Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests.
In this single ...institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score.
Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes.
Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future.
Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.
SEARCH for Diabetes in Youth (SEARCH) was initiated in 2000 as a multicenter study to address major gaps in the understanding of childhood diabetes in the United States. An active registry of youth ...diagnosed with diabetes at age <20 years since 2002 assessed prevalence, annual incidence, and trends by age, race/ethnicity, sex, and diabetes type. An observational cohort nested within the population‐based registry was established to assess the natural history and risk factors for acute and chronic diabetes‐related complications, as well as the quality of care and quality of life of children and adolescents with diabetes from diagnosis into young adulthood. SEARCH findings have contributed to a better understanding of the complex and heterogeneous nature of youth‐onset diabetes. Continued surveillance of the burden and risk of type 1 and type 2 diabetes is important to track and monitor incidence and prevalence within the population. SEARCH reported evidence of early diabetes complications highlighting that continuing the long‐term follow‐up of youth with diabetes is necessary to further our understanding of its natural history and to develop the most appropriate approaches to primary, secondary, and tertiary prevention of diabetes and its complications. This review summarizes two decades of research and suggests avenues for further work.
We provide a summary of the design and methods used, and an overview of major findings since the inception of the SEARCH for Diabetes in Youth Study in 2000. These include a summary of the risk, burden, and prognosis of diabetes diagnosed under the age of 20 years, with an emphasis on the disparities that were identified over these years. We also summarize morbidity and mortality information; patterns of, and barriers to, care of diabetes in youth; behavioral and social correlates; issues related to sustainable surveillance; and what the increase in young adults with diabetes who become parents implies.
Building well-performing machine learning (ML) models in health care has always been exigent because of the data-sharing concerns, yet ML approaches often require larger training samples than is ...afforded by one institution. This paper explores several federated learning implementations by applying them in both a simulated environment and an actual implementation using electronic health record data from two academic medical centers on a Microsoft Azure Cloud Databricks platform.
Using two separate cloud tenants, ML models were created, trained, and exchanged from one institution to another via a GitHub repository. Federated learning processes were applied to both artificial neural networks (ANNs) and logistic regression (LR) models on the horizontal data sets that are varying in count and availability. Incremental and cyclic federated learning models have been tested in simulation and real environments.
The cyclically trained ANN showed a 3% increase in performance, a significant improvement across most attempts (
< .05). Single weight neural network models showed improvement in some cases. However, LR models did not show much improvement after federated learning processes. The specific process that improved the performance differed based on the ML model and how federated learning was implemented. Moreover, we have confirmed that the order of the institutions during the training did influence the overall performance increase.
Unlike previous studies, our work has shown the implementation and effectiveness of federated learning processes beyond simulation. Additionally, we have identified different federated learning models that have achieved statistically significant performances. More work is needed to achieve effective federated learning processes in biomedicine, while preserving the security and privacy of the data.
Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the ...United States.
The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry.
Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in
, DNA damage repair genes (
and
and chromatin remodeling genes (the lysine methyltransferases
or
, and
or
. These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the
gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g.
) significantly amplified in the African-American population.
These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer.
mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.
Objective To evaluate the effects of smoking on early markers of cardiovascular disease (arterial stiffness) in adolescents with and without type 1 diabetes (T1D) in the SEARCH Cardiovascular Disease ...Study. Study design Participants included 606 youth (18.9 ± 3.3 years, 83% non-Hispanic white; 50% male). Six groups were defined: (1) smokers with T1D (n = 80); (2) former smokers with T1D (n = 88); (3) nonsmokers with T1D (n = 232); (4) smokers without T1D (n = 40); (5) former smokers without T1D former (n = 51); and (6) nonsmokers without T1D (n = 115). Arterial stiffness measurements included pulse wave velocity (PWV), augmentation index, and brachial distensibility. Multivariate linear regression was used to assess the independent and joint effects of T1D and smoking on arterial stiffness. Results Nearly 20% of both youth with and without T1D and T1D were smokers. In youth without T1D, smokers had higher trunk and arm PWV. After adjustment for potential confounders, T1D, but not smoking, was an independent predictor of PWV ( P < .05). Moreover, smoking status did not modify the association between T1D and increased arterial stiffness. Conclusions We found a high prevalence of smoking among youth with and without T1D; however, smoking status was not independently associated with increased arterial stiffness in youth with T1D.
