In last few years, there have been significant advances in our understanding of a newly recognized condition known as IgG4-related systemic disease. This review will focus on IgG4-related systemic ...disease as a cause of thoracic aortitis, inflammatory abdominal aortic aneurysm or periaortitis, and retroperitoneal fibrosis.
A significant fraction of thoracic lymphoplasmacytic aortitis cases, about 40% of inflammatory abdominal aortic aneurysms/abdominal periaortitis cases, and a portion of retroperitoneal fibrosis cases are all caused by IgG4-related systemic disease. Assessing pathologic specimens for the fraction of plasma cells that express IgG4 is useful in identifying patients with this disorder. Recently reported data may indicate IgG4-related aortic disease to be more common than widely realized.
IgG4-related systemic disease is a newly recognized disorder that may manifest as thoracic aortitis, inflammatory abdominal aortic aneurysm or retroperitoneal fibrosis. IgG4-related systemic disease should be considered in any patient found to have aortitis or periaortitis. Further studies into diagnostic criteria, disease prevalence, prognosis, therapeutic interventions, and differentiating possible localized hypersensitivity reactions from systemic disease are areas of active investigation. Criteria are presented for the pathologic diagnosis of IgG4-related aortitis.
Immune checkpoint inhibitor therapy for malignancy has been associated with adverse events including myocarditis. It has been unclear if there are distinct pathologic grades of this myocarditis that ...are associated with distinct clinical outcomes. Cardiac tissue from ten patients with immune checkpoint inhibitor myocarditis (nine biopsies and one autopsy) were evaluated using immunohistochemistry for CD3, CD8, CD68, tryptase, PD-L1, and C4D. The immune checkpoint inhibitor myocarditis cases were classified as either high grade (>50 CD3
cells/hpf) or low grade (≤50 CD3
cells/hpf). The densities of macrophages, T cells, eosinophils, necrotic myocytes, and PD-L1
macrophages and myocytes were compared between the two groups and with 13 cases of grade 2R acute cellular allograft rejection. Three patients were classified as high-grade myocarditis and seven as low grade. There were higher densities of CD3
cells and CD8
cells in high-grade immune checkpoint inhibitor myocarditis and rejection compared with low-grade myocarditis. The number of CD68
macrophages was higher in high-grade myocarditis compared with low-grade myocarditis and rejection. For both grades of myocarditis, there was a higher CD68/CD3 ratio and a higher density of PD-L1
macrophages and myocytes compared with rejection. Clinically, there were trends toward higher serum troponin levels and shorter interval from first immune checkpoint inhibitor treatment in the high-grade myocarditis group compared with the low-grade group. All the patients with high-grade myocarditis died, while all the patients with low-grade myocarditis were still living. These data suggest that immune checkpoint inhibitor myocarditis occurs in two forms, a high-grade form with increased inflammatory cell infiltration and a more fulminant clinical course, and a low-grade form with a lower degree of inflammatory cell infiltration and a more indolent clinical course. Compared with acute cellular rejection, immune checkpoint inhibitor myocarditis is characterized by a more lymphohistiocytic inflammatory infiltrate with an increased CD68/CD3 ratio and increased PD-L1
macrophages and myocytes.
Many studies of the human brain have explored the relationship between cortical thickness and cognition, phenotype, or disease. Due to the subjectivity and time requirements in manual measurement of ...cortical thickness, scientists have relied on robust software tools for automation which facilitate the testing and refinement of neuroscientific hypotheses. The most widely used tool for cortical thickness studies is the publicly available, surface-based FreeSurfer package. Critical to the adoption of such tools is a demonstration of their reproducibility, validity, and the documentation of specific implementations that are robust across large, diverse imaging datasets. To this end, we have developed the automated, volume-based Advanced Normalization Tools (ANTs) cortical thickness pipeline comprising well-vetted components such as SyGN (multivariate template construction), SyN (image registration), N4 (bias correction), Atropos (n-tissue segmentation), and DiReCT (cortical thickness estimation). In this work, we have conducted the largest evaluation of automated cortical thickness measures in publicly available data, comparing FreeSurfer and ANTs measures computed on 1205 images from four open data sets (IXI, MMRR, NKI, and OASIS), with parcellation based on the recently proposed Desikan–Killiany–Tourville (DKT) cortical labeling protocol. We found good scan–rescan repeatability with both FreeSurfer and ANTs measures. Given that such assessments of precision do not necessarily reflect accuracy or an ability to make statistical inferences, we further tested the neurobiological validity of these approaches by evaluating thickness-based prediction of age and gender. ANTs is shown to have a higher predictive performance than FreeSurfer for both of these measures. In promotion of open science, we make all of our scripts, data, and results publicly available which complements the use of open image data sets and the open source availability of the proposed ANTs cortical thickness pipeline.
