64%, aortic valve in 38% prosthetic/mechanical valve in 11%, and tricuspid valve in 5%. NBTE was identified at the time of autopsy in 34% of patients. NBTE recurred in 3 patients during follow-up. Excluding patients diagnosed at the time of autopsy, 9% of patients died within 1 year of NBTE diagnosis. Conclusion NBTE was diagnosed pathologically in the presence of hyper-inflammatory states due to critical illness or immunological diseases. It was predominantly on the left side of the heart and was associated with embolic phenomena, either clinically or on imaging. Patients diagnosed with antemortem with NBTE have a high mortality in the first year (9%).

Objective Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices. Methods We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed. Results The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) ( P = .025) and selecting Wada with subdural grid/strips ( P = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers ( P = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P = .002). Significance In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors’ patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.

Objectives: The role of psychological factors in the clinical presentation and outcomes of treated is increasingly recognized in orthopaedic surgery. Particularly, in prearthritic hip disorders, young adult hip patients often have significant psychological undertones. Patient resiliency, as quantified by the brief resiliency scale (BRS), is a static patient characteristic and has been increasingly recognized for its potential role in pain and symptomatology. The purpose of the current study was to investigate the correlation between BRS and traditional hip patient-reported outcome measures (PROMs). Methods: A prospective multicenter cohort study of 696 patients undergoing femoroacetabular impingement (FAI) primary hip arthroscopy surgery was performed and utilized for the current study. Inclusion criteria are patients aged 14 to 45 years old with idiopathic FAI not caused by childhood disease. Exclusion criteria are previous ipsilateral hip procedures or disease processes such as neuromuscular disease or high-grade osteoarthritis. PROMs included the Patient-Reported Outcomes Measurement Information System (PROMIS) domains of pain interference, physical function, mobility, anxiety, and depression, as well as hip disability and osteoarthritis and outcome score (HOOS), modified Harris hip score (mHHS), international hip outcome tool (iHOT-12), and short form-12 (SF-12). Resiliency was divided into low resiliency (score < 3), normal resiliency (score 3 to 4.3), and high resiliency (score > 4.3) as described by Smith et al 1 to use as categorical variables to compare to the other patient-reported scores. The Pearson correlation coefficient (r) was calculated and the Kruskall Willis test was used to measure association between BRS and the other PROMs for continuous and categorical values, respectively. R values ≥0.7, ≥0.4, and ≥0.1 signify a strong, moderate, and weak correlation, respectively. For categorical analysis, P values < 0.05 were considered significant. Results: The cohort of 696 patients had mean age was 24.9 ± 7.9 years and a female predominance at 56%. Average BRS scores were 3.7 ± 0.7. Overall, 13.7% of patients had low resiliency, while 65.8% had normal resiliency and 20.5% had high resiliency. Linear correlation, using Pearson coefficients, found associations between BRS and all other scores. There were only weak associations between BRS scores and PROs (all r < 0.25) except a moderate correlation with PROMIS depression (r = -0.476, p < 0.001) and PROMIS anxiety (r = -0.481, p < 0.001). Patients in higher resiliency groups reported less severe symptoms in HOOS – quality of life (p < 0.001), HOOS – sports and recreation (p = 0.004), HOOS – activities of daily living (p = 0.004), HOOS – pain (p = 0.026), iHOT-12 (p = 0.01), mHHS (p = 0.004), SF-12 mental (p < 0.001), PROMIS physical function (p = 0.003), PROMIS pain (p < 0.001), PROMIS mobility (p < 0.001), PROMIS depression (p < 0.001), and PROMIS anxiety (p < 0.001). Patients with higher activity levels (UCLA ≥9) demonstrated higher resiliency (p = 0.04). Conclusions: In FAI patients, patient resiliency appears to influence baseline PROs. Overall, 14% of patients had low resiliency while 21% had high resiliency. Further studies are needed to investigate this relationship and whether concurrent psychological treatment will help improve patient outcomes after hip arthroscopy for FAI. [Figure: see text]