EFSUMB Technical Review - Update 2023: Dynamic Contrast-Enhanced Ultrasound (DCE-CEUS) for the Quantification of Tumor Perfusion.

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.

Contrast-Enhanced Ultrasound for Musculoskeletal Applications: A World Federation for Ultrasound in Medicine and Biology Position Paper.

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.

Low radiation dose in computed tomography: the role of iodine.

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.

Dynamic contrast-enhanced ultrasound and elastography assess deltoid muscle integrity after reverse shoulder arthroplasty.

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). Contrast-enhanced 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, Δ = -12% ± 22%, P = .0001) and shoulder function (Constant score, Δ = -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, Δ = 33% ± 13%, P = .038). The operated-on deltoid muscles showed higher stiffness than the contralateral muscles (ARFI, Δ = 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.

Dynamic Contrast-Enhanced Sonography and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Preoperative Diagnosis of Infected Nonunions.

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.

Evaluation of a high iodine delivery rate in combination with low tube current for dose reduction in pulmonary computed tomography angiography.

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.

Assessment of skeletal muscle microcirculation in type 2 diabetes mellitus using dynamic contrast-enhanced ultrasound: a pilot study.

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.

Multicenter comparison of high concentration contrast agent iomeprol-400 with iso-osmolar iodixanol-320: contrast enhancement and heart rate variation in coronary dual-source computed tomographic angiography.

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.

Dynamic contrast-enhanced ultrasound for assessment of skeletal muscle microcirculation in peripheral arterial disease.

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.

Comparison of transient arterial occlusion and muscle exercise provocation for assessment of perfusion reserve in skeletal muscle with real-time contrast-enhanced ultrasound.

OBJECTIVE: Contrast-enhanced ultrasound (CEUS) is able to quantify muscle perfusion and changes in perfusion due to muscle exercise in real-time. However, reliable measurement of standardized muscle exercise is difficult to perform in clinical examinations. We compared perfusion reserve assessed by CEUS after transient arterial occlusion and exercise to find the most suitable measurement for clinical application. METHODS: Contrast pulse sequencing (7 MHz) during continuous IV infusion of SonoVue(®) (4.8 mL/300 s) was used in 8 healthy volunteers to monitor muscle perfusion of the gastrocnemius muscle during transient (1 min) arterial occlusion produced by a thigh cuff of a venous occlusion plethysmograph. Isometric muscle exercise (50% of individual maximum strength for 20s) was subsequently performed during the same examination, and several CEUS parameters obtained from ultrasound-signal-intensity-time curves and its calculation errors were compared. RESULTS: The mean maximum local blood volume after occlusion was 13.9 [∼mL] (range, 4.5-28.8 [∼mL]), and similar values were measured after sub-maximum exercise 13.8 [∼mL], (range, 4.6-22.2 [∼mL]. The areas under the curve during reperfusion vs. recovery were also similar (515.2±257.5 compared to 482.2±187.5 [∼mLs]) with a strong correlation (r=0.65), as were the times to maximum (15.3s vs. 15.9s), with a significantly smaller variation for the occlusion method (±2.1s vs. ±9.0s, p=0.03). The mean errors for all calculated CEUS parameters were lower for the occlusion method than for the exercise test. CONCLUSIONS: CEUS muscle perfusion measurements can be easily performed after transient arterial occlusion. It delivers data which are comparable to CEUS measurements after muscle exercise but with a higher robustness. This method can be easily applied in clinical examination of patients with e.g. PAOD or diabetic microvessel diseases to assess perfusion reserve.

Where contrast agent concentration really matters - a comparison of CT and MRI.

