Ultrasound is a noninvasive imaging modality that provides anatomical and functional information of various human body areas. It is one of the most widely used imaging modalities worldwide, with frequent use in oncology. Novel ultrasound techniques, such as elastography and contrast-enhanced ultrasound, have evolved and have led to new clinical applications beyond conventional anatomical imaging with conventional ultrasound or blood flow assessment using Doppler ultrasound. Contrast-enhanced ultrasound (CEUS) uses microbubbles as a contrast medium, and specific contrast-enhanced ultrasound techniques have been developed, making CEUS an extremely sensitive imaging modality. Classic microbubbles remain strictly intravascular due to their size and can be detected down to the capillary level. Together with the most recent techniques (super-resolution imaging), bubbles even allow for an extremely high spatial resolution ultrasound imaging beyond the wavelength barrier. This chapter within Recent Results in Cancer Research Under Molecular Imaging in Oncology provides an overview of current applications in humans. Since specific microbubbles are not yet available as commercial products and their wide clinical use is still limited, results of first experiences with molecular ultrasound imaging in humans are presented. Furthermore, to give an overview in a broader sense-not only of molecular ultrasound imaging but also of contrast-enhanced ultrasound for molecular or specific diagnosis-also related studies with nonspecific, commercial ultrasound contrast agents are briefly described within the field of molecular diagnosis and monitoring of targeted therapies in oncology. Furthermore, first experiences in humans with super-resolution ultrasound imaging as a potential breakthrough technique are presented.

In all imaging methods, including contrast-enhanced ultrasound (CEUS), enhancement in the late phase (LP) is an important criterion for differentiating between benign and malignant focal liver lesions (FLLs). In general, malignant liver lesions are characterized by hypoenhancement and washout in the LP. A lesion with LP hyperenhancement or isoenhancement in the non-cirrhotic liver is usually benign. However, LP hypoenhancement in benign lesions is not so rare, and is even normal and the standard for some lesions, and there are exceptions for each tumor entity that can represent a diagnostic challenge. Knowing these contrast patterns and exceptions is key for correct diagnosis and patient management. The following narrative review describes the contrast behaviors and the frequency of washout and LP hypoenhancement for common as well as rare benign liver lesions and analyzes its causes.

Dynamic contrast-enhanced ultrasound (DCE-US) is a technique to quantify tissue perfusion based on phase-specific enhancement after the injection of microbubble contrast agents for diagnostic ultrasound. The guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) published in 2004 and updated in 2008, 2011, and 2020 focused on the use of contrast-enhanced ultrasound (CEUS), including essential technical requirements, training, investigational procedures and steps, guidance regarding image interpretation, established and recommended clinical indications, and safety considerations. However, the quantification of phase-specific enhancement patterns acquired with ultrasound contrast agents (UCAs) is not discussed here. The purpose of this EFSUMB Technical Review is to further establish a basis for the standardization of DCE-US focusing on treatment monitoring in oncology. It provides some recommendations and descriptions as to how to quantify dynamic ultrasound contrast enhancement, and technical explanations for the analysis of time-intensity curves (TICs). This update of the 2012 EFSUMB introduction to DCE-US includes clinical aspects for data collection, analysis, and interpretation that have emerged from recent studies. The current study not only aims to support future work in this research field but also to facilitate a transition to clinical routine use of DCE-US.

This World Federation for Ultrasound in Medicine and Biology position paper reviews the diagnostic potential of ultrasound contrast agents for clinical decision-making and provides general advice for optimal contrast-enhanced ultrasound performance in musculoskeletal issues. In this domain, contrast-enhanced ultrasound performance has increasingly been investigated with promising results, but still lacks everyday clinical application and standardized techniques; therefore, experts summarized current knowledge according to published evidence and best personal experience. The goal was to intensify and standardize the use and administration of ultrasound contrast agents to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients.

Das Operationsergebnis nach Implantation einer inversen Schulterprothese hängt maßgeblich vom Zustand des Musculus deltoideus ab, welcher in dieser Studie mit neuen Ultraschallmodalitäten und Elektromyografie (EMG) untersucht wurde. Kontrastverstärkter dynamischer Ultraschall (contrast-enhanced ultrasound – CEUS) und Elastografie (acoustic radiation force impulse – ARFI) wurden eingesetzt um die Perfusion und Elastizität des Deltamuskels zu erfassen. Diese wurden mit funktionellen und klinischen Ergebnissen verglichen, um so ein umfassenderes Bild der Integrität des Deltamuskels zu erhalten.

