Christopher J. Harvey

Ultrasound of focal liver lesions

Abstract. This paper gives a comprehensive overview of ultrasound of focal liver lesions. Technical aspects such as examination technique and the use of Doppler modes as well as recent developments such as tissue harmonic imaging and microbubble contrast agents are discussed. The clinical significance and sonographic features of various liver lesions such as haemangioma, focal nodular hyperplasia, adenoma, regenerative nodule, metastasis, hepatocellular carcinoma and various types of focal infections are described. With the exception of cysts and typical haemangiomas, definitive characterisation of a liver lesion is often not possible on conventional ultrasound. This situation has changed with the recent advent of ultrasound contrast agents, which permit definitve diagnosis of most lesions. Contrast-enhanced sonography using recently developed contrast-specific imaging modes dramatically extends the role of liver ultrasound by improving its specificity in the detection and characterisation of focal lesions to rival CT and MRI.

Developments in ultrasound contrast media

Abstract Ultrasound microbubble contrast agents are effective and safe echo enhancers. An ingenious array of methods are employed to achieve stability and provide a clinically useful enhancement period. Microbubbles enhance ultrasound signals by up to 25 dB (greater than 300-fold increase) due to resonant behaviour. This is used to rescue failed Doppler studies and may be extended to image the microcirculation of tumours and the myocardium using non-linear modes. Functional studies open up a whole range of applications by using a variety of active and passive quantitation techniques to derive indices from the transit of contrast through a tissue of interest. This has been especially successful in the detection of liver metastases and cirrhosis and shows great promise as a clinical tool. It also has great potential in measuring microcirculatory flow velocity. The demonstration that some microbubbles are not just pure blood pool agents but have a hepatosplenic specific phase has extended the versatility of ultrasound. Imaging of this stationary phase with non-linear modes such as phase inversion and stimulated acoustic emission, has improved the sensitivity and specificity of ultrasound in the detection and characterisation of focal liver lesions to rival that of CT and MR.

Pulse-inversion mode imaging of liver specific microbubbles : improved detection of subcentimetre metastases

Pulse-inversion mode (a new ultrasound mode) can be used to image the late liver-specific parenchymal phase of the microbubble contrast-agent Levovist. Scanning in pulse-inversion mode after Levovist improves the detection of liver metastases and reveals more lesions of smaller size than conventional ultrasonography and computed tomography.

Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study.

Background: A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. Aim: To see if this index can also grade diffuse liver disease. Patients: Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child’s A, seven Child’s B, and eight Child’s C). Methods: Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase >10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. Results: Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child’s A 21 (1) s, Child’s B 16 (3) s, and Child’s C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child’s A 8 (1) s, Child’s B 4 (4) s, and Child’s C 3 (3) s. These differences were highly significant (p<0.001, ANOVA comparison). A HVTT <24 s and a CDT <10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values <10 s and 3/9 had HVTT <24 s. Conclusion: This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.

Contrast-Enhanced Ultrasound and Prostate Cancer; A Multicentre European Research Coordination Project

CONTEXT Contrast-enhanced ultrasound is a real-time imaging technique with the capability of visualizing perfusion patterns. Since tumour growth is associated with changes in vascularisation, this modality is under research for imaging of various tumour types. Studies have shown promising results for the diagnosis of prostate cancer for various imaging techniques; however, the exact value of each technique is still unclear. OBJECTIVE To determine the value of contrast-enhanced ultrasound (CEUS) in the detection, localisation, and follow-up of treatment for prostate cancer. EVIDENCE ACQUISITION In the period 2002-2006, research in four European centres regarding CEUS of the prostate was coordinated in a combined program. This paper describes and combines the results of these studies. EVIDENCE SYNTHESIS Various techniques were developed and researched during the period of this program. Studies showed that prostate cancer could be visualized and localized in up to 78%. Visualization of the tumour enabled better detection; targeted biopsies lead to fewer biopsies per session without loss of detection rate. A combined approach offered the highest detection rate. CEUS could be used to visualize the effects of high-intensity focussed ultrasound and hormonal therapy for prostate cancer with success, and identified patients with an early relapse. Unfortunately, pretreatment evaluation could not identify the nonresponders beforehand. CONCLUSIONS This research project was a first step towards routine use of CEUS in the clinical detection and follow-up of prostate cancer; and new combined studies are initiated.

