History of contrast enhanced ultrasound (CEUS).

The 50th year of the European Federation of Societies in Ultrasound in Medicine and Biology (EFSUMB) has been celebrated 2022 publishing articles on the history of US. Contrast enhanced ultrasound (CEUS) allows to visualize blood flow and tissue perfusion. CEUS has proven to be safe without risk of nephrotoxicity. The availability of a contrast agent (tracer) for ultrasound imaging allows for the first time a dynamic assessment of tissue perfusion (blood flow and wash-in/wash-out pattern) which is an essential part for the detection and characterisation of pathological tissue and abnormal organ function. It was an outstanding achievement of academic centers in close cooperation with EFSUMB to investigate and validate the clinical potential of this new technology for the diagnosis and monitoring of various diseases and to develop clinical guidelines based on an in-depth assessment of the existing scientific publications. An important part of the implementation of CEUS in clinical practice was the development of contrast-specific imaging modes on the ultrasound scanners (in close cooperation with the machine manufacturers), the optimization of the machine setups for contrast imaging and the education provided to clinical users in form of workshops, webinars, textbooks and scientific congresses.

Acceptance of Telemedicine Compared to In-Person Consultation From the Providers' and Users' Perspectives: Multicenter, Cross-Sectional Study in Dermatology.

BACKGROUND: Teledermatology is currently finding its place in modern health care worldwide as a rapidly evolving field. OBJECTIVE: The aim of this study was to investigate the acceptance of teledermatology compared to in-person consultation from the perspective of patients and professionals. METHODS: This multicenter, cross-sectional pilot study was performed at secondary and tertiary referral centers of dermatology in Switzerland from August 2019 to January 2020. A customized questionnaire addressing demographics and educational data, experience with telemedicine, and presumed willingness to replace in-patient consultations with teledermatology was completed by dermatological patients, dermatologists, and health care workers in dermatology. RESULTS: Among a total of 664 participants, the ones with previous telemedicine experience (171/664, 25.8%) indicated a high level of overall experience with it (patients: 73/106, 68.9%, dermatologists: 6/8, 75.0%, and health care workers: 27/34, 79.4%). Patients, dermatologists, and health care workers were most likely willing to replace in-person consultations with teledermatology for minor health issues (353/512, 68.9%; 37/45, 82.2%; and 89/107, 83.2%, respectively). We observed a higher preference for telemedicine among individuals who have already used telemedicine (patients: P<.001, dermatologists: P=.03, and health care workers, P=.005), as well as among patients with higher educational levels (P=.003). CONCLUSIONS: This study indicates that the preference for teledermatology has a high potential to increase over time since previous experience with telemedicine and a higher level of education were associated with a higher willingness to replace in-patient consultations with telemedicine. We assume that minor skin problems are the most promising issue in teledermatology. Our findings emphasize the need for dermatologists to be actively involved in the transition to teledermatology. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495036; https://classic.clinicaltrials.gov/ct2/show/NCT04495036.

Smart e-Skin Cancer Care in Europe During and after the Covid-19 Pandemic: a Multidisciplinary Expert Consensus.

INTRODUCTION: Melanoma is the deadliest of all the skin cancers and its incidence is increasing every year in Europe. Patients with melanoma often present late to the specialist and treatment is delayed for many reasons (delay in patient consultation, misdiagnosis by general practitioners, and/or limited access to dermatologists). Beyond this, there are significant inequalities in skin cancer between population groups within the same country and between countries across Europe. The emergence of the COVID-19 pandemic only aggravated these health deficiencies. OBJECTIVES: The aim was to create an expert opinion about the challenges in skin cancer management in Europe during the post COVID-19 acute pandemic and to identify and discuss the implementation of new technologies (including e-health and artificial intelligence defined as "Smart Skin Cancer Care") to overcome them. METHODS: For this purpose, an ad-hoc questionnaire with items addressing topics of skin cancer care was developed, answered independently and discussed by a multidisciplinary European panel of experts comprising dermatologists, dermato-oncologists, patient advocacy representatives, digital health technology experts, and health technology assessment experts. RESULTS: After all panel of experts discussions, a multidisciplinary expert opinion was created. CONCLUSIONS: As a conclusion, the access to dermatologists is difficult and will be aggravated in the near future. This fact, together with important differences in Skin Cancer Care in Europe, suggest the need of a new approach to skin health, prevention and disease management paradigm (focused on integration of new technologies) to minimize the impact of skin cancer and to ensure optimal quality and equity.