Recent approaches to reducing radiation exposure during CT examinations typically utilize automated dose modulation strategies on the basis of lower tube voltage combined with iterative reconstruction and other dose-saving techniques. Less clearly appreciated is the potentially substantial role that iodinated contrast media (CM) can play in low-radiation-dose CT examinations. Herein we discuss the role of iodinated CM in low-radiation-dose examinations and describe approaches for the optimization of CM administration protocols to further reduce radiation dose and/or CM dose while maintaining image quality for accurate diagnosis. Similar to the higher iodine attenuation obtained at low-tube-voltage settings, high-iodine-signal protocols may permit radiation dose reduction by permitting a lowering of mAs while maintaining the signal-to-noise ratio. This is particularly feasible in first pass examinations where high iodine signal can be achieved by injecting iodine more rapidly. The combination of low kV and IR can also be used to reduce the iodine dose. Here, in optimum contrast injection protocols, the volume of CM administered rather than the iodine concentration should be reduced, since with high-iodine-concentration CM further reductions of iodine dose are achievable for modern first pass examinations. Moreover, higher concentrations of CM more readily allow reductions of both flow rate and volume, thereby improving the tolerability of contrast administration.

Recent approaches to reducing radiation exposure during CT examinations typically utilize automated dose modulation strategies on the basis of lower tube voltage combined with iterative reconstruction and other dose-saving techniques. Less clearly appreciated is the potentially substantial role that iodinated contrast media (CM) can play in low-radiation-dose CT examinations. Herein we discuss the role of iodinated CM in low-radiation-dose examinations and describe approaches for the optimization of CM administration protocols to further reduce radiation dose and/or CM dose while maintaining image quality for accurate diagnosis. Similar to the higher iodine attenuation obtained at low-tube-voltage settings, high-iodine-signal protocols may permit radiation dose reduction by permitting a lowering of mAs while maintaining the signal-to-noise ratio. This is particularly feasible in first pass examinations where high iodine signal can be achieved by injecting iodine more rapidly. The combination of low kV and IR can also be used to reduce the iodine dose. Here, in optimum contrast injection protocols, the volume of CM administered rather than the iodine concentration should be reduced, since with high-iodine-concentration CM further reductions of iodine dose are achievable for modern first pass examinations. Moreover, higher concentrations of CM more readily allow reductions of both flow rate and volume, thereby improving the tolerability of contrast administration.

Objectives-Bone regeneration depends on perfusion of the fracture tissue, whereby hypervascularity is associated with infection, which itself causes nonunions. To date, nonunion perfusion has not been assessed with contrast-enhanced sonography. The aim of this study was to evaluate the potential of contrast-enhanced sonography in the analysis of nonunion tissue perfusion.Methods-Nonunion vascularity of 31 patients before revision surgery was prospectively examined with qualitative contrast-enhanced sonography and dynamic contrast-enhanced magnetic resonance imaging (MRI). Time-intensity curves from 2-minute contrast-enhanced sonographic video clips were generated, and parameters such as wash-in rate, rise time, and peak enhancement were quantified. On dynamic contrast-enhanced MRI, the initial area under the enhancement curve was quantified. Preoperative radiographs, computed tomograms, the clinical nonunion score, laboratory infection features, as well as contrast-enhanced sonographic and dynamic contrast-enhanced MRI perfusion were correlated with microbiological results from the nonunion tissue.Results-Both qualitative and quantitative contrast-enhanced sonography showed significant differences between infected and aseptic nonunions (P=.015 and .020). The qualitative dynamic contrast-enhanced MRI analysis was not significant (P=.244), but after quantification, a strong correlation (P=.007) with microbiological results was noted. A receiver operating characteristic analysis calculated ideal cutoff values for quantitative contrast-enhanced sonography and dynamic contrast-enhanced MRI so that their combination detected infected nonunions with sensitivity and specificity of 88.9% and 77.3%, respectively. Clinical, radiologic, and laboratory examinations did not correlate with microbiological results (P > .05).Conclusions-Contrast-enhanced sonography can visualize the vascularity of nonunions in real time, while quantification software allows for a semiobjective evaluation of bone perfusion. The correlations of both quantitative contrast-enhanced sonography and dynamic contrast-enhanced MRI with microbiological results show their high value for differentiation of infected from aseptic nonunions.

