Low Mechanical Index Contrast Research Articles

Quantitative low mechanical index contrast-enhanced endoscopic ultrasound for the differential diagnosis of chronic pseudotumoral pancreatitis and pancreatic cancer

BackgroundSecond-generation intravenous blood-pool ultrasound contrast agents are increasingly used in endoscopic ultrasound (EUS) for characterization of microvascularization, differential diagnosis of benign and malignant focal lesions, as well as improved staging and guidance of therapeutic procedures.MethodsThe aim of our study was to prospectively compare the vascularisation patterns in chronic pseudotumoral pancreatitis and pancreatic cancer using quantitative low mechanical index (MI) contrast-enhanced EUS. We included 51 patients with chronic pseudotumoral pancreatitis (n = 19) and pancreatic cancer (n = 32). Perfusion imaging started with a bolus injection of Sonovue (2.4 ml), followed by analysis in the early arterial (wash-in) and late venous (wash-out) phase. Perfusion analysis was performed by post-processing of the raw data (time intensity curve [TIC] analysis). TIC analysis was performed inside the tumor and the pancreatic parenchyma, with depiction of the dynamic vascular pattern generated by specific software. Statistical analysis was performed on raw data extracted from the TIC analysis. Final diagnosis was based on a combination of EUS-FNA, surgery and follow-up of minimum 6 months in negative cases.ResultsThe sensitivity and specificity of low MI contrast enhanced EUS using TIC were sensitivity and specificity of low MI contrast enhanced EUS using TIC analysis were 93.75% (95% CI = 77.77 - 98.91%) and 89.47% (95% CI = 65.46 - 98.15%), respectively. Pseudotumoral chronic pancreatitis showed in the majority of cases a hypervascular appearance in the early arterial phase of contrast-enhancement, with a dynamic enhancement pattern similar with the rest of the parenchyma. Statistical analysis of the resulting series of individual intensities revealed no statistically relevant differences (p = .78). Pancreatic adenocarcinoma was usually a hypovascular lesion, showing low contrast-enhancement during the early arterial and also during the late venous phase of contrast-enhancement, also lower than the normal surrounding parenchyma. We found statistically significant differences in values during TIC analysis (p < .001).ConclusionsLow MI contrast enhanced EUS technique is expected to improve the differential diagnosis of focal pancreatic lesions. However, further multicentric randomized studies will confirm the exact role of the technique and its place in imaging assessment of focal pancreatic lesions.

Parametric imaging with contrast-enhanced ultrasound: Usefulness for characterization of dynamic effects of microvascularization for hepatocellular carcinoma and focal nodular hyperplasia

To evaluate whether parametric imaging with contrast-enhanced ultrasound (CEUS) is equal to experienced radiologists after review of CEUS in differentiating hepatocellular carcinoma (HCC) from focal nodular hyperplasia (FNH). An image processing software was used to quantitatively analyze the CEUS clips of 30 HCCs (mean diameter, 3.4±0.9 cm; range, 1.8-5.0 cm) and 30 FNHs (mean diameter, 3.0±1.1 cm; range, 1.1-5.0 cm). Low mechanical index contrast specific imaging modes and contrast agent of SonoVue® were applied for CEUS. Fourteen HCCs were pathologically diagnosed and 16 were clinically diagnosed, whereas all the FNHs were confirmed by pathological examination. Quantitative parameters of HCC and FNH were compared. The diagnostic performance between parametric imaging and two experienced readers was compared using the receiver operating characteristic (ROC) curve analysis. On parametric imaging, the rise time, time to peak and mean transit time for HCC and FNH were 16.7±11.1 s vs. 21.9±9.0 s (P=0.052), 29.9±14.1 s vs. 33.2±11.1 s (P=0.322), 115.0±90.9 s vs. 271.5±147.6 s (P<0.001), respectively. The ROC analysis showed that, for the differentiation between HCC and FNH, the cut-off point for mTT was 107.93 s with the Az value of 0.817 (95% CI: 0.703-0.931), and the Az value was 0.834 (95%CI: 0.728-0.941) for two experienced readers (P=0.417 compared with mTT). The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were 96.7%, 66.7%, 81.7%, 74.4%, and 95.2%, respectively, for parametric imaging, and 86.7%, 76.7%, 81.7%, 78.8%, and 85.2%, respectively, for two experienced readers (all P>0.05 compared with parametric imaging). Parametric imaging with CEUS is helpful for characterization the typical dynamic effects of microvascularization of HCC and FHH and is equal to experienced readers in the differential diagnosis between HCC and FNH.

