Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin-treated breast cancer patients: a prospective exploratory study.

BACKGROUND: Soluble urokinase plasminogen activator receptor is an inflammatory biomarker that may prognosticate cardiovascular outcomes. We sought to determine the associations between soluble urokinase plasminogen activator receptor and established markers of cardiotoxicity in breast cancer patients receiving doxorubicin. METHODS: We conducted a prospective cohort study of women with newly diagnosed breast cancer receiving standard-dose doxorubicin (240 mg/m2) at Rush University Medical Center and Rush Oak Park Hospital (Chicago, IL) between January 2017 and May 2019. Left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers (N-terminal prohormone B-type natriuretic peptide, troponin-I, and high-sensitivity C-reactive protein) were measured at baseline and at intervals up to 12-month follow-up after end of treatment. The associations between soluble urokinase plasminogen activator receptor and these endpoints were evaluated using multivariable mixed effects linear regression. RESULTS: Our study included 37 women (mean age 47.0 ± 9.3 years, 60% white) with a median baseline soluble urokinase plasminogen activator receptor level of 2.83 ng/dL. No participant developed cardiomyopathy based on serial echocardiography by one-year follow-up. The median percent change in left ventricular strain was -4.3% at 6-month follow-up and absolute changes in cardiac biomarkers were clinically insignificant. There were no significant associations between soluble urokinase plasminogen activator receptor and these markers of cardiotoxicity (all p > 0.05). CONCLUSIONS: In this breast cancer cohort, doxorubicin treatment was associated with a very low risk for cardiotoxicity. Across this narrow range of clinical endpoints, soluble urokinase plasminogen activator receptor was not associated with markers of subclinical cardiotoxicity. Further studies are needed to clarify the prognostic utility of soluble urokinase plasminogen activator receptor in doxorubicin-associated cardiomyopathy and should include a larger cohort of leukemia and lymphoma patients who receive higher doses of doxorubicin.

Juvenile-Type Granulosa Cell Tumor in Pregnancy Presenting as a Ruptured Abdominal Mass.

Introduction: Granulosa cell tumors (GCTs) are part of the sex cord-stromal tumors occurring with a rare incidence rate that only makes up about 2-5% of all ovarian malignancies. Case Presentation: A 28-year-old woman, gravida 2, para 1, presented with a juvenile-type granulosa cell tumor at 31 weeks gestation, which appeared as a rapidly growing mass with rupture. She under-went an exploratory laparotomy with unilateral salpingo-oophorectomy, and consequently had a successful vaginal delivery. Post-operatively she was treated with paclitaxel and carboplatin chemotherapy regimen with no evidence of recurrence after one year. Conclusion: Radical surgical management is recommended for these tumors due to the high recurrence rate, but more conservative surgical options may be considered based on the fertility goals of the patient.

3D-Arterial analysis software and CEUS in the assessment of severity and vulnerability of carotid atherosclerotic plaque: a comparison with CTA and histopathology.

PURPOSE: Our purpose is to assess Multiparametric Ultrasound (MPUS) efficacy for evaluation of carotid plaque vulnerability and carotid stenosis degree in comparison with Computed Tomography angiography (CTA) and histology. MATERIAL AND METHODS: 3D-Arterial Analysis is a 3D ultrasound software that automatically provides the degree of carotid stenosis and a colorimetric map of carotid plaque vulnerability. We enrolled 106 patients who were candidates for carotid endarterectomy. Prior to undergoing surgery, all carotid artery plaques were evaluated with Color-Doppler-US (CDUS), Contrast-Enhanced Ultrasound (CEUS), and 3D Arterial analysis (3DAA) US along with Computerized Tomographic Angiography (CTA) to assess the carotid artery stenosis degree. Post-surgery, the carotid specimens were fixed with 10% neutral buffered formalin solution, embedded in paraffin and used for light microscopic examination to assess plaque vulnerability morphological features. RESULTS: The results of the CTA examinations revealed 91 patients with severe carotid stenoses with a resultant diagnostic accuracy of 82.3% for CDUS, 94.5% for CEUS, 98.4% for 3DAA, respectively. The histopathological examination showed 71 vulnerable plaques with diagnostic accuracy values of 85.8% for CDUS, 93.4% for CEUS, 90.3% for 3DAA, 92% for CTA, respectively. CONCLUSIONS: The combination of CEUS and 3D Arterial Analysis may provide a powerful new clinical tool to identify and stratify "at-risk" patients with atherosclerotic carotid artery disease, identifying vulnerable plaques. These applications may also help in the postoperative assessment of treatment options to manage cardiovascular risks.