OBJECTIVES: First pass contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) are influenced by parameters that characterize the injected bolus. The aim of this study was to assess the role of contrast agent concentration and the differences between MRI and CT. MATERIAL AND METHODS: We systematically evaluated the published literature to define the differences between MRI and CT with regards to the influence of contrast agent concentration and flow rate on signal enhancement and image quality. Subsequently, we used a simulation model to simulate bolus dispersion in the human body for contrast agents with different concentration. We performed this simulation for different injection times (3-25 seconds) as well as for single and double contrast agent dose, and calculated the effect of contrast agent concentration and dose on the increase of local contrast agent concentration. RESULTS: Although CT studies have shown that even a moderate increase in contrast agent concentration leads to higher peak concentration in the tissue or artery of interest, MRI studies have failed to show a marked benefit of higher concentration. The simulation demonstrated that the use of high concentrated contrast agent leads to an increase in local contrast agent concentration within the tissue or artery of interest, only if injection time is long (in CT commonly >10 seconds) compared with the time constant of bolus dispersion (about 5 seconds in humans). If the injection time is shorter (in MRI commonly 1-4 seconds), the local contrast agent concentration is mainly affected by the injected dose. CONCLUSION: Contrast agent concentration is a key parameter for the optimization of dynamic imaging techniques such as angiography or perfusion in CT, whereas in dynamic MRI, contrast agent dose and relaxivities are the leading parameters.

High-contrast computed tomographic angiography better detects residual intracranial arteriovenous malformations in long-term follow-up after radiotherapy than 1.5-Tesla time-of-flight magnetic resonance angiography.

BACKGROUND: Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are noninvasive alternatives for therapy monitoring of cerebral arteriovenous malformation (AVM). PURPOSE: To evaluate if CTA is able to detect residual AVM in the long-term follow-up after radiotherapy when time-of-flight (TOF) MRA could no longer detect a remaining nidus. MATERIAL AND METHODS: 18 patients with intracranial AVM were included between November 2005 and August 2007 who were scheduled for CTA (16-slice CT, 1-mm slice thickness, 90 ml iomeprol 400 mg I/ml, 4 ml/s) in the follow-up of radiotherapy. In these patients, MRA (3D-TOF, and bolus tagging at 1.5 T) could no longer detect a remaining nidus. RESULTS: The previously performed MRA (median time between CTA and MRA, 2.5 months) described total obliterations in 14 and subtotal obliterations in two AVM cases. Two MRA diagnoses were inconclusive due to artifacts. CTA (median time after therapy, 28 months; range, 5-66 months) could provide a diagnosis in all cases, but confirmed the MRA diagnosis only in 50% of the cases. A residual nidus was shown in an additional six cases, and subtotal obliteration in another three cases. The interval between radiotherapy and the follow-up examination was significantly different (P<0.05) between false- and true-negative MRA examinations (median, 18 vs. 30 months). CONCLUSION: High-contrast CTA is a sensitive tool in the detection of AVM and is able to identify residual AVM after radiotherapy even if previously performed TOF MRA at 1.5 T shows total obliteration.

Changes in the micro-circulation of skeletal muscle due to varied isometric exercise assessed by contrast-enhanced ultrasound.

PURPOSE: To quantitatively assess local muscle micro-circulation with real-time contrast-enhanced ultrasound (CEUS) during different exercises and compare the results with performed muscle work and global blood flow. MATERIALS AND METHODS: Sixteen low mechanical index CEUS examinations of the right lower leg flexors of healthy volunteers were performed using a continuous infusion of SonoVue(®) (4.8 mL/300 s). Several muscle perfusion parameters were extracted from derived CEUS signal intensity time curves during different isometric exercises (10-50% of maximum individual strength for 20-30s) and then correlated with the performed muscle work or force, and the whole lower leg blood flow which we measured simultaneously by venous occlusion plethysmography (VOP). RESULTS: The shapes of the CEUS curve during and after exercise differed individually depending on the performed muscle work. The maximum blood volume MAX was observed only after exercise cessation and was significantly correlated with the performed muscle force (r=0.77, p<0.0001). The blood volume over exercise time was inversely correlated with the spent muscle work (r=-0.60, p=0.006). CEUS and VOP measurements correlated only at rest and after the exercise. During exercise, mean CEUS local blood volume decreased (from 3.48 to 2.19 (∼mL)), while mean VOP global blood flow increased (mean, from 3.96 to 7.71 mL/100 mg/min). CONCLUSION: Real-time low-MI CEUS provides complementary information about the local muscle micro-circulation compared to established blood flow measures. CEUS may be used for a better understanding of muscle perfusion physiology and in the diagnosis of micro-circulation alterations such as in peripheral arterial occlusive disease or diabetic angiopathy.

