Fabrizio Calliada

EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology.

The technical part of these Guidelines and Recommendations, produced under the auspices of EFSUMB, provides an introduction to the physical principles and technology on which all forms of current commercially available ultrasound elastography are based. A difference in shear modulus is the common underlying physical mechanism that provides tissue contrast in all elastograms. The relationship between the alternative technologies is considered in terms of the method used to take advantage of this. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided on optimisation of scanning technique, image display, image interpretation and some of the known image artefacts.

EFSUMB Guidelines and Recommendations on the Clinical Use of Ultrasound Elastography. Part 2: Clinical Applications

The clinical part of these Guidelines and Recommendations produced under the auspices of the European Federation of Societies for Ultrasound in Medicine and Biology EFSUMB assesses the clinically used applications of all forms of elastography, stressing the evidence from meta-analyses and giving practical advice for their uses and interpretation. Diffuse liver disease forms the largest section, reflecting the wide experience with transient and shear wave elastography . Then follow the breast, thyroid, gastro-intestinal tract, endoscopic elastography, the prostate and the musculo-skeletal system using strain and shear wave elastography as appropriate. The document is intended to form a reference and to guide clinical users in a practical way.

Ultrasound contrast agents: Basic principles

INTRODUCTION Ultrasonography lacked substances to be administered to patients to improve or increase the diagnostic yield, which is peculiar considering that contrast agents have long been used with all the other imaging techniques. Fortunately some contrast agents, most of them consisting in gas microbubbles, have been recently introduced for ultrasound imaging too: this review will focus on their history, behavior, current applications and future developments. Echocontrast agent research is in progress and many new agents are expected to be marketed this and next year, to be added to Levovist by Schering AG (Berlin, Germany), to enhance the ultrasound signal safely and effectively. No definitive conclusions can be drawn yet on the actual merits of each contrast agent, but all of them seem to be both effective and safe, meaning that their future success will depend on the relative cost-effectiveness and peculiarities. THE BASIC PRINCIPLES OF ECHOCONTRAST AGENTS The microbubbles act as echo-enhancers by basically the same mechanism as that determining echo-scattering in all the other cases of diagnostic ultrasound, namely that the backscattering echo intensity is proportional to the change in acoustic impedance between the blood and the gas making the bubbles. The different acoustic impedance at this interface is very high and in fact all of the incident sound is reflected, even though not all of it will of course go back to the transducer. But the acoustic wave reflection, though nearly complete, would not be sufficient to determine a strong US enhancement because the microbubbles are very small and are sparse in the circulation. Moreover, reflectivity is proportional to the fourth power of a particle diameter but also directly proportional to the concentration of the particles themselves. SECOND HARMONIC IMAGING As we said above, the microbubbles reached by an ultrasound signal resonate with a specific frequency depending on microbubble diameter. However, the main resonance frequency is not the only resonance frequency of the bubble itself and multiple frequencies of the fundamental one are emitted, just like in a musical instrument. These harmonic frequencies have decreasing intensity, but the second frequency, known as the second harmonic, is still strong enough to be used for diagnostic purposes. The theoretical advantage of the harmonic over the fundamental frequency is that only contrast agent microbubbles resonate with harmonic frequencies, while adjacent tissues do not resonate, or else their harmonic resonation is very little. Thus, using a unit especially set to produce ultrasounds at a given frequency (3.5 MHz) and receive an ultrasound signal twice as powerful (7 MHz) it will be possible to show the contrast agent only, without any artifact from the surrounding anatomical structures, with a markedly improved signal-to-noise ratio. A similar effect to digital subtraction in angiography can thus be obtained, even though through a totally different process. Moreover, second harmonic imaging permits to show extremely small vessels (down to 40 microm) with very slow flow, which would be missed with a conventional method. B-mode imaging can also depict the microbubbles in the myocardium suppressing nearly all the artifacts from cardiac muscle motion. Recently a peculiar behavior of microbubbles has been observed which may permit contrast agent detection even in capillaries. This method is variously known as sonoscintigraphy, loss of correlation, stimulated acoustic emission and transient scattering. The contrast agent microbubbles reached by an ultrasound beam powerful enough explode producing a strong and very short backscatter echo which is read by the unit as a Doppler signal and results in a color pixel where the individual microbubble exploded. CONCLUSIONS The microbubble contrast agents developed and introduced as safe and effective echo-enhancers in present-day clinical practice will open up new oppurtunities

Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease

Objective External fistulas represent a disabling manifestation of Crohns disease with a difficult curability and a high relapse rate despite a large therapeutic armamentarium. Stem cell therapy is a novel and promising approach for treatment of chronic inflammatory conditions. We therefore investigated the feasibility, safety and efficacy of serial intrafistular injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in the treatment of fistulising Crohns disease. Patients and methods We enrolled 12 consecutive outpatients (eight males, median age 32 years) refractory to or unsuitable for current available therapies. MSCs were isolated from bone marrow and expanded ex vivo to be used for both therapeutic and experimental purposes. Ten patients (two refused) received intrafistular MSC injections (median 4) scheduled every 4 weeks, and were monitored by surgical, MRI and endoscopic evaluation for 12 months afterwards. The feasibility of obtaining at least 50×106 MSCs from each patient, the appearance of adverse events, and the efficacy in terms of fistula healing and reduction of both Crohns disease and perianal disease activity indexes were evaluated. In addition, the percentage of both mucosal and circulating regulatory T cells expressing FoxP3, and the ability of MSCs to influence mucosal T cell apoptosis were investigated. Results MSC expansion was successful in all cases; sustained complete closure (seven cases) or incomplete closure (three cases) of fistula tracks with a parallel reduction of Crohns disease and perianal disease activity indexes (p<0.01 for both), and rectal mucosal healing were induced by treatment without any adverse effects. The percentage of mucosal and circulating regulatory T cells significantly increased during the treatment and remained stable until the end of follow up (p<0.0001 and p<0.01, respectively). Furthermore, MSCs have been proven to affect mucosal T cell apoptotic rate. Conclusions Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohns disease.

Contrast-Enhanced Versus Conventional and Color Doppler Sonography for the Detection of Thrombosis of the Portal and Hepatic Venous Systems

OBJECTIVE We conducted a prospective study to compare sonography, color Doppler sonography, and contrast-enhanced sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancies. SUBJECTS AND METHODS Three hundred sixteen patients with biopsy-proved hepatic tumors were studied at baseline and 3 months later with sonography, color Doppler sonography, and contrast-enhanced sonography. Thrombosis was defined as the presence of intraluminal echogenic material at sonography, absence of intraluminal color signals at color Doppler sonography, and presence of nonenhancing intraluminal area at contrast-enhanced sonography. Thrombi were considered malignant if they displayed continuity with tumor tissue at sonography, intrathrombus color signals at color Doppler sonography, and enhancing signals at contrast-enhanced sonography, both having arterial waveforms at Doppler spectral examination. Definitive diagnoses were obtained by sonographically guided biopsy except for thrombi displaying at conventional sonography unequivocal continuity with tumor tissue. RESULTS Thrombosis was detected in 79 (25.0%) of 316 patients at baseline and in 83 (26.3%) of 316 patients after 3 months. Eighty-one (97.6%) of the 83 thrombi were malignant. Definitive diagnosis was performed by imaging in 60 (72.3%) of the 83 cases and by biopsy in 23 cases (27.7%). For thrombus detection, contrast-enhanced sonography displayed significantly higher sensitivity than color Doppler sonography (p = 0.004) and borderline superiority over sonography (p = 0.058). For thrombus characterization, contrast-enhanced sonography was significantly more sensitive than color Doppler sonography (p < 0.0005) and conventional sonography (p = 0.02). CONCLUSION Contrast-enhanced sonography is superior to sonography and color Doppler sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancies.

Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: A long‐term cohort study

In most patients with cirrhosis, successful percutaneous ablation or surgical resection of hepatocellular carcinoma (HCC) is followed by recurrence. Radiofrequency ablation (RFA) has proven effective for treating HCC nodules, but its repeatability in managing recurrences and the impact of this approach on survival has not been evaluated. To this end, we retrospectively analyzed a prospective series of 706 patients with cirrhosis (Child‐Pugh class ≤B7) who underwent RFA for 859 HCC ≤35 mm in diameter (1‐2 per patient). The results of RFA were classified as complete responses (CRs) or treatment failures. CRs were obtained in 849 nodules (98.8%) and 696 patients (98.5%). During follow‐up (median, 29 months), 465 (66.8%) of the 696 patients with CRs experienced a first recurrence at an incidence rate of 41 per 100 person‐years (local recurrence 6.2; nonlocal 35). Cumulative incidences of first recurrence at 3 and 5 years were 70.8% and 81.7%, respectively. RFA was repeated in 323 (69.4%) of the 465 patients with first recurrence, restoring disease‐free status in 318 (98.4%) cases. Subsequently, RFA was repeated in 147 (65.9%) of the 223 patients who developed a second recurrence after CR of the first, restoring disease‐free status in 145 (98.6%) cases. Overall, there were 877 episodes of recurrence (1‐8 per patient); 577 (65.8%) of these underwent RFA that achieved CRs in 557 (96.5%) cases. No procedure‐related deaths occurred in 1,921 RFA sessions. Estimated 3‐ and 5‐year overall and disease‐free (after repeated RFAs) survival rates were 67.0% and 40.1% and 68.0 and 38.0%, respectively. Conclusion: RFA is safe and effective for managing HCC in patients with cirrhosis, and its high repeatability makes it particularly valuable for controlling intrahepatic recurrences. (HEPATOLOGY 2011)

Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto’s thyroiditis

Objective  ShearWave™ Elastography (SWE) is real‐time, quantitative and user‐independent technique, recently introduced in the diagnostic work‐up of thyroid nodules. Hashimoto’s thyroiditis (HT), characterized by variable degrees of lymphocytic infiltration and fibrosis, might affect shear wave propagation. The aim of this study was to assess the feasibility of SWE in cytologically benign thyroid nodules within both Hashimoto’s and nonautoimmune thyroid glands. The effect of autoimmunity on the gland stiffness was also evaluated.

Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma

The aim was to compare the performances of contrast-enhanced (CE) ultrasonography (US) and spiral computed tomography (CT) in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma (HCC). We studied 50 patients with HCC who had biopsy-proven portal vein thrombi that had been detected with US and color Doppler US. Thirteen of the thrombi involved the main portal trunk and 37 the segmental branches. CEUS and CT were performed within a week of thrombus biopsies. For each imaging technique, diagnoses of thrombosis (present/absent) and thrombus nature (malignancy/benignancy) were made by experienced readers under blinded conditions and compared with pathological findings to determine accuracy rates for thrombus detection and characterization. Forty-four of the 50 thrombi were pathologically diagnosed as malignant and the remaining six were benign. CEUS detected 50/50 (100%) thrombi and correctly characterized 49/50 (98%). CT detected 34/50 (68%) thrombi and correctly characterized 23 of these 34 (68%). CEUS outperformed CT in terms of both thrombus detection (P < 0.0001) and characterization (P = 0.0001). CEUS appears to be significantly superior to CT for detection and characterization of portal vein thrombosis complicating HCC, and it should be considered in the staging of these tumors.

Ultrasound elastography in the evaluation of thyroid pathology. Current status

Thyroid pathology including thyroid nodules and diffuse thyroid diseases represents often a diagnosing challenge for clinicians. US, although highly accurate in identifying thyroid nodules and diffuse thyroid diseases, is still not sufficiently accurate to evaluate them. US-elastography has been introduced in order to further increase US accuracy in many fields and eventually for thyroid disease. The aim of the present paper it to provide an update of the literature on different available techniques and the results reported both for thyroid nodules differentiation and for diffuse thyroid disease evaluation. Advantages and limitations of elastography are also discussed.

New prospects for ultrasound contrast agents

Considering the several suggestions regarding the future developments of echocontrast agents, there is a striking difference between the few compounds actually available on the market and used in clinical practice and those undergoing experimental clinical trials. It is therefore difficult to predict what will be the actual impact of these agents in the next future. Future developments will probably go beyond color enhancement which was the end-point till a very short time ago. They can be schematically summarized as follows: (1) development of new substances which enhance both color and gray scales; (2) use of new-generation substances, such as BR1 (Bracco, Milan, Italy) and EchoGen (Sonus, Bothell, WA), which use a gas other than air, such as perfluorate compounds which are more stable and guarantee longer and stronger effects; (3) use of more complex compounds acting at different levels. For example, SHU 536A (Sonovist) produces resonance phenomena with the second and third harmonics, and also stimulated acoustic emission which permits the morphological study of liver parenchyma. Other promising compounds are liposomes and aerosomes. Among the new possibilities in recording and observing phenomena, we can distinguish two main application fields: one is based on the physics of ultrasound and related to the presence of microbubbles in an acoustic field. These phenomena are generally obtained increasing the emission acoustic pressure, which eventually results in microbubble destruction and they are called nonlinear because there is no direct relationship between emission and return frequencies. These phenomena, which are detectable only with dedicated equipment, include: the resonance phenomenon with harmonic emission; intermittent harmonic emission and stimulated acoustic emission. The other application field is not strictly related to ultrasound physics and includes all the systems which can detect the presence of microbubles qualitatively or quantitatively. Other possible applications are related to the possibility of acquiring not only morphological but also functional data, especially in cardiology and neurology. Finally, targeted agents are potentially capable of demonstrating receptor sites or specific molecules, which may open very interesting therapeutic routes.