Since its introduction early in the 1990s, helical CT has become the predominant technology for obtaining CT images for medical applications. Recent improvements in the temporal resolution of helical ...CT (subsecond) and the addition of retrospective cardiac gating are combined in this report evaluating cardiac-gated helical CT for quantifying coronary artery calcium. We compare total calcium scores determined on subsecond gated helical CT with the current reference for coronary calcium evaluation, electron beam CT.
We compared total calcium scores obtained using a general purpose, unmodified helical CT scanner with scores obtained using electron beam CT in 36 individuals who were 68+/-11 years old (age range, 41-85 years).
Correlation coefficients ranged from 0.97 to 0.98 (Pearson's product moment) and from 0.95 to 0.96 (Spearman's rank order), depending on the coronary calcium scoring method used. Agreement in the classification of participants as "healthy" or "diseased" at threshold total calcium scores of 10, 100, 160, 200, 400, and 680 was, respectively, 94%, 97%, 89%, 92%, 94%, and 100% using the conventional electron beam CT scoring method and an equivalent method with helical CT.
A general purpose, current generation helical CT scanner equipped for retrospective cardiac gating can accurately quantify coronary calcium, and the results are highly correlated to scores obtained with electron beam CT. As an alternative method for measuring coronary calcium, gated subsecond cardiac helical CT offers greater availability and lower cost, thereby making population-based screening for coronary artery calcium more feasible.
Background
Reports comparing waist circumference (WC) measurements from young populations are scarce.
Objectives
We compared two protocols for measuring waist circumference in a sample of youth with ...diabetes.
Methods
Participants were enrolled in the SEARCH for Diabetes in Youth Study (SEARCH). WC was measured at least twice by the National Health and Nutrition Examination Survey (NHANES) protocol and twice by the World Health Organization (WHO) protocol. Method‐specific averages were used in these analyses.
Results
Among 6248 participants, the mean NHANES WC (76.3 cm) was greater than the mean WHO WC (71.9 cm). Discrepancies between protocols were greater for females than males, among older participants, and in those with higher body mass index (BMI). In both sexes and four age strata, the WCs using either method were highly correlated with BMI z‐score. The within‐method differences between the first and second measurements were similar for the two methods.
Conclusions
These analyses do not provide evidence that one of these two methods is more reproducible or is a better indicator of obesity as defined by BMI z‐scores.
Doxorubicin (DOX) is associated with premature cardiovascular events including myocardial infarction. This study was performed to determine if the weekly administration of DOX influenced coronary ...arteriolar medial and/or adventitial wall thickening.
Thirty-two male Sprague-Dawley rats aged 25.1± 2.4 weeks were randomly divided into three groups and received weekly intraperitoneal injections of normal saline (saline, n = 7), or low (1.5 mg/kg to 1.75 mg/kg, n = 14) or high (2.5 mg/kg, n = 11) doses of DOX. The animals were treated for 2-12 weeks, and euthanized at pre-specified intervals (2, 4, 7, or 10+ weeks) to obtain histopathologic assessments of coronary arteriolar lumen diameter, medial wall thickness, adventitial wall thickness, and total wall thickness (medial thickness + adventitial thickness).
Lumen diameter was similar across all groups (saline: 315±34 µm, low DOX: 286±24 µm, high DOX: 242±27 µm; p = 0.22). In comparison to animals receiving weekly saline, animals receiving weekly injections of 2.5 mg/kg of DOX experienced an increase in medial (23±2 µm vs. 13±3 µm; p = 0.005), and total wall thickness (51±4 µm vs. 36±5 µm; p = 0.022), respectively. These increases, as well as adventitial thickening became more prominent after normalizing for lumen diameter (p<0.05 to p<0.001) and after adjusting for age, weight, and total cumulative DOX dose (p = 0.02 to p = 0.01). Animals receiving low dose DOX trended toward increases in adventitial and total wall thickness after normalization to lumen diameter and accounting for age, weight, and total cumulative DOX dose (p = 0.06 and 0.09, respectively).
In conclusion, these data demonstrate that weekly treatment of rats with higher doses of DOX increases coronary arteriolar medial, adventitial, and total wall thickness. Future studies are warranted to determine if DOX related coronary arteriolar effects are reversible or preventable, exacerbate the known cardiomyopathic effects of DOX, influence altered resting or stress-induced myocardial perfusion, or contribute to the occurrence of myocardial infarction.
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