Concentric resistance training increases muscle strength without affecting microcirculation.

PURPOSE: While the evidence is conclusive regarding the positive effects of endurance training, there is still some controversy regarding the effects of resistance training on muscular capillarity. Thus, the purpose was to assess whether resistance strength training influences resting skeletal muscle microcirculation in vivo. MATERIALS AND METHODS: Thirty-nine middle-aged subjects (15 female, 24 male; mean age, 54+/-9 years) were trained twice a week on an isokinetic system (altogether 16 sessions lasting 50 min, intensity 75% of maximum isokinetic and isometric force of knee flexors and extensors). To evaluate success of training, cross-sectional area (CSA) of the quadriceps femoris muscle and its isokinetic and isometric force were quantified. Muscular capillarization was measured in biopsies of the vastus lateralis muscle. In vivo, muscular energy and lipid metabolites were quantified by magnetic resonance spectroscopy and parameters of muscular microcirculation, such as local blood volume, blood flow and velocity, by contrast-enhanced ultrasound analyzing replenishment kinetics. RESULTS: The significant (P<0.001) increase in CSA (60+/-16 before vs. 64+/-15 cm(2) after training) and in absolute muscle strength (isometric, 146+/-44 vs. 174+/-50 Nm; isokinetic, 151+/-53 vs. 174+/-62 Nm) demonstrated successful training. Neither capillary density ex vivo (351+/-75 vs. 326+/-62) nor ultrasonographic parameters of resting muscle perfusion were significantly different (blood flow, 1.2+/-1.2 vs. 1.1+/-1.1 ml/min/100g; blood flow velocity, 0.49+/-0.44 vs. 0.52+/-0.74 mms(-1)). Also, the intensities of high-energy phosphates phosphocreatine and beta-adenosintriphosphate were not different after training within the skeletal muscle at rest (beta-ATP/phosphocreatine, 0.29+/-0.06 vs. 0.28+/-0.04). CONCLUSION: The significant increase in muscle size and strength in response to concentric isokinetic and isometric resistance training occurs without an increase in the in vivo microcirculation of the skeletal muscles at rest.

Real-time contrast-enhanced ultrasound for the assessment of perfusion dynamics in skeletal muscle.

We developed a real-time low-MI contrast-enhanced ultrasound method (CEUS), compared it with venous occlusion plethysmography (VOP) and evaluated its robustness in the quantification of skeletal muscle perfusion during exercise. Contrast pulse sequencing (7 MHz) during continuous intravenous infusion of SonoVue (4.8 mL/300 s) was used repeatedly in eight healthy volunteers to monitor changes of the muscle perfusion before, during and after isometric exercises (10 to 50% of individual maximum strength for 20 to 30 s) of the gastrocnemius muscle in real time. CEUS was correlated with VOP at different time points, and the exactness of several CEUS parameters obtained from ultrasound-signal-intensity-time curves was evaluated. Real-time CEUS depicted a large variability of the skeletal muscle blood volume at rest (mean, 3.48; range, 0.60 to 9.92 [approximately mL]), with a significant reproducibility (r=0.72, p<0.05) and correlation with VOP (r=0.59, p<0.001). Mean blood volume during exercise was 1.58(approximately mL), increased to a mean maximum after exercise of 8.88 (approximately mL), the mean change of the local blood volume during and directly after the exercise was -0.10 and +1.57(approximately mL/s). The average CEUS signal during exercise decreased (mean area under the curve, -50.4 [approximately mL.s]) and subsequently increased post exercise (mean 118.6 [approximately mL.s]). CEUS parameters could be calculated with mean relative errors between 6 and 36%. Continuous assessment of local muscle microcirculation during exercise is possible with real-time CEUS with an acceptable robustness. Its application may be of particular interest in a better understanding of the role of perfusion during muscle training, and the monitoring of pathological vascular response, such as in diabetic microvessel diseases.

Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia.

PURPOSE: Cancer-related cachexia is an obscure syndrome leading to muscle wasting, reduced physical fitness and quality of life. The aim of this study was to assess morphology, metabolism, and microcirculation in skeletal muscles of patients with cancer-related cachexia and to compare these data with matched healthy volunteers. METHODS: In 19 patients with cancer-induced cachexia and 19 age-, gender-, and body-height-matched healthy volunteers body composition and aerobic capacity (VO(2max)) were analyzed. Skeletal muscle fiber size and capillarization were evaluated in biopsies of the vastus lateralis muscle. The cross-sectional area (CSA) of the quadriceps femoris muscle was measured by magnetic resonance imaging as well as its isokinetic and isometric force. The energy and lipid metabolism of the vastus lateralis muscle was quantified by (31)P and (1)H spectroscopy and parameters of its microcirculation by contrast-enhanced ultrasonography (CEUS). RESULTS: Morphologic parameters were about 30% lower in cachexia than in volunteers (body mass index: 20 +/- 3 vs. 27 +/- 4 kg m(-2), CSA: 45 +/- 13 vs. 67 +/- 14 cm(2), total fiber size: 2854 +/- 1112 vs. 4181 +/- 1461 microm(2)). VO(2max) was reduced in cachexia (23 +/- 9 vs. 32 +/- 7 ml min(-1) kg(-1), p=0.03), whereas histologically determined capillary density and microcirculation in vivo were not different. Both concentrations of muscular energy metabolites, pH, and trimethyl-ammonium-containing compounds were comparable in both groups. Absolute strength of quadriceps muscle was reduced in cachexia (isometric: 107 +/- 40 vs. 160 +/- 40 Nm, isokinetic: 101 +/- 46 vs. 167 +/- 50 Nm; p=0.03), but identical when normalized on CSA (isometric: 2.4 +/- 0.5 vs. 2.4 +/- 0.4 Nm cm(-2), isokinetic: 2.2 +/- 0.4 vs. 2.5 +/- 0.5 Nm cm(-2)). CONCLUSIONS: Cancer-related cachexia is associated with a loss of muscle volume but not of functionality, which can be a rationale for muscle training.

Assessment of metabolism and microcirculation of healthy skeletal muscles by magnetic resonance and ultrasound techniques.

PURPOSE: To assess metabolism and microcirculation of healthy skeletal muscle by magnetic resonance (MR) and ultrasound techniques and to compare these data with muscle histology, and anthropometric and blood parameters. METHODS: Thirty-four healthy volunteers were selected such that their measured aerobic capacity (VO2max) per body weight ranged between 23 and 66 mL/minute/kg to render a large variability of skeletal muscle capillarization as a result of their different physical activity. We analyzed body composition, blood parameters, and skeletal muscle fiber size and capillarization in biopsies of the vastus lateralis muscle. These data were compared with knee extensor cross-sectional area (CSA) obtained by MR imaging, microcirculation of the vastus lateralis muscle by contrast-enhanced ultrasound (CEUS), and its energy and lipid metabolism measured with 31P and 1H MR spectroscopy. Statistical analysis was performed using Pearson's correlation coefficient and significance was tested at a level of .5%. RESULTS: The variable physical activity was reflected in a large variability of vastus lateralis muscle perfusion and metabolism at rest with highest histologic capillarization and CEUS-perfusion values observed in the best-trained volunteers. Levels of high-energy phosphates, such as phosphocreatine, were positively correlated with CSA (r= .5) and histologic fiber size (r= .6 for type IIA and IIX fibers), while phosphocreatine concentration was significantly negatively correlated to myocellular lipids (r=-.6) and trimethyl ammonium containing compounds (r=-.8). Local blood volume measured in vivo with CEUS was positively correlated with several histologic capillarization parameters. CONCLUSIONS: Dedicated MR- and CEUS-methods deliver (patho-)physiologic information about capillarization and fiber characteristics of skeletal muscles in vivo and hence establish a useful diagnostic tool for muscular diseases.