Background: The outcome after reverse shoulder arthroplasty (RSA) depends on the condition of the deltoid muscle, which we assessed with new ultrasound modalities and electromyography (EMG). Contrastenhanced ultrasound (CEUS) and acoustic radiation force impulse (ARFI) were applied to assess perfusion and elasticity of the deltoid muscle compared with the clinical and functional outcome. Methods: The study recruited 64 patients (mean age, 72.9 years) treated with RSA between 2004 and 2013. The deltoid muscle was examined with EMG and ultrasound imaging. Functional scores such as Constant score and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score were assessed. Among other CEUS parameters, the wash-in perfusion index, time to peak, and rise time were compared between the operated-on and contralateral shoulders as well as between patients with above-average and below-average outcome. The stiffness of the deltoid muscle was analyzed with ARFI. Results: After RSA, deltoid perfusion (wash-in perfusion index Delta = -12% +/- 22%, P = .0001) and shoulder function (Constant score, Delta = -14 +/- 24, P < .0001) were both inferior compared with the contralateral side. This perfusion deficit was associated with a limited range of motion (time to peak and anteversion: r = -0.290, P = .022). Deltoid perfusion was higher in patients with above-average outcome (rise time, Delta = 33% +/- 13%, P = .038). The operated-on deltoid muscles showed higher stiffness than the contralateral muscles (ARFI, Delta = 0.2 +/- 0.9 m/s, P = .0545). EMG excluded functionally relevant axillary nerve injuries in the study population. Conclusions: CEUS revealed reduced mean perfusion of the deltoid muscle after RSA. Reduced perfusion was associated with limited range of motion and below-average outcome. Functional shoulder impairment after RSA might be predicted by noninvasive CEUS as a surrogate parameter for the integrity of the deltoid muscle. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

Ziel: Pseudarthrosen treten in bis zu 10% nach Röhrenknochenfrakturen auf. Die Knochenregeneration hängt wesentlich von der Perfusion des Frakturgewebes ab, wohingegen Hypervaskularität mit Infekten assoziiert ist, welche wiederum zu Pseudarthrosen führen. Bisher wurde die Pseudarthrosenperfusion mit kontrastverstärkter Magnetresonanztomografie (DCE-MRT) evaluiert. Kontrastverstärkter Ultraschall (CEUS) ist im klinischen Alltag bei dieser Fragestellung noch nicht etabliert.

PURPOSE:The present study evaluates the combination of a high iodine delivery rate with a low tube current-time product for pulmonary computed tomography angiography (CTA).MATERIALS AND METHODS:One-hundred nineteen consecutive patients undergoing pulmonary CTA for suspected pulmonary embolism were included and imaged on a 128-row computed tomography scanner at 100 kVp using highly concentrated contrast material (85 mL Iomeprol; 400 mg iodine/mL). The protocol entailed a flow rate of 5 mL/s and 90 mAs for group A, 3.5 mL/s and 135 mAs for group B, 5 mL/s and 135 mAs for group C, and 3.5 mL/s and 90 mAs for group D. Signal-to-noise ratio and contrast-to-noise ratio (CNR) were determined for the pulmonary artery. Subjective image quality (IQ) was rated on a 5-point scale (1=nondiagnostic IQ to 5=excellent IQ).RESULTS:CNR did not differ significantly between groups A (43.7±27.7), B (34.5±17.9), and C (38.9±13.8), as well as between groups B and D (29.9±11.2). CNR was higher in groups A and C than in group D (P<0.02). Subjective IQ was higher in group A than in groups B and D (P<0.05). Subjective IQ was significantly higher in group A compared with group D (P=0.026) and in group C compared with group D (P=0.007).CONCLUSIONS:A high iodine delivery rate permits dose reduction in pulmonary CTA and can be recommended in patients with suspected pulmonary embolism.