Unmet digital health service needs in dermatology patients.

BACKGROUND: Digital health services are rapidly gaining acceptance in healthcare systems. Dermatology as an image-centric specialty is particularly well suited for telemedical services. However, dermatology patients' demands of electronic services remain largely unexplored. METHODS: This study investigated patients' views in primary, secondary, and tertiary referral centers. In August 2017, 841 questionnaires were filled in by dermatology patients. RESULTS: 76.34% expressed interest in using digital healthcare services as part of medical consultations. 84.41% of all patients would complete their initial registration form electronically. Fewer patients were comfortable with sending pictures of skin changes to their doctors using email (40.89%) or mobile health applications (40.61%). Specific interest was indicated for arranging appointments online (90.80%) and electronically-placed prescriptions (76.56%), rather than online learning videos (42.03%), and actual online consultations (34.53%). 65.37% of patients would pay for online consultations themselves. CONCLUSIONS: Taken together, interest in electronic health services is high in dermatology patients. Our data suggest that readily understandable electronic services such as online-arranged appointments and electronic prescriptions are of higher interest to patients than the current type of online consultations. Therefore, the full potential of teledermatology still remains to be tapped by newer, more attractive forms of services closely adapted to patients' demands.

Intestinal T lymphocyte homing is associated with gastric emptying and epithelial barrier function in critically ill: a prospective observational study.

BACKGROUND: Impaired gastric emptying is common in critically ill patients. Intestinal dysmotility, a major cause of feed intolerance, may foster infectious complications due to mucosal barrier disruption. However, little is known about gut-directed immune activation, intestinal barrier function and its association with impaired gastric emptying in critically ill patients at ICU admission. METHODS: We conducted a prospective observational study at two tertiary care medical ICUs. Fifty consecutive patients needing invasive mechanical ventilation were recruited within 24 h of ICU admission, prior to any nutritional support. The acute physiology and chronic health evaluation (APACHE) II score, the sequential organ failure assessment (SOFA) score and the multiple organ dysfunction score (MODS) were used to assess illness severity and multiple organ dysfunction. Gastric emptying was assessed by paracetamol absorption test. Peripheral blood mononuclear cells were freshly isolated and cultured for 24 h, and TNF-α, IL-1ß and IL-10 measured in cell culture supernatants and in serum by ELISA. The intestinal epithelial barrier was assessed, quantifying serum concentrations of intestinal fatty acid binding protein (I-FABP), ileal bile-acid binding protein (I-BABP) and zonulin-1 by ELISA. Small bowel homing T lymphocytes (CD4+ α4ß7 + CCR9+) were analyzed by flow cytometry. The Mann-Whitney test and Spearman correlation were used in statistical evaluation. RESULTS: CD4 + α4ß7 + CCR9+ T lymphocytes were inversely correlated with gastric emptying. Patients with delayed gastric emptying at ICU admission (n = 35) had significantly higher serum and PBMC-induced TNF-α and IL-1ß and increased intestinal barrier disruption reflected by higher I-FABP, I-BABP and zonulin-1. Patients who died in the ICU had significantly impaired gastric empting at admission compared to ICU survivors. No differences were observed in APACHE II, SOFA or MODS in patients with delayed gastric emptying compared to patients with normal gastric emptying. CONCLUSIONS: Exaggerated CD4 + α4ß7 + CCR9+ T lymphocyte homing with increased pro-inflammatory cytokine release and intestinal epithelial barrier disruption are associated with delayed gastric emptying. This is not simply due to differences in overall severity of illness at ICU admission and may represent a pathophysiological mechanism of gut-directed immune activation leading to impaired barrier function in the critically ill.

[How to perform contrast enhanced ultrasound]. / Kontrastmittelsonografie des Abdomens.

This review article reports on practical and clinical aspects of contrast enhanced ultrasound (CEUS). We discuss practical recommendations and advice on the use of CEUS.

Analysis of left ventricular volumes and function: a multicenter comparison of cardiac magnetic resonance imaging, cine ventriculography, and unenhanced and contrast-enhanced two-dimensional and three-dimensional echocardiography.