CEUS cardiac exam protocols International Contrast Ultrasound Society (ICUS) recommendations.

The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents (UEAs) in echocardiography, based on more than two decades of experience in the use of UEAs for cardiac imaging. The protocols reflect current clinical CEUS practice in many modern echocardiography laboratories throughout the world. Specific attention is given to preparation and dosing of three UEAs that have been approved by the United States Food and Drug Administration (FDA) and additional regulatory bodies in Europe, the Americas and Asia-Pacific. Consistent with professional society guidelines (J Am Soc Echocardiogr 31:241-274, 2018; J Am Soc Echocardiogr 27:797-810, 2014; Eur Heart J Cardiovasc Imaging 18:1205, 2017), these protocols cover unapproved "off-label" uses of UEAs-including stress echocardiography and myocardial perfusion imaging-in addition to approved uses. Accordingly, these protocols may differ from information provided in product labels, which are generally based on studies performed prior to product approval and may not always reflect state of the art clinical practice or guidelines.

The 35th annual advances in contrast ultrasound international bubble conference, Chicago 2021: synopsis and take-home messages.

The 35th Annual Advances in Contrast Ultrasound International Bubble Conference convened in Chicago, IL, USA, on September 30th to October 1st, 2021. It featured a range of novel research from animal studies to clinical applications in multiple organ systems, demonstrating the utility of contrast enhanced ultrasound (CEUS). A multidisciplinary group of experts on the use of CEUS, including physicians, basic scientists, engineers, and industry partners, convened to discuss cutting edge research and new applications for CEUS. The conference demonstrated the wide range of CEUS uses and potential uses, including cardiac risk stratification, sonothrombolysis, peripheral vascular reperfusion, liver and renal mass evaluation, lymphatic evaluation, sentinel node identification, and CEUS use in pediatrics. The International Contrast Ultrasound Society uses this information to continue advocating for the safe and appropriate use of CEUS.

Plaque Elasticity and Intraplaque Neovascularisation on Carotid Artery Ultrasound: A Comparative Histological Study.

OBJECTIVE: Plaque elasticity and intraplaque neovascularisation are strongly suggestive of vulnerable plaque. This study aimed to investigate the relationship between intraplaque neovascularisation and plaque elasticity, and to compare the ultrasound findings with histopathological changes. METHODS: Patients enrolled in this study presented with symptomatic carotid stenosis (> 70%) and later underwent both pre-operative ultrasonography and endarterectomy. Contrast enhanced ultrasound (CEUS) and shear wave elastography (SWE) were used to measure the neovascularisation and elasticity of the plaque, respectively. After removal, plaques were histologically assessed to determine the microvessel density (MVD), matrix metalloproteinase (MMP)-9 expression, and type I/type III collagen ratio using immunohistochemistry staining and morphometry. A correlation analysis was used to establish the relationship among the aforementioned quantitative parameters. Inter- and intra-observer consistency evaluations were performed using the intraclass correlation coefficient and Bland-Altman plots. RESULTS: Ninety-four symptomatic patients with 98 plaques were included. The area under the curve (AUC) of the carotid plaque detected using CEUS correlated with its shear wave velocity (SWV) (r = -.714; p < .001), MVD (r = .842; p < .001), collagen type I/III ratio (r = -.833; p < .001), and MMP-9 (r = .738; p < .001). SWE was positively correlated with the type I/III collagen ratio (r = .805; p < .001). The overall interexaminer consistency of the SWE was acceptable (r = .638; p < .001). The interobserver correlation coefficient of the AUC, time to peak (TP), mean transit time (MTT), and SWV were .719, .756, .733, and .686, respectively. The intra-observer variability values of the AUC, TP, MTT, and SWV were .826, .845, .633, and .748, respectively. CONCLUSION: SWE and CEUS can comprehensively evaluate the vulnerability of the carotid plaque by assessing the elasticity of the plaque and neovascularisation within it. The negative correlation between the intraplaque neovascularisation and elasticity, further validated by histological findings, suggests that the more abundant the neovascularisation, the less elasticity.