Purpose: To investigate muscular micro-perfusion by employing dynamic contrast-enhanced ultrasound (CEUS) and performing transient arterial occlusion in patients with type 2 diabetes mellitus (DM-2). Methods: Twenty DM-2 patients (mean age, 58 ± 8.6 years; duration of diabetes, 15.4 ± 12.1 years) and 20 healthy volunteers (mean age, 54 ± 5.4 years) participated. CEUS was applied to the calf, while 4.8 mL of SonoVue® was injected intravenously. At the thigh level, arterial occlusion (60 s) was performed. CEUS parameters (tmax, max, AUCpost and m) were evaluated and Pearson-product-moment correlation coefficients were computed. Results: A moderate negative correlation of HbA1c and max was established (−0.53). Max in patients with DM-2 >10 years was 79.89 ± 37.4. Max in patients with DM-2 duration <10 years was 137.62 ± 71.72 (p = 0.04). AUCpost in patients with DM-2 duration >10 years was 3924.01 ± 1630.52. AUCpost in patients with DM-2 duration <10 years was 6453.59 ± 3206.23 (p = 0.04). Conclusion: Patients with long history of DM-2 present with impaired muscular perfusion. CEUS and transient arterial occlusion may provide appropriate methods for semi-quantitative evaluation of muscular micro-perfusion in patients with DM-2.

German Cancer Research Center, Research Program Imaging and Radiooncology, Department of Radiology, INF 280, D-69120 Heidelberg, Germany Bracco Imaging Germany, Max-Stromeyer-Str. 116, D-78467 Konstanz, Germany German Cancer Research Center, Department of Translational Oncology, INF 280, D-69120 Heidelberg, Germany University Hospital of Heidelberg, Department of Vascular Surgery, INF 110, D-69120 Heidelberg, Germany University Hospital of Heidelberg, Department of Diagnostic and Interventional Radiology, INF 110, D-69120 Heidelberg, Germany

Objective: To quantify muscular micro-perfusion and arterial perfusion reserve in peripheral arterial disease (PAD) with dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion.Materials and methods: This study had local institutional review board approval and written informed consent was obtained from all subjects. We examined the dominant lower leg of 40 PAD Fontaine stage IIb patients (mean age, 65 years) and 40 healthy volunteers (mean age, 54 years) with CEUS (7 MHz; MI, 0.28) during continuous intravenous infusion of 4.8 mL microbubbles. Transient arterial occlusion at mid-thigh level simulated physical exercise. With time-CEUS-intensity curves obtained from regions of interest within calf muscles, we derived the maximum CEUS signal after occlusion (max) and its time (t(max)), slope to maximum (m), vascular response after occlusion (AUC(post)), and analysed accuracy, receiver operating characteristic (ROC) curves, and correlations with ankle-brachial index (ABI) and walking distance.Results: All parameters differed in PAD and volunteers (p < 0.014). In PAD, t(max) was delayed (31.2 +/- 13.6 vs. 16.7 +/- 8.5 s, p < 0.0001) and negatively correlated with ankle-brachial-index (r = -0.65). m was decreased in PAD (4.3 +/- 4.6 mL/s vs. 13.1 +/- 8.4 mL/s, p < 0.0001) and had highest diagnostic accuracy (sensitivity/specificity, 75%/93%) for detection of diminished muscular micro-perfusion in PAD (cut-off value, m < 5 similar to mL/s). Discriminant analysis and ROC curves revealed m, and AUC(post) as optimal parameter combination for diagnosing PAD and therefore impaired arterial perfusion reserve.Conclusions: Dynamic CEUS with transient arterial occlusion quantifies muscular micro-perfusion and arterial perfusion reserve. The technique is accurate to diagnose PAD. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Purpose: To prospectively compare a compact bolus (CB) injection protocol using high-iodine concentration contrast medium with a standard bolus (SB) injection protocol at equi-iodine doses for run-off computed tomographic angiography (CTA).Materials and Methods: 64 patients with suspected peripheral arterial disease who underwent 40 or 64-slice run-off CTA were included in this IRB-approved study. Patients were randomized to undergo the CB protocol (32 patients, iomeprol 400mgl/mL, 100 mL, 4 mL/sec) or the SB protocol (32 patients, iomeprol 300mgl/mL, 134 mL, 4 mL/sec). Luminal contrast density (CD) values were measured and arterial opacification (AO) was scored (5-point scale). Cases of venous overlay or bolus overriding were documented.Results: Overall arterial CD was significantly higher with the compact bolus (CB: 279 +/- 57HU, SB: 234 +/- 32HU, p = 0.0017). Segmental CD was significantly higher (p<0.05) in 7 of 16 evaluated segments. Patency-based comparison revealed superior AO in vessels with relevant (50 - 99%) stenoses (CB: 4.54 vs. SB: 4.18, p = 0.04). Contrast bolus overriding without pathological reasons, i.e., acute occlusions, was noted in one patient in each group. Venous overlay was observed less frequently in the CB group (CB vs. SB: 12 vs. 19 patients, n. s.: 29 of 64 legs [45%] vs. 44 of 64 legs [69%], p = 0.01).Conclusion: At equi-iodine doses, the CB protocol led to a quantitatively and qualitatively higher arterial opacification compared to the SB protocol. Therefore, a CB protocol should be favored for run-off CTA.

