Citations

Purpose: Magnetic resonance elastography (MRE) has been established as the most accurate noninvasive technique for diagnosing liver fibrosis. Recent publications have suggested that the measurement of splenic stiffness is useful in setting where portal hypertension may be present. The goal of the current study was to compile normative data for MRE-assessed stiffness measurements of the spleen in young adults. Materials and Methods: A total of 100 healthy young Caucasian volunteers (65 females and 35 males) in the age range of 20 to 32 years were enrolled in this study. The participants reported no history of chronic spleen and liver disease, normal alcohol consumption, and a normal diet. The MRE data were acquired by using a 1.5 T whole-body scanner and a 2D GRE pulse sequence with 60 Hz excitation. Spleen stiffness was calculated as a weighted mean of stiffness values in the regions of interest manually drawn by the radiologist on three to five spleen slices. Results: Mean spleen stiffness was 5.09 ± 0.65 kPa for the whole group. Male volunteers had slightly higher splenic stiffness compared to females: 5.28 ± 0.78 vs. 4.98 ± 0.51 kPa, however, this difference was not statistically significant (p = 0.12). Spleen stiffness did not correlate with spleen fat content and liver stiffness but a statistically significant correlation with spleen volume was found. Conclusions: The findings of this study provide normative values for 2D MRE-based measurement of spleen stiffness in young adults, a basis for assessing the value of this biomarker in young patients with portal system pathologies.

AbstractIntroductionIncreasingly, early‐stage non–small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K‐AKT‐mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC.MethodsPatients with T1‐3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin‐fixed paraffin‐embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan–Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation.ResultsA total of 92 patients were included, with a median follow‐up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40–98.0; p = .023) and worse disease‐free survival (DFS) (HR, 3.98; 95% CI, 1.57–10.09; p = .0035), but not OS (p = .49), regional recurrence (p = .15), or distant recurrence (p = .85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log‐rank p = .013) but not DFS (p = 0.54).ConclusionsThis study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early‐stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation.

Background/Objective: To share technical pearls of a basic knee arthroscopy in a pediatric patient by presenting tips and tricks used by experienced pediatric arthroscopists. Indications: Knee arthroscopy is a common procedure performed by most orthopedic surgeons. However, technical considerations and equipment should be considered before performing this procedure in a pediatric patient. This video provides information on indications, equipment, and patient positioning, as well as outlining a systematic approach to diagnostic arthroscopy and pertinent pediatric anatomy. Discussion/Conclusion: This video provides an excellent overview as well as specific pathology-dependent considerations for the inexperienced orthopedic surgeon, or the orthopedic surgeon who rarely performs knee arthroscopy. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

ImportanceWhile the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited.ObjectiveTo evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors.Design, Setting, and ParticipantsThis cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022.ExposuresMetastatic colorectal cancer.Main Outcomes and MeasuresSurvival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years.ResultsIn the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002).Conclusions and RelevanceIn this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Background: Tibial spine fractures (TSFs) are uncommon injuries that may result in substantial morbidity in children. A variety of open and arthroscopic techniques are used to treat these fractures, but no single standardized operative method has been identified. Purpose: To systematically review the literature on pediatric TSFs to determine the current treatment approaches, outcomes, and complications. Study Design: Meta-analysis; Level of evidence, 4. Methods: A systematic review of the literature was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines using PubMed, Embase, and Cochrane databases. Studies evaluating treatment and outcomes of patients <18 years old were included. Patient demographic characteristics, fracture characteristics, treatments, and outcomes were abstracted. Descriptive statistics were used to summarize categorical and quantitative variables, and a meta-analytic technique was used to compare observational studies with sufficient data. Results: A total of 47 studies were included, totaling 1922 TSFs in patients (66.4% male) with a mean age of 12 years (range, 3-18 years). The operative approach was open reduction and internal fixation in 291 cases and arthroscopic reduction and internal fixation in 1236 cases; screw fixation was used in 411 cases and suture fixation, in 586 cases. A total of 13 nonunions were reported, occurring most frequently in Meyers and McKeever type III fractures (n = 6) and in fractures that were treated nonoperatively (n = 10). Arthrofibrosis rates were reported in 33 studies (n = 1700), and arthrofibrosis was present in 190 patients (11.2%). Range of motion loss occurred significantly more frequently in patients with type III and IV fractures ( P < .001), and secondary anterior cruciate ligament (ACL) injury occurred most frequently in patients with type I and II fractures ( P = .008). No statistically significant differences were found with regard to rates of nonunion, arthrofibrosis, range of motion loss, laxity, or secondary ACL injury between fixation methods (screw vs suture). Conclusion: Despite variation in TSF treatment, good overall outcomes have been reported with low complication rates in both open and arthroscopic treatment and with both screw and suture fixation. Arthrofibrosis remains a concern after surgical treatment for TSF, but no significant difference in incidence was found between the analysis groups. Larger studies are necessary to compare outcomes and form a consensus on how to treat and manage patients with TSFs.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

