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"Glaser, Kevin L"
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Measuring the Characteristic Topography of Brain Stiffness with Magnetic Resonance Elastography
To develop a reliable magnetic resonance elastography (MRE)-based method for measuring regional brain stiffness.
First, simulation studies were used to demonstrate how stiffness measurements can be biased by changes in brain morphometry, such as those due to atrophy. Adaptive postprocessing methods were created that significantly reduce the spatial extent of edge artifacts and eliminate atrophy-related bias. Second, a pipeline for regional brain stiffness measurement was developed and evaluated for test-retest reliability in 10 healthy control subjects.
This technique indicates high test-retest repeatability with a typical coefficient of variation of less than 1% for global brain stiffness and less than 2% for the lobes of the brain and the cerebellum. Furthermore, this study reveals that the brain possesses a characteristic topography of mechanical properties, and also that lobar stiffness measurements tend to correlate with one another within an individual.
The methods presented in this work are resistant to noise- and edge-related biases that are common in the field of brain MRE, demonstrate high test-retest reliability, and provide independent regional stiffness measurements. This pipeline will allow future investigations to measure changes to the brain's mechanical properties and how they relate to the characteristic topographies that are typical of many neurologic diseases.
Journal Article
Novel 3D Magnetic Resonance Elastography for the Noninvasive Diagnosis of Advanced Fibrosis in NAFLD: A Prospective Study
Recent studies show two-dimensional (2D)-magnetic resonance elastography (MRE) is accurate in diagnosing advanced fibrosis (stages 3 and 4) in nonalcoholic fatty liver disease (NAFLD) patients. Three-dimensional (3D)-MRE is a more advanced version of the technology that can image shear-wave fields in 3D of the entire liver. The aim of this study was to prospectively compare the diagnostic accuracy of 3D-MRE and 2D-MRE for diagnosing advanced fibrosis in patients with biopsy-proven NAFLD.
This cross-sectional analysis of a prospective study included 100 consecutive patients (56% women) with biopsy-proven NAFLD who also underwent MRE. Area under the receiver operating characteristic (AUROC) analysis was performed to assess the accuracy of 2D- and 3D-MRE in diagnosing advanced fibrosis.
The mean (±s.d.) of age and body mass index were 50.2 (±13.6) years and 32.1 (±5.0) kg/m(2), respectively. The AUROC for diagnosing advanced fibrosis was 0.981 for 3D-MRE at 40 Hz, 0.927 for 3D-MRE at 60 Hz (standard shear-wave frequency), and 0.921 for 2D-MRE at 60 Hz (standard shear-wave frequency). At a threshold of 2.43 kPa, 3D-MRE at 40 Hz had sensitivity 1.0, specificity 0.94, positive predictive value 0.72, and negative predictive value 1.0 for diagnosing advanced fibrosis. 3D-MRE at 40 Hz had significantly higher AUROC (P<0.05) than 2D-MRE at 60 Hz for diagnosing advanced fibrosis.
Utilizing a prospective study design, we demonstrate that 3D MRE at 40 Hz has the highest diagnostic accuracy in diagnosing NAFLD advanced fibrosis. Both 2D- and 3D-MRE at 60 Hz, the standard shear-wave frequency, are also highly accurate in diagnosing NAFLD advanced fibrosis.
Journal Article
An end-to-end workflow for nondestructive 3D pathology
Recent advances in 3D pathology offer the ability to image orders of magnitude more tissue than conventional pathology methods while also providing a volumetric context that is not achievable with 2D tissue sections, and all without requiring destructive tissue sectioning. Generating high-quality 3D pathology datasets on a consistent basis, however, is not trivial and requires careful attention to a series of details during tissue preparation, imaging and initial data processing, as well as iterative optimization of the entire process. Here, we provide an end-to-end procedure covering all aspects of a 3D pathology workflow (using light-sheet microscopy as an illustrative imaging platform) with sufficient detail to perform well-controlled preclinical and clinical studies. Although 3D pathology is compatible with diverse staining protocols and computationally generated color palettes for visual analysis, this protocol focuses on the use of a fluorescent analog of hematoxylin and eosin, which remains the most common stain used for gold-standard pathological reports. We present our guidelines for a broad range of end users (e.g., biologists, clinical researchers and engineers) in a simple format. The end-to-end workflow requires 3–6 d to complete, bearing in mind that data analysis may take longer.