•A complete, volumetric-based cortical thickness pipeline is proposed.•The pipeline consists of well-vetted components fine-tuned by the original developers.•Approximately 1200 data were analyzed with no major failures.•All software is open source as part of the ANTs repository.•Analysis and visualization scripts using the R statistical package are also publicly available.
Abstract
Aims
Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement ...including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described.
Methods and results
In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.
Conclusions
In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.
The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research ...communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. ...This work was undertaken to develop and validate an international set of classification criteria for IgG4‐RD.
Methods
An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included.
Results
A 3‐step classification process was developed. First, it must be demonstrated that a potential IgG4‐RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4‐RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4‐RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval 95% CI 97.2–99.8%) and a sensitivity of 85.5% (95% CI 81.9–88.5%). In the second, the specificity was 97.8% (95% CI 93.7–99.2%) and the sensitivity was 82.0% (95% CI 77.0–86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds.
Conclusion
ACR/EULAR classification criteria for IgG4‐RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.
Graphical Abstract
Graphical abstract
Clinical role of autopsy in patients who die unexpectedly or of known cardiac disease: identification of cardiac disease; confirmation of cardiac disease; and ...assessment of treatment and disease progression. Top: myocardial disease. Stage 1: Asymptomatic, subclinical (not detectable by current imaging, but detectable at autopsy). Stage 2: Asymptomatic, mildly dilated (detectable by imaging and at autopsy). Stage 3: Symptomatic, dilated (detectable by imaging, confirmed at autopsy). Stage 4: Symptomatic, dilated, post-treatment (assessment of therapy, verification of diagnosis). Bottom: coronary artery disease. Stage 1: Asymptomatic, mild atherosclerosis, complicated by acute thrombosis. Stage 2: Asymptomatic, moderate atherosclerosis, complicated by thrombosis. Stage 3: Symptomatic, severe atherosclerosis. Stage 4: Symptomatic, atherosclerosis post treatment (stent), complicated by thrombosis.
Abstract
Historically, autopsy contributed to our current knowledge of cardiovascular anatomy, physiology, and pathology. Major advances in the understanding of cardiovascular diseases, including atherosclerosis and coronary artery disease, congenital heart diseases, and cardiomyopathies, were possible through autopsy investigations and clinicopathological correlations. In this review, the importance of performing clinical autopsies in people dying from cardiovascular disease, even in the era of advanced cardiovascular imaging is addressed. Autopsies are most helpful in the setting of sudden unexpected deaths, particularly when advanced cardiovascular imaging has not been performed. In this setting, the autopsy is often the only chance to make the correct diagnosis. In previously symptomatic patients who had undergone advanced cardiovascular imaging, autopsies still play many roles. Post-mortem examinations are important for furthering the understanding of key issues related to the underlying diseases. Autopsy can help to increase the knowledge of the sensitivity and specificity of advanced cardiovascular imaging modalities. Autopsies are particularly important to gain insights into both the natural history of cardiovascular diseases as well as less common presentations and therapeutic complications. Finally, autopsies are a key tool to quickly understand the cardiac pathology of new disorders, as emphasized during the recent coronavirus disease 2019 pandemic.
Audio Abstract
10.1093/eurheartj/ehac220_audio1
Audio Abstract
ehac220media1
6305689076112
Hydrogen peroxide (H2O2) is a well-documented component of living cells. It plays important roles in host defense and oxidative biosynthetic reactions. In addition there is growing evidence that at ...low levels, H2O2 also functions as a signaling agent, particularly in higher organisms. This review evaluates the evidence that H2O2 functions as a signaling agent in higher organisms in light of the known biology and biochemistry of H2O2. All aerobic organisms studied to date from prokaryotes to humans appear to tightly regulate their intracellular H2O2 concentrations at relatively similar levels. Multiple biochemical strategies for rapidly reacting with these low endogenous levels of H2O2 have been elucidated from the study of peroxidases and catalases. Well-defined biochemical pathways involved in the response to exogenous H2O2 have been described in both prokaryotes and yeast. In animals and plants, regulated enzymatic systems for generating H2O2 have been described. In addition oxidation-dependent steps in signal transduction pathways are being uncovered, and evidence is accumulating regarding the nature of the specific reactive oxygen species involved in each of these pathways. Application of physiologic levels of H2O2 to mammalian cells has been shown to stimulate biological responses and to activate specific biochemical pathways in these cells.
Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) ...inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting
progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of
observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical
resistance mutation and subsequent frameshift
mutation, whereas a distinct branch exhibited a novel
/
missense mutation. Reconstitution experiments demonstrated that TROP2
confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. SIGNIFICANCE: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.
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