Objectives:To compare a contrast agent with high iodine concentration with an iso-osmolar contrast agent for coronary dual-source computed tomography angiography (DS-CTA), and to assess whether the contrast agent characteristics may affect the diagnostic quality of coronary DS-CTA. Materials and Methods:Patients were randomized to receive either 80 mL of iodixa:nol-320 (Visipaque, GE Healthcare, Chalfont St. Giles, United Kingdom) or iomeprol-400 (Iomeron, Bracco Imaging SpA, Milan, Italy) at 5 mL/s. Mean, minimum, maximum heart rate, and its variation (max-min) were assessed during calcium scoring scan and coronary DS-CTA. Three off-site readers independently evaluated the image sets in terms of technical adequacy, reasons for inadequacy, vessel visualization, diagnostic confidence (based on a 5-point scale), and arterial contrast opacification in Hounsfield units (HUs). Results:Ninety-six patients were included in the final evaluation. No significant differences were observed for pre- and postdose heart rate values for iomeron-400 compared with iodixanol-320, and changes in heart rate variation were also not significantly different (−2.3 ± 11.7 vs. −2.5 ± 7.3 bpm, P > 0.1). Contrast measurements in all analyzed vessels were significantly higher for iomeprol-400 (mean, 391.5–441.4 HU) compared with iodixanol-320 (mean, 332.3–365.5 HU, all P ≤ 0.0038). There was no significant difference in qualitative visualization of coronary arteries (mean scores, 4.3–4.5 for iomeprol, 4.1–4.3 for iodixanol, P = 0.15–0.28), or in diagnostic confidence scores. HU were inversely correlated with the number of insufficiently opacified segments (all readers P ≤ 0.0006). Conclusions:The high-iodine concentration contrast medium iomeprol-400 demonstrated significant benefit for coronary arterial enhancement compared with the iso-osmolar contrast medium iodixanol-320 when administered at identical flow rates and volumes for coronary DS-CTA. In addition, higher enhancement levels were found to be associated with lower numbers of inadequately visualized segments. Finally, observed mean heart rate changes after intravenous contrast injection were generally small during the examination and comparable for both agents.

OBJECTIVE:: This feasibility study was performed to assess whether dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion are able to detect alterations in the microvascular perfusion and arterial perfusion reserve in patients suffering from peripheral arterial disease (PAD) in comparison with healthy volunteers.MATERIALS AND METHODS:: Twenty patients with PAD, Rutherford classification grade I, category III (mean age, 64 years; mean height, 173 cm; mean weight, 81.8 kg), and 20 volunteers (mean age, 50 years; mean height, 174 cm; mean weight, 77.8 kg) participated in the study. Low-mechanical index CEUS (7 MHz; MI, 0.28) was performed to the dominant lower leg after start of a continuous automatic intravenous injection of 4.8 mL suspension with microbubbles containing sulfur hexafluoride (SonoVue) within 5 minutes. Perfusion of the calf muscle was monitored by CEUS before, during, and after release of arterial occlusion at the thigh level lasting for 60 seconds. Several parameters, especially the time to maximum enhancement after release of occlusion (tmax), the maximum enhancement after release of occlusion (maxenh), the total vascular response after release of occlusion (AUCpost), and the resulting slope (m2) to maximum enhancement were calculated.RESULTS:: After release of the occlusion, a significantly delayed increase of the CEUS signal to maxenh was observed in the patients with PAD (32 ± 17 seconds) compared with volunteers (17 ± 8 seconds, P = 0.0009). maxenh was 66.5 ± 36.6 (∼mL) in PAD versus 135.6 ± 75.1 (∼mL) in volunteers (P = 0.0016). AUCpost was 3016.5 ± 1825.8 (∼mL·s) in PAD versus 5906.4 ± 3173.1 (∼mL·s) in volunteers (P = 0.0013), and m2 was significantly lower in PAD (3.8 ± 5.2 vs. 14.8 ± 9.7 [∼mL/s], P = 0.0001).CONCLUSIONS:: Microvascular perfusion deficits and reduced arterial perfusion reserve in patients with PAD are clearly detectable with dynamic CEUS after transient arterial occlusion.