BACKGROUND: Contrast echocardiography improves accuracy and reduces interreader variability on left ventricular (LV) functional analyses in the setting of two-dimensional (2D) echocardiography. The need for contrast imaging using three-dimensional (3D) echocardiography is less defined. The aim of this multicenter study was to define the accuracy and interreader agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography for the assessment of LV volumes and ejection fraction (EF). METHODS: A multicenter, open-label study was conducted including 63 patients, using intrasubject comparisons to assess the agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography as well as calibrated biplane cine ventriculography with cardiac magnetic resonance for the determination of LV volumes and EF. Each of the imaging techniques used to define LV function was assessed by two independent, off-site readers unaware of the results of the other imaging techniques. RESULTS: LV end-systolic and end-diastolic volumes were underestimated by 2D and 3D unenhanced echocardiography compared with cardiac magnetic resonance. Contrast enhancement resulted in similar significant increases in LV volumes on 2D and 3D echocardiography. The mean percentage of interreader variability for LV EF was reduced from 14.3% (95% confidence interval [CI], 11.7%-16.8%) for unenhanced 2D echocardiography and 14.3% (95% CI, 9.7%-18.9%) for unenhanced 3D echocardiography to 8.0% (95% CI, 6.3%-9.7%; P < .001) for contrast-enhanced 2D echocardiography and 7.4% (95% CI, 5.7%-9.1%; P < .01) for contrast-enhanced 3D echocardiography and thus to a similar level as for cardiac magnetic resonance (7.9%; 95% CI, 5.4%-10.5%). A similar effect was observed for interreader variability for LV volumes. CONCLUSIONS: Contrast administration on 3D echocardiography results in improved determination of LV volumes and reduced interreader variability. The use of 3D echocardiography requires contrast application as much as 2D echocardiography to reduce interreader variability for volumes and EF.

Comparison of two- and three-dimensional unenhanced and contrast-enhanced echocardiographies versus cineventriculography versus cardiac magnetic resonance for determination of left ventricular function.

Contrast enhancement has been shown to improve detection of regional wall motion abnormalities (RWMA) in 2-dimensional (2D) echocardiography. This study determined the use of contrast enhancement in the setting of 3-dimensional (3D) echocardiography for definition of left ventricular RWMA compared with 2D echocardiography, cineventriculography, and cardiac magnetic resonance (CMR). In 63 patients, unenhanced and contrast-enhanced (SonoVue; Bracco Imaging S.p.A., Milan, Italy) 2D and 3D echocardiographies, CMR, and cineventriculography were performed. Hypokinesia in ≥1 segment defined the presence of RWMA. Interreader agreement (IRA) between 2 blinded off-site readers on presence of RWMA was determined within each imaging technique. Intermethod agreement among imaging techniques was analyzed. A standard of truth for the presence of RWMA was obtained by an independent expert panel decision. IRA on presence of RWMA expressed as Cohen's κ coefficient was 0.27 for unenhanced 3D echocardiography, 0.40 for unenhanced 2D echocardiography, 0.57 for CMR, and 0.51 for cineventriculography. The use of contrast increased IRA on RWMA to 0.42 for 3D echocardiography and to 0.56 for 2D echocardiography. Agreement with CMR on RWMA increased for 3D echocardiography when contrast enhancement was used (κ 0.40 vs 0.22 for unenhanced 3D echocardiography). Similarly, agreement of 2D echocardiography with CMR on RWMA increased with contrast enhancement (κ 0.50 vs 0.32). Accuracy to detect expert panel-defined RWMA was highest for CMR (84%) followed by 2D contrast echocardiography (78%) and 3D contrast echocardiography (76%). It was lesser for 2D and 3D unenhanced echocardiographies. In conclusion, analysis of RWMA is characterized by considerable interreader variability even using high-quality imaging techniques. IRA on RWMA is lower with 3D echocardiography compared with 2D echocardiography. IRA on RWMA and accuracy to detect panel-defined RWMA improve with contrast enhancement irrespective of the 2D or 3D echocardiography use.

Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS).

Ultrasound contrast agents consist of tiny gas-filled microbubbles the size of red blood cells. Due to their size distribution, they are purely intravascular tracers which do not extravasate into the interstitial fluid, and thus they are perfect agents for imaging blood distribution and flow. Using ultrasound scanners with contrast-specific software, the specific microbubble-derived echo signals can be separated from tissue signals in realtime, allowing selective imaging of the contrast agent. The signal intensity obtained lies in a linear relationship to the amount of microbubbles in the target organ, which allows easy and reliable assessment of relative blood volume. Imaging of the contrast wash-in and wash-out after bolus injection, or more precisely using the flash-replenishment technique, allows assessment of regional blood flow velocity. Commercially available quantification software packages can calculate time-related intensity values from the contrast wash-in and wash-out phase for each image pixel from stored video clips. After fitting of a mathematical model curve according to the respective kinetic model (bolus or flash-replenishment kinetics), time/intensity curves (TIC) can be calculated from single pixels or user-defined regions of interest (ROI). Characteristic parameters of these TICs (e.g. peak intensity, area under the curve, wash-in rate, etc.) can be displayed as color-coded parametric maps on top of the anatomical image, to identify cold and hot spots with abnormal perfusion.

Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.

AIM: To evaluate in a multicenter study whether the sonographic characterization of focal liver lesions can be improved using SonoVue-enhancement; and to compare this method with computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: One hundred and thirty four patients with one focal liver lesion detected in baseline ultrasound (US) were examined with conventional US, contrast-enhanced US (n = 134), contrast-enhanced CT (n = 115) and/or dynamic contrast-enhanced MRI (n = 70). The lesions were classified as malignant, benign or indeterminate and the type of lesion was determined. The final diagnosis based on the combined information of all imaging examinations, clinical information and histology (n = 32) was used. Comparisons were made to see whether the addition of contrast-enhanced US led to the improvement of the characterization of doubtful focal liver lesions. RESULTS: In comparison with unenhanced US, SonoVue markedly improves sensitivity and specificity for the characterization (malignant/benign) of focal liver lesions. In comparison with CT and/or dynamic MRI, SonoVue-enhanced sonography applied for characterization of focal liver lesions was 30.2% more sensitive in the recognition of malignancy and 16.1% more specific in the exclusion of malignancy and overall 22.9% more accurate. In the subgroup with confirmative histology available (n = 30), sensitivity was 95.5% (CEUS), 72.2% (CT) and 81.8% (MRI), and specificity was 75.0% (CEUS), 37.5% (CT) and 42.9% (MRI). The sensitivity and specificity of CEUS for the identification of focal nodular hyperplasia (FNH) and hemangiomas was 100% and 87%, resulting in an accuracy of 94.5%. CONCLUSION: SonoVue-enhanced sonography emerges as the most sensitive, most specific and thus most accurate imaging modality for the characterization of focal liver lesions.

Ultrasound contrast agents as markers of vascularity and microcirculation.

Ultrasound contrast agents contain tiny gas-filled microbubbles which on intravenous injection are transported like red blood cells by the bloodstream. They are distributed to the entire macro- and microvascular system without extravasation (blood-pool tracer). Contrast-specific ultrasound modalities allow selective imaging of these microbubble contrast agents in real time, with excellent separation from underlying tissue signals. The dynamic wash-in and wash-out of a contrast bolus allows the detection and quantitative assessment of vascular flow and parenchymal perfusion. On complete filling of vascular structures the microbubble distribution delineates the vascular lumen and depicts the vascular architecture, down to tiny branches within parenchymal tissue. Mathematical models for bolus kinetics and flash/replenishment kinetics allow precise quantification of relative blood volume and blood flow, with high temporal and spatial resolution. Contrast-enhanced ultrasound examinations can be repeated at short intervals and performed at the bedside, making this diagnostic method convenient for guidance of interventions and therapy monitoring. Future applications include the use of microbubbles as target-specific molecular imaging agents and as delivery systems for local drug and gene therapies.

Analysis of myocardial perfusion or myocardial function for detection of regional myocardial abnormalities. An echocardiographic multicenter comparison study using myocardial contrast echocardiography and 2D echocardiography.

BACKGROUND: Echocardiography based myocardial perfusion imaging and regional wall motion analysis are used for evaluation of coronary artery disease and regional myocardial abnormalities. AIM: This study sought to compare myocardial contrast echocardiography (MCE) and 2D echocardiography with regard to interobserver variability and detection of regional myocardial abnormalities. METHODS: In 70 patients evenly distributed between three ejection fraction groups based on biplane cineventriculography ( > 55%, 35-55%, < 35%), unenhanced and contrast enhanced 2D echocardiography and myocardial contrast echocardiography (MCE; SonoVue; Bracco) were performed. Regional wall motion and myocardial perfusion were assessed referring to a 16 segment model. Interobserver agreement (IOA) among 2 readers was determined within each imaging modality. To define a standard of truth for the presence of segmental myocardial disease an independent expert-panel decision was obtained based on clinical data, ECG, coronary angiography and blinded information from the imaging modalities. RESULTS: Regional wall motion assessment was possible in 98.1% of segments using contrast enhanced 2D echocardiography and in 87.2% using unenhanced 2D echocardiography (p < 0.001), while perfusion assessment was possible in 90.1% of segments (p < 0.001). IOA on presence of any regional wall motion abnormality expressed as Kappa coefficient was 0.71 (95% CI 0.53-0.89) for contrast enhanced echocardiography and 0.37 (95% CI 0.14-0.59) for unenhanced echocardiography. IOA on presence of any perfusion abnormality was 0.53 (95% CI 0.34-0.73). For MCE there was high IOA for the apical segments (kappa = 0.57) and lower IOA for the basal segments (kappa=0.14), while no such gradient was found for the IOA on wall motion abnormalities. Mean accuracy to detect expert-panel defined myocardial abnormalities was 80.6% for unenhanced echocardiography, 85.0% for contrast enhanced 2D echocardiography and 80.6% for MCE. CONCLUSIONS: MCE is inferior to contrast enhanced 2D echocardiography with regard to visibility of all LV segments and appears slightly inferior with regards to IOA, while both are superior to unenhanced 2D echocardiography. The methods demonstrated high accuracy in detection of panel defined regional myocardial abnormalities.

Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.

AIM: To evaluate contrast-enhanced ultrasonography (CEUS) using SonoVue in the detection of liver metastases in patients with known extrahepatic primary tumors versus the combined gold standard comprising CT, MRI and clinical/histological data. METHODS: It is an international multicenter study, and there were 12 centres and 125 patients (64 males, 61 females, aged 59+/-11 years) involved, with 102 patients per protocol. Primary tumors were colorectal in 35%, breast in 27%, pancreatic in 17% and others in 21%. CEUS using SonoVue was employed with a low-mechanical-index technique and contrast-specific software using Siemens Elegra, Philips HDI 5000 and Acuson Sequoia; continuous scanning for at least five minutes. RESULTS: CEUS with SonoVue increased significantly the number of focal liver lesions detected versus unenhanced sonography. In 31.4% of the patients, more lesions were found after contrast enhancement. The total numbers of lesions detected were comparable with CEUS (55), triple-phase spiral CT (61) and MRI with a liver-specific contrast agent (53). Accuracy of detection of metastatic disease (i.e. at least one metastatic lesion) was significantly higher for CEUS (91.2%) than for unenhanced sonography (81.4%) and was similar to that of triple-phase spiral CT (89.2%). In 53 patients whose CEUS examination was negative, a follow-up examination 3-6 mo later confirmed the absence of metastatic lesions in 50 patients (94.4%). CONCLUSION: CEUS is proved to be reliable in the detection of liver metastases in patients with known extrahepatic primary tumors and suspected liver lesions.

Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, and unenhanced and contrast-enhanced echocardiography: a multicenter comparison of methods.

OBJECTIVES: To define the use of cineventriculography, cardiac magnetic resonance imaging (cMRI), and unenhanced and contrast-enhanced echocardiography for detection of left ventricular (LV) regional wall motion abnormalities (RWMA). BACKGROUND: Detection of RWMA is integral to the evaluation of LV function. METHODS: In 100 patients, cineventriculography and unenhanced and contrast-enhanced echocardiography were performed. Fifty-six of the patients underwent additional cMRI. RWMA were assessed referring to a 16-segment model for cMRI, unenhanced and contrast echocardiography. Cineventriculography was evaluated on a 7-segment model. Hypokinesia in one or more segments defined presence of RWMA. Interobserver agreement among three readers was determined within each imaging modality. Intermethod agreement between imaging modalities was analyzed. A standard of truth for the presence of RWMA was obtained by an independent expert panel decision (EPD) based on clinical data, electrocardiogram, coronary angiography, and blinded information from the imaging modalities. RESULTS: Sixty-seven patients were found to have an RWMA by EPD. Interobserver agreement expressed as kappa coefficient was 0.41 (range 0.37 to 0.44) for unenhanced echocardiography, 0.43 (range 0.29 to 0.79) for cMRT, 0.56 (range 0.44 to 0.70) for cineventriculography, and 0.77 (range 0.71 to 0.88) for contrast echocardiography. Contrast enhancement compared to unenhanced echocardiography improved agreement of echocardiography related to cMRI (kappa 0.46 vs. 0.29) and related to cineventriculography (kappa 0.59 vs. 0.28). Accuracy to detect EPD-defined RWMA was highest for contrast echocardiography, followed by cMRI, unenhanced echocardiography, and cineventriculography. CONCLUSIONS: Analysis of RWMA is characterized by considerable interobserver variability even using high-quality imaging modalities. Interobserver agreement on RWMA and accuracy to detect panel-defined RWMA is good using contrast echocardiography.