Quantification of blood flow

Abstract. Traditionally, Doppler ultrasound has been used to estimate blood flow as the mean velocity multiplied by the vessel area, but this is subject to significant errors and may be difficult to perform accurately. Microbubbles, developed as contrast agents for ultrasound, were initially envisaged as useful for increasing the intensity of echoes and thus rescuing Doppler studies that were technical failures because of attenuated signals or very slow flow. However, they can act as tracers and, by analogy with isotope techniques, can be used to measure blood flow with transit-time methods which exploit both arterial and venous time–intensity data. An acceptable compromise is to acquire both a tissue intensity curve and one from the feeding artery. The transit of microbubbles across an organ or tissue can be used to estimate haemodynamic alterations, e.g. the arterialisation of the supply to the liver in malignancies and cirrhosis and the delayed arterio-venous transit in the transplant kidney during rejection. The fragility of microbubbles can be turned to advantage by being exploited to create a negative bolus by exposing a tissue slice to a high power beam. The rate of refilling of this slice by circulating microbubbles can then be followed with a low-intensity monitoring beam and the resulting rising exponential curve analysed to extract indices of both the reperfusion rate (the slope) and the fractional vascular volume (the asymptote). The product of these is a measure of true tissue perfusion.

Clinical uses of microbubbles in diagnosis and treatment

The development of microbubbles as ultrasound contrast agents (USCA) has opened the way for new and extended applications of ultrasound in clinical practise as well as offering rich new research opportunities. Some of the experimentally developed applications have been accepted into clinical practise and the European Federation has published guidelines on their use, particularly in the liver [18]. Many new applications are being explored and the field is unusual in imaging because its proper exploration depends on parallel development by the pharmaceutical and ultrasound equipment manufacturers. Microbubbles are unique amongst contrast agents for imaging in that the imaging process changes the agent and even destroys it. They contain gases that respond to the pressure changes of the ultrasound by changing size and this forms the basis for their selective imaging. In addition, when the volume changes reach a threshold, the oscillations become sufficiently violent that the microbubbles disintegrate (either by fragmentation or dissolution) and thus the contrast effect can be switched off remotely. Their body distribution is different from most contrast agents in that they are too large to diffuse through the endothelium and so behave as pure blood pool agents after intravenous injection. Their main diagnostic uses depend on detecting them in the blood circulation and, in a simple way, this represents an extension of Doppler which is given a boost by the 20? dB additional signal that the microbubbles produce. This is especially useful in situations where Doppler signal are poor. The best example is the cerebral vessels, from which signals are attenuated by the skull: adding microbubbles boosts the signals so that they are more reliably obtained. However, of more general interest is the fact that nonlinear detection techniques do not depend on microbubble movement, instead depending on their presence in the blood vessels regardless of calibre. Thus, not only can the macrovasculature be interrogated but, for the first time, the microvasculature, including the capacious capillary bed, can be imaged. Of course, these ten micron vessels cannot be resolved, as they would be by a microscope, but the signals from microbubbles within them can be displayed, much as in an angiogram. In addition to exploiting the distribution in space of microbubbles, e.g. for tumour diagnosis, the dynamics of their arrival and disappearance, e.g. after bolus injection, can be tracked using the high temporal resolution of ultrasound. This is mostly done in a qualitative way when, for example, the haemodynamics of the blood supply to liver masses is accessed by eye. It can also be measured more formally, using scanner software to quantify the microbubble signal intensity over time and generate time– intensity curves (TICs). This has been shown to be especially promising in evaluating the microvasculature of tumours and of the myocardium.

Functional CT imaging of the acute hyperemic response to radiation therapy of the prostate gland: early experience.