Contrast-enhanced ultrasound in pediatric echocardiography.

The safety and benefits of cardiac contrast-enhanced ultrasound (CEUS) have been demonstrated in children and adolescents for a variety of clinical indications, including congenital heart disease. Cardiac CEUS is performed with US and the intravenous administration of ultrasound contrast agents (UCAs). It improves transthoracic echocardiography, which can be challenging in children and adults with acoustic window limitations (e.g., from obesity) and alterations in chest wall and cardiac geometry (e.g., from prior surgical procedures). Cardiac CEUS is also used to evaluate ischemia in the follow-up of congenital and acquired heart disease. In 2019, the United States Food and Drug Administration (FDA) approved a UCA for pediatric echocardiography. This article focuses on the clinical applications of UCAs in pediatric and adult echocardiography, outlining its diagnostic value, safety and potential for future applications.

Pediatric contrast-enhanced ultrasound: shedding light on the pursuit of approval in the United States.

For two decades, pediatric contrast US has been well accepted throughout Europe and other parts of the world outside the United States because of its high diagnostic efficacy and extremely favorable safety profile. This includes intravenous (IV) administration, contrast-enhanced US (CEUS) and the intravesical application, contrast-enhanced voiding urosonography (ceVUS). However, the breakthrough for pediatric contrast US in the United States did not come until 2016, when the U.S. Food and Drug Administration (FDA) approved the first pediatric indication for a US contrast agent. This initial approval covered the use of Lumason (Bracco Diagnostics, Monroe Township, NJ) for the evaluation of focal liver lesions via IV administration in children. A second pediatric indication followed shortly thereafter, when the FDA extended the use of Lumason for assessing known or suspected vesicoureteral reflux via intravesical application in children. Both initial pediatric approvals were granted without prospective pediatric clinical trials, based instead on published literature describing favorable safety and efficacy in children. Three years later, in 2019, the FDA approved Lumason for pediatric echocardiography following a clinical trial involving a total of 12 subjects at 2 sites. The story of how we achieved these FDA approvals spans more than a decade and involves the extraordinary dedication of two professional societies, namely the International Contrast Ultrasound Society (ICUS) and the Society for Pediatric Radiology (SPR). Credit also must be given to the FDA staff for their commitment to the welfare of children and their openness to compelling evidence that contrast US is a safe, reliable, radiation-free imaging option for our pediatric patients. Understanding the history of this approval process will impact the practical application of US contrast agents, particularly when expanding off-label indications in the pediatric population. This article describes the background of the FDA's approval of pediatric contrast US applications to better illuminate the potential pathways to approvals of future indications.

Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography.

Atherosclerotic plaque detection by carotid ultrasound provides cardiovascular disease risk stratification. The advantages and disadvantages of two-dimensional (2D) and three-dimensional (3D) ultrasound methods for carotid arterial plaque quantification are reviewed. Advanced and emerging methods of carotid arterial plaque activity and composition analysis by ultrasound are considered. Recommendations for the standardization of focused 2D and 3D carotid arterial plaque ultrasound image acquisition and measurement for the purpose of cardiovascular disease stratification are formulated. Potential clinical application towards cardiovascular risk stratification of recommended focused carotid arterial plaque quantification approaches are summarized.

The 34th Annual Advances in Contrast Ultrasound International Bubble Conference, Chicago 2019: synopsis and take-home messages.

The 34th annual Advances in Contrast Ultrasound (ACU) International Bubble Conference convened in Chicago, IL, USA, on September 5-6, 2019 to feature new directions of research, preclinical and first-in-man clinical trials, and novel clinical applications highlighting the diversity and utility of contrast enhanced ultrasound (CEUS). An expert group comprising clinicians, engineers, basic scientists, government officials, attorneys, and industry partners convened to collaborate on cutting-edge ultrasound enhancement technology. Utilizing this information, the International Contrast Ultrasound Society (ICUS) continues to have cause to advocate for the safe and appropriate use of CEUS with expanding indications and applications.