Quantitative evaluation of muscle perfusion with CEUS and with MR.

Functional imaging might increase the role of imaging in muscular diseases, since alterations of muscle morphology alone are not specific for a particular disease. Perfusion, i.e., the blood flow per tissue and time unit including capillary flow, is an important functional parameter. Pathological changes of skeletal muscle perfusion can be found in various clinical conditions, such as degenerative or inflammatory myopathies or peripheral arterial occlusive disease. This article reviews the theoretical basics of functional radiological techniques for assessing skeletal muscle perfusion and focuses on contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) techniques. Also, the applications of microvascular imaging, such as in detection of myositis and for discriminating myositis from other myopathies or evaluating peripheral arterial occlusive disease, are presented, and possible clinical indications are discussed. In conclusion, dedicated MR and CEUS methods are now available that visualize and quantify (patho-)physiologic information about microcirculation within skeletal muscles in vivo and hence establish a useful diagnostic tool for muscular diseases.

Contrast-enhanced ultrasound for examining tumor biology.

This paper reviews the potential of ultrasound for assessing the viability and biological behavior of tumors. Unlike color Doppler sonography, modern techniques for contrast-enhanced ultrasound permit the measurement of tissue perfusion irrespective of vessel size or flow velocity. Perfusion can also be assessed quantitatively, using replenishment kinetics or derivates thereof. The perfusion of tumors is a surrogate parameter of their viability and may mirror their response to therapy. Furthermore, the degree of vascularity in a tumor may express its aggressiveness and help to predict its response to treatment. In animal models, a decrease in blood flow has been shown to precede a shrinkage of tumors treated with anti-angiogenic compounds. In liver metastases, arterial and portal blood supply can be assessed separately, and a response to stereotactic radiotherapy was found to go along with a decrease in arterial perfusion. Moreover, a relatively high arterial perfusion of liver metastases may predict a response to chemotherapy. Contrast-enhanced ultrasound may be a potent tool for assessing the effects of anti-angiogenic treatment in patients.

Relationship of skeletal muscle perfusion measured by contrast-enhanced ultrasonography to histologic microvascular density.

OBJECTIVE: The purpose of this study was to compare skeletal muscle perfusion measured by contrast-enhanced ultrasonography (CEUS) with microvascular density in muscle biopsies. METHODS: Power Doppler sonography after intravenous bolus injection of Levovist (SH U 508A; Schering AG, Berlin, Germany) was used to examine perfusion of vastus lateralis muscle in 23 healthy volunteers. Local blood volume (B), blood flow velocity (v), and blood flow (f) were calculated by analyzing replenishment kinetics. CEUS perfusion was compared with vascularization of biopsy samples from vastus lateralis muscle. Subjects were selected such that their aerobic capacity (maximal oxygen uptake [VO(2)max]) per body weight ranged between 23 and 66 mL . min(-1) . kg(-1) to render a large variability of skeletal muscle capillarization. Moreover, subjects' venous blood hematocrit (Hkt) was determined to estimate the plasmatic intravascular volume fraction (1-Hkt=PVF) in which the microbubbles can distribute. RESULTS: Median capillary density was 331/mm(2) (range, 207-469/mm(2)), and median capillary fiber contacts (CFC) were 3.6 (range, 2.3-6.5). CFC was correlated with VO(2)max (r=0.59; P<.01). Among CEUS parameters, B showed the closest correlation to CFC (r=0.53; P<.01). When CFC was normalized for PVF, correlation of B to CFC was r=0.64 (P<.01). CEUS could depict the physiologic large variability of vastus lateralis muscle perfusion at rest (median [range]: B, 2.5 [0.1-12.3] approximately mL; v, 0.3 [0.1-3.7] mm/s; f, 0.7 [0.1-5.3] approximately mL . min(-1) . 100 g tissue(-1)). CONCLUSIONS: B is significantly related to fiber-adjacent capillarization and may represent physiologic capillary recruitment (eg, through metabolic fiber-related signals). CEUS is feasible for skeletal muscle perfusion quantification.