Purpose Functional CT can measure perfusion and permeability. We hypothesized that acute changes could be measured in these indexes following radiation therapy (RT) to the prostate gland. Method Twenty-two patients with prostatic cancer were studied before and 1–2 and 6–12 weeks after RT. A single section through the prostate was repeatedly scanned after contrast medium bolus injection. Contrast agent clearance per unit volume (&agr;/ V) and fractional vascular volume (fvv) were calculated using Patlak graphical analysis. Perfusion was calculated as the ratio between maximal rate of tissue enhancement and peak arterial enhancement. Results Significant increases in all indexes occurred after RT. Mean perfusion rose from 0.122 to 0.263 ml/min/ml at 1–2 weeks, mean &agr;/ V increased from 0.0012 to 0.0016 ml/min/ml at 1–2 weeks, and mean fvv increased from 13.7 to 21% at 1–2 weeks. All three indexes remained elevated at 6–12 weeks after the start of RT. Conclusion Functional CT demonstrated an acute hyperemic response following RT to the prostate gland.

Imaging of tumour therapy responses by dynamic CT.

The objective of this study was to investigate whether functional CT with Patlak analysis could be used to demonstrate acute changes associated with radiotherapy. Patlak analysis yields fractional vascular volume and contrast clearance per unit volume (a measure of permeability). Four tumour types (prostate, bronchus, breast and cervix) were studied pre-radiotherapy and at 1-2 weeks and 6-12 weeks post-therapy. Significant rises in fractional vascular volume and contrast clearance were shown at 1-2 weeks. These indices were still significantly elevated at 6-12 weeks post-therapy. In the prostates perfusion values were also elevated reflecting a hyperemic response to radiotherapy. Dynamic CT with Patlak analysis can be used to measure important pathophysiological indices which may prove useful in assessing response to therapy of tumours.

Which continuous US scanning mode is optimal for the detection of vascularity in liver lesions when enhanced with a second generation contrast agent

OBJECTIVES Microbubble echo-enhancers help in the assessment of focal liver masses by enhancing the signal from blood vessels. A variety of linear and nonlinear scanning modes are now available, but it is unclear which is optimal. A controlled comparison was performed during the infusion of such an agent (SonoVue: Bracco, Milan, Italy). METHODS AND MATERIALS Ten patients with known focal liver lesions were studied. The diagnoses, confirmed on dual phase helical computed tomography (CT) at the same attendance were metastasis (n = 7), haemangioma (n = 2) and focal nodular hyperplasia FNH (n = 1). A dose of 12 ml SonoVue concentrated at 5 mg/ml was infused intravenously at a rate of 1 ml/min. The enhancement level was monitored with a continuous wave (CW) Doppler probe over the right radial artery and the intensity of the signal was registered at 1 s intervals. When a plateau of enhancement was reached, a single lesion in each patient was imaged using five different continuous scanning modes, fundamental grey scale (FGS); fundamental colour Doppler (FCD); fundamental power Doppler (FPD); second harmonic grey scale (HGS); and pulse inversion mode (Pim) using an HDI5000 scanner and C5-2 probe (ATL, Bothell, WA). The order of scanning modes was varied between patients using a predefined randomisation protocol. The videos (super video home system (SVHS)) were analysed offsite by two blinded readers, both experienced in contrast ultrasound of the liver. The readers were asked to score each mode in terms of its ability to detect vessels within/around the lesion at optimal enhancement. This was done using a ranking system (1, worst; 5, best) for each patient. RESULTS Both observers scored FPD as the optimal imaging method, followed by Pim. (Scores summed across all patients, observer 1: FPD 48, Pim 42, FCD 37, HGS 21, FGS 10; observer 2: FPD 49, Pim 40, FCD 38, HGS 21, FGS 10). The differences from FPD were significant for FCD, HGS and FGS using a unpaired analysis of variance (ANOVA) comparison, with Bonferroni multiple corrections, (P<0.01, both observers). The differences between FPD and Pim were also significant both for observer 2 and for both observers combined (P<0.01), but did not reach significance for observer 1 (P = 0.19). CONCLUSIONS In this study, FPD performed best, and the non-linear modes, performed continuously (pulse inversion and second HGS), showed no clear advantage.