Value of contrast‐enhanced sonography in the diagnosis of peripheral intrahepatic cholangiocarcinoma

To illustrate contrast-enhanced harmonic ultrasonography (CEUS) findings of peripheral intrahepatic cholangiocarcinoma (PICC) and to assess the usefulness of CEUS in the diagnosis of this disease. This study is a retrospective analysis of 46 patients (20 men, 26 women) with PICC who underwent both preoperative CEUS and pathologic examination. Sonographic examinations were performed with sonographic instruments equipped with low mechanical index contrast imaging software. The contrast agent SonoVue was used. The wash-in and wash-out features of the lesions were documented and the enhancement patterns were analyzed by visual inspection of the real-time cine loops. During the hepatic arterial phase of CEUS, the majority of PICC lesions (43/46, 93.5%) showed hypervascularity compared with the liver parenchyma, whereas three lesions (3/46, 6.5%) showed hypovascularity. In the portal phases, all lesions were either isoechoic or hypoechoic, while they were all hypoechoic in the late phase. Of all the hypervascular lesions, 48.8% (21/43) showed diffuse enhancement and 51.2% (22/43) showed rim-like or thick, rim-like enhancement. In 62.8% (27/43) of cases, progressive dendritic and centripetal fill-in of the contrast agent was observed. There were 83.7% (36/43) of hypervascular nodules showing heterogeneous enhancement during peak contrast enhancement of the lesions. CEUS provided clearer visualization of lesion margins than did conventional sonography. CEUS examination yields some specific findings that are useful in the diagnosis of PICC.

Use of contrast-enhanced ultrasound imaging with microbubbles targeted to αvβ3 integrins to enhance detection of early-stage ovarian tumors.

5076 Background: Lack of an early detection test makes ovarian cancer (OVCA) a lethal gynecological malignancy. Tumor associated neo-angiogenesis (TAN) is an early event in tumor development and represents a potential target for early detection. Traditional transvaginal ultrasound (TVUS) cannot detect TAN at early stage. The goal of this pilot study was to examine the enhancement of TVUS using αvβ3 integrins targeted microbubble ultrasound contrast agent (UCA) in laying hens, a preclinical spontaneous model of human OVCA. Methods: 3-4 years old hens (n=50) were selected randomly and scanned continuously by TVUS before, during and after UCA (Visister-integrins, Targeson Inc. CA) injection at brachial veins. UCA was visualized using a low mechanical index contrast imaging pulse sequence. All pre- and post-contrast injection images were archived and analyzed off-line. Gross diagnosis was recorded at euthanasia and tissues were processed for histology. Tumors and their types were confirmed by routine histology. TAN markers (SMA and αvβ3 integrins) were detected by immunohistochemistry. TAN vessels were counted and correlation with ultrasound prediction was examined. Results: αvβ3-integrins targeted UCA enhanced the visualization of ovarian tumors significantly in laying hens. At gray scale, UCA bounded areas appeared as a ring on the ovarian surfaces of 8 of 50 hens and were suspected for ovarian tumors. Tumors were confirmed in all hens predicted to have OVCA. In 7 hens tumors were early stage and in one hen the tumor metastasized to the oviduct. A microscopic lesion was found in one hen which was not detected by ultrasound imaging. Thus 9 of 50 hens had ovarian tumors and UCA detected approximately 88% at early stages. The frequency of immunopositive TAN vessels (SMA and αvβ3 integrins positive) were significantly higher in OVCA hens than normal hens (P<0.05) and was positively correlated (0.86, P< 0.05) with ultrasound prediction. Conclusions: Our results demonstrate that UCA targeting αvβ3 integrin enhanced TVUS detection of early stage ovarian tumors in a pre-clinical model and may form the foundation for a clinical study. Support: Department of Defense (#09-3303), Sramek Foundation.

Ultrasound Molecular Imaging of Tumor Angiogenesis With an Integrin Targeted Microbubble Contrast Agent

Ultrasound molecular imaging is an emerging technique for sensitive detection of intravascular targets. Molecular imaging of angiogenesis has strong potential for both clinical use and as a research tool in tumor biology and the development of antiangiogenic therapies. Our objectives are to develop a robust ultrasound contrast agent platform using microbubbles (MB) to which targeting ligands can be conjugated by biocompatible, covalent conjugation chemistry, and to develop a pure low mechanical index (MI) imaging processing method and corresponding quantification method. The MB and the imaging methods were evaluated in a mouse model of breast cancer in vivo. We used a cyclic arginine-glycine-aspartic acid (cRGD) pentapeptide containing a terminal cysteine group conjugated to the surface of MB bearing pyridyldithio-propionate (PDP) for targeting αvβ3 integrins. As negative controls, MB without a ligand or MB bearing a scrambled sequence (cRAD) were prepared. To enable characterization of peptides bound to MB surfaces, the cRGD peptide was labeled with FITC and detected by plate fluorometry, flow cytometry, and fluorescence microscopy. Targeted adhesion of cRGD-MB was demonstrated in an in vitro flow adhesion assay against recombinant murine αvβ3 integrin protein and αvβ3 integrin-expressing endothelial cells (bEnd.3). The specificity of cRGD-MB for αvβ3 integrin was demonstrated by treating bEnd.3 EC with a blocking antibody. A murine model of mammary carcinoma was used to assess targeted adhesion and ultrasound molecular imaging in vivo. The targeted MB were visualized using a low MI contrast imaging pulse sequence, and quantified by intensity normalization and 2-dimensional Fourier transform analysis. The cRGD ligand concentration on the MB surface was ∼8.2 × 10(6) molecules per MB. At a wall shear stress of 1.0