Key points
The protocol details tissue preparation and staining using TO-PRO-3, a fluorescent analog of hematoxylin, and eosin. Tissue imaging using light-sheet fluorescence microscopy is described, including strategies for quality control in tissue preparation and 3D microscopy.
A fully open-source workflow requiring basic programming skills in Python is explained for initial 3D data processing, such as stitching, intensity leveling and digital staining to mimic the appearance of standard H&E histology.
A detailed workflow covering 3D pathology, including tissue preparation, imaging with light-sheet fluorescence microscopy, tools for initial data processing in Python (e.g., stitching, intensity leveling and false coloring) and data quality control.
Journal Article
Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients
In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.
The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.
Journal Article
Imaging brain function with simultaneous BOLD and viscoelasticity contrast: fMRI/fMRE
Magnetic resonance elastography (MRE) is emerging as a new tool for studying viscoelastic changes in the brain resulting from functional processes. Here, we demonstrate a novel time series method to generate robust functional magnetic resonance elastography (fMRE) activation maps in response to a visual task with a flashing checkerboard stimulus. Using a single-shot spin-echo (SS-SE) pulse sequence, the underlying raw images inherently contain blood-oxygen-level dependent (BOLD) contrast, allowing simultaneous generation of functional magnetic resonance imaging (fMRI) activation maps from the magnitude and functional magnetic resonance elastography (fMRE) maps from the phase. This allows an accurate comparison of the spatially localized stiffness (fMRE) and BOLD (fMRI) changes within a single scan, eliminating confounds inherent in separately acquired scans. Results indicate that tissue stiffness within the visual cortex increases 6–11% with visual stimuli, whereas the BOLD signal change was 1–2%. Furthermore, the fMRE and fMRI activation maps have strong spatial overlap within the visual cortex, providing convincing evidence that fMRE is possible in the brain. However, the fMRE temporal SNR (tSNRfMRE) maps are heterogeneous across the brain. Using a dictionary matching approach to characterize the time series, the viscoelastic changes are consistent with a viscoelastic response function (VRF) time constant of 12.1 s ± 3.0 s for a first-order exponential decay, or a shape parameter of 8.1 s ± 1.4 s for a gamma-variate.
•Robust functional MR elastography activation is achieved using a time series method.•Tissue stiffness within the human visual cortex increases with visual stimulation.•Viscoelastic response functions are modeled using a dictionary matching approach.•Simultaneous fMRI and fMRE are extracted from the magnitude and phase time series.
Journal Article
High-frequency shear wave MR elastography of parotid glands: custom driver design and preliminary results
Parotid glands are one of the most common sites for salivary gland tumors. Conventional imaging techniques have limited usefulness in the quantitative assessment of the parotid glands, making it difficult to differentiate between healthy tissue and tumors, as well as between benign and malignant tumors. Magnetic resonance elastography (MRE) is a non-invasive technique that may potentially overcome these limitations. Nevertheless, due to the size of the parotid gland, increased elastographic resolution is required. This may be achieved by applying shear waves at higher frequencies. However, it also results in stronger attenuation, making the illumination of the parotid challenging. Here, we describe a novel passive driver tailored to the anatomy of the human face, which minimizes the distance shear waves need to travel from the source to the area of interest and thus decreases shear wave attenuation, making high-frequency shear wave MRE feasible.
Journal Article
Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations—2019 update
This is the first updated Enhanced Recovery After Surgery (ERAS) Society guideline presenting a consensus for optimal perioperative care in gynecologic/oncology surgery.
A database search of publications using Embase and PubMed was performed. Studies on each item within the ERAS gynecologic/oncology protocol were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.
All recommendations on ERAS protocol items are based on best available evidence. The level of evidence for each item is presented accordingly.
The updated evidence base and recommendation for items within the ERAS gynecologic/oncology perioperative care pathway are presented by the ERAS® Society in this consensus review.