Contrast-Enhanced Ultrasound to Assess Carotid Intraplaque Neovascularization.

Contrast-enhanced ultrasound (CEUS) is increasingly being used to identify patients with carotid plaques that are vulnerable to rupture, so-called vulnerable atherosclerotic plaques, by assessment of intraplaque neovascularization. A complete overview of the strengths and limitations of carotid CEUS is currently not available. The aim of this systematic review was to provide a complete overview of existing publications on the role of CEUS in assessment of carotid intraplaque neovascularization. The systematic review of the literature yielded 52 studies including a total of 4660 patients (mean age: 66 y, 71% male) who underwent CEUS for the assessment of intraplaque neovascularization. The majority of the patients (76%) were asymptomatic and had no history of transient ischemic attack (TIA) or stroke. The assessment of intraplaque neovascularization was mostly performed using a visual scoring system; several studies used time-intensity curves or dedicated quantification software to optimize analysis. In 17 studies CEUS was performed in patients before carotid surgery (endarterectomy), allowing a comparison of pre-operative CEUS findings with histologic analysis of the tissue sample that is removed from the carotid artery. In a total of 576 patients, the CEUS findings were compared with histopathological analysis of the plaque after surgery. In 16 of the 17 studies, contrast enhancement was found to correlate with the presence and degree of intraplaque neovascularization on histology. Plaques with a larger amount of contrast enhancement had significantly increased density of microvessels in the corresponding region on histology. In conclusion, CEUS is a readily available imaging modality for the assessment of patients with carotid atherosclerosis, providing information on atherosclerotic plaques, such as ulceration and intraplaque neovascularization, which may be clinically relevant. The ultimate clinical goal is the early identification of carotid atherosclerosis to start early preventive therapy and prevent clinical complications such as TIA and stroke.

Carotid intraplaque neovascularization predicts coronary artery disease and cardiovascular events.

AIMS: It is thought that the majority of cardiovascular (CV) events are caused by vulnerable plaque. Such lesions are rupture prone, in part due to neovascularization. It is postulated that plaque vulnerability may be a systemic process and that vulnerable lesions may co-exist at multiple sites in the vascular bed. This study sought to examine whether carotid plaque vulnerability, characterized by contrast-enhanced ultrasound (CEUS)-assessed intraplaque neovascularization (IPN), was associated with significant coronary artery disease (CAD) and future CV events. METHODS AND RESULTS: We investigated carotid IPN using carotid CEUS in 459 consecutive stable patients referred for coronary angiography. IPN was graded based on the presence and location of microbubbles within each plaque (0, not visible; 1, peri-adventitial; and 2, plaque core). The grades of each plaque were averaged to obtain an overall score per patient. Coronary plaque severity and complexity was also determined angiographically. Patients were followed for 30 days following their angiogram. This study found that a higher CEUS-assessed carotid IPN score was associated with significant CAD (≥50% stenosis) (1.8 ± 0.4 vs. 0.5 ± 0.6, P < 0.0001) and greater complexity of coronary lesions (1.7 ± 0.5 vs. 1.3 ± 0.8, P < 0.0001). Furthermore, an IPN score ≥1.25 could predict significant CAD with a high sensitivity (92%) and specificity (89%). The Kaplan-Meier analysis demonstrated a significantly higher proportion of participants having CV events with an IPN score ≥1.25 (P = 0.004). CONCLUSION: Carotid plaque neovascularization was found to be predictive of significant and complex CAD and future CV events. CEUS-assessed carotid IPN is a clinically useful tool for CV risk stratification in high-risk cardiac patients.

Takotsubo cardiomyopathy in a man with no trigger and multiple cardioembolic complications-A rare constellation.