Abstract Objective Social determinants of health (SDoH) play critical roles in health outcomes and well-being. Understanding the interplay of SDoH and health outcomes is critical to reducing healthcare inequalities and transforming a “sick care” system into a “health-promoting” system. To address the SDOH terminology gap and better embed relevant elements in advanced biomedical informatics, we propose an SDoH ontology (SDoHO), which represents fundamental SDoH factors and their relationships in a standardized and measurable way. Material and Methods Drawing on the content of existing ontologies relevant to certain aspects of SDoH, we used a top-down approach to formally model classes, relationships, and constraints based on multiple SDoH-related resources. Expert review and coverage evaluation, using a bottom-up approach employing clinical notes data and a national survey, were performed. Results We constructed the SDoHO with 708 classes, 106 object properties, and 20 data properties, with 1,561 logical axioms and 976 declaration axioms in the current version. Three experts achieved 0.967 agreement in the semantic evaluation of the ontology. A comparison between the coverage of the ontology and SDOH concepts in 2 sets of clinical notes and a national survey instrument also showed satisfactory results. Discussion SDoHO could potentially play an essential role in providing a foundation for a comprehensive understanding of the associations between SDoH and health outcomes and paving the way for health equity across populations. Conclusion SDoHO has well-designed hierarchies, practical objective properties, and versatile functionalities, and the comprehensive semantic and coverage evaluation achieved promising performance compared to the existing ontologies relevant to SDoH.

Spatially resolved sequencing technologies help us dissect how cells are organized in space. Several available computational approaches focus on the identification of spatially variable genes (SVGs), genes whose expression patterns vary in space. The detection of SVGs is analogous to the identification of differentially expressed genes and permits us to understand how genes and associated molecular processes are spatially distributed within cellular niches. However, the expression activities of SVGs fail to encode all information inherent in the spatial distribution of cells. Here, we devised a deep learning model, Spatially Informed Artificial Intelligence (SPIN-AI), to identify spatially predictive genes (SPGs), whose expression can predict how cells are organized in space. We used SPIN-AI on spatial transcriptomic data from squamous cell carcinoma (SCC) as a proof of concept. Our results demonstrate that SPGs not only recapitulate the biology of SCC but also identify genes distinct from SVGs. Moreover, we found a substantial number of ribosomal genes that were SPGs but not SVGs. Since SPGs possess the capability to predict spatial cellular organization, we reason that SPGs capture more biologically relevant information for a given cellular niche than SVGs. Thus, SPIN-AI has broad applications for detecting SPGs and uncovering which biological processes play important roles in governing cellular organization.

Anticipating and understanding cancers’ need for specific gene activities is key for novel therapeutic development. Here we utilized DepMap, a cancer gene dependency screen, to demonstrate that machine learning combined with network biology can produce robust algorithms that both predict what genes a cancer is dependent on and what network features coordinate such gene dependencies. Using network topology and biological annotations, we constructed four groups of novel engineered machine learning features that produced high accuracies when predicting binary gene dependencies. We found that in all examined cancer types, F1 scores were greater than 0.90, and model accuracy remained robust under multiple hyperparameter tests. We then deconstructed these models to identify tumor type-specific coordinators of gene dependency and identified that in certain cancers, such as thyroid and kidney, tumors’ dependencies are highly predicted by gene connectivity. In contrast, other histologies relied on pathway-based features such as lung, where gene dependencies were highly predictive by associations with cell death pathway genes. In sum, we show that biologically informed network features can be a valuable and robust addition to predictive pharmacology models while simultaneously providing mechanistic insights.