Journal Article
Magnetic Resonance Elastography for the Evaluation of Liver Fibrosis in Chronic Hepatitis B and C by Using Both Gradient-Recalled Echo and Spin-Echo Echo Planar Imaging: A Prospective Study
Magnetic resonance elastography (MRE) with three-dimensional spin-echo echo planar imaging (3D-SE-EPI) is a newly emerging noninvasive method for assessing liver fibrosis. We hypothesized that 3D-SE-EPI might have better diagnostic accuracy than conventional two-dimensional gradient-recalled echo (2D-GRE).
We prospectively included 179 consecutive patients with chronic hepatitis B (CHB) or C (CHC) who underwent both MRE and liver biopsy. Liver stiffness was measured by both 3D-SE-EPI and 2D-GRE for staging biopsy-proven liver fibrosis (using METAVIR scores). A receiver-operating characteristic analysis using the area under the receiver-operating characteristic curve (AUC) was used to compare the diagnostic performance in predicting liver fibrosis between these two techniques, and compared them to serum markers of fibrosis.
The technical failure rate of 3D-SE-EPI (2.2%, n=4/179) was lower compared with 2D-GRE (8.3%, n=15/179). The stiffness measured by 3D-SE-EPI was slightly lower compared with 2D-GRE, with the mean difference of 0.57 kPa (Bland and Altman plot, 95% limits of agreement: -0.32 and 1.45 kPa). AUCs for the characterization of ≥F1, ≥F2, ≥F3, and F4 were 0.957 (95% confidence interval (CI): 0.913-0.983), 0.971 (0.932-0.991), 0.991 (0.961-0.999), and 0.979 (0.942-0.995) for 3D-SE-EPI, which was slightly higher compared with the AUCs for 2D-GRE at each fibrosis stage (0.948 (0.901-0.977), 0.959 (0.915-0.981), 0.979 (0.943-0.995), and 0.976 (0.938-0.994), respectively), although none reached statistical significance (P=0.160-0.585). In an \"intention-to-diagnose\" analysis, the diagnostic accuracy (the proportion of well-classified patients) by EPI (86.7-91.3%, n=169) was higher compared with GRE (80.9-82.1%, n=158) after applying optimal cutoffs. Both 3D-SE-EPI and 2D-GRE performed better than serum fibrosis markers.
With respect to 2D-GRE, 3D-SE-EPI has the advantage of lower failure rate with equivalent high diagnostic performance for staging liver fibrosis in CHB/CHC patients, and thus more helpful for those challenging cases in 2D-GRE.
Journal Article
Value of liver iron concentration in healthy volunteers assessed by MRI
Iron overload is a relatively common clinical condition resulting from disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, and myelodysplasia that can lead to progressive fibrosis and eventually cirrhosis of the liver. Therefore, it is essential to recognize the disease process at the earliest stage. Liver biopsy is the reference test for the assessment of liver fibrosis. It also allows for quantifying liver iron concentration (LIC) in patients. However, this is an invasive method with significant limitations and possible risks. Magnetic resonance imaging (MRI) and evaluation of the R2* relaxation rate can be an alternative to biopsy for assessing LIC. However, it causes a need for accurate R2* data corresponding to standard value for further comparison with examined patients. This study aimed to assess the normative values of liver R2* in healthy individuals. A total of 100 volunteers that met established criteria were enrolled in the study: 36 (36%) men and 64 (64%) women. The mean age was 22.9 years (range 20 to 32 years). R2* was estimated by an MRI exam with a 1.5 T clinical magnetic resonance scanner. Images for measuring the LIC and liver fat concentration were obtained using the IDEAL-IQ technique for liver imaging. The Mean (SD) liver R2* was 28.34 (2.25) s
−1
(95% CI, 27.78–28.90, range 23.67–33.00 s
−1
) in females, 29.57 (3.20) s
−1
(95% CI, 28.49–30.66, range 23.93–37.77 s
−1
) in males, and 28.72 (2.69) s
−1
(range 23.67–37.77 s
−1
) in the whole group. R2* value in this particular population with a high proportion of young women did not exceed 38 s
−1
. In the absence of fibrosis or steatosis, liver stiffness and fat fraction did not show any relationship with R2*.
Journal Article