Takotsubo Cardiomyopathy (TC) is an uncommon, transient, reversible cardiomyopathy, with a classic pattern of wall-motion abnormalities, usually seen in women after an emotional stressor. Despite its increased recognition, there remain gaps in the exact mechanisms, predisposing factors, and predictors of recovery; this is particularly true for males where the condition occurs far less frequently than in females. TC typically resolves within weeks, and the prognosis is favorable compared to acute coronary syndromes. Nonetheless, about 1% of cases may be complicated by left ventricular (LV) thrombus and embolism. Herein we describe an atypical case of a man with no obvious trigger, who developed TC with left ventricular thrombus and multiple embolic complications, but subsequently showed complete and full resolution. Multimodality imaging including echocardiography, cardiac CT and cardiac MRI was instrumental in this diagnostic dilemma, as well as useful in guiding treatment options and informing prognosis.

Use of ultrasound enhancing agents in transesophageal echocardiography to improve interpretive confidence of left atrial appendage thrombus.

BACKGROUND: The value of ultrasound enhancing agents (UEA) in patients undergoing transesophageal echocardiography (TEE) for the exclusion of left atrial appendage (LAA) thrombi prior to direct current cardioversion (DCCV) is evolving. METHODS: We retrospectively identified 88 consecutive TEEs, where a commercial UEA was used during LAA interrogation. De-identified non-enhanced (pre-UEA) and enhanced cine loop images (post-UEA) from the same subjects were randomly reviewed by four expert readers in a blinded fashion. RESULTS: In 33% of the cases, UEA use was associated with a statistically insignificant improvement in physician confidence (scale, 0-3) in determining the presence or absence of a LAA thrombus (P = 0.071). In instances where non-enhanced images yielded an uncertain interpretation or when the left atrium contained spontaneous echo contrast (SEC), UEA use was associated with an improvement in interpretive confidence in 49% (P < 0.001) and 41% of the cases (P = 0.001), respectively. Overall, the absolute rate of hypothetical decision to proceed with DCCV rose by 9% with the application of UEA (P = 0.004). In instances where non-enhanced images were interpreted with limited confidence or when SEC was present, there were absolute increases of 16% (P < 0.001) and 21% (P < 0.001) in hypothetical procession to DCCV, respectively. In cases of a combination of limited interpretive confidence and SEC, UEA use was associated with a 29% absolute increase in the rate of procession to DCCV (P < 0.001). CONCLUSIONS: In patients undergoing TEE interrogation of the LAA, the use of UEA is associated with an increase in the level of interpretive confidence and higher rates of theoretical procession to DCCV.

In-hospital statin underutilization among high-risk patients: delayed uptake of the 2013 cholesterol guidelines in a U.S. cohort.

OBJECTIVES: Clinician utilization of the 2013 cholesterol lowering guidelines remains variable and unknown. We sought to examine statin prescribing patterns and compare rates among specialists who treat high-risk cardiovascular patients admitted to the hospital. METHODS: We retrospectively (via chart review) examined four specialty groups: (i) Cardiology, (ii) Cardiovascular or Vascular (CV) Surgery, (iii) Neurology, and (iv) Internal Medicine. Adult patients were included based on a discharge diagnosis of acute coronary syndrome, coronary artery bypass graft surgery, carotid endarterectomy, acute ischemic stroke, transient ischemic attack, or high-risk chest pain. Prescribing patterns were evaluated 6 months and 18 months after the release of the 2013 guidelines. High-intensity statin was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg per day. RESULTS: 632 patients were included in our study. The following percentages of patients were discharged on high-intensity statin (6 months; 18 months): (i) Cardiology (80%; 85%), (ii) CV Surgery (52%, 65%), (iii) Neurology (59%; 66%), and (iv) Internal Medicine (45%; 48%). Among the four groups, Cardiology was the most likely to discharge patients on high-intensity statin (p < 0.001) in 2014 and in 2015. Cardiology, CV Surgery, and Neurology significantly increased the percentage of patients on high-intensity statin from pre-admission to time of discharge in both years. CONCLUSION: High-intensity statin therapy is underutilized among high-risk cardiovascular patients admitted to the hospital. Variations exist in prescribing patterns of different specialties who manage high-risk populations. This data can be used to test quality improvement interventions to improve rates of high-intensity statin utilization among high-risk patients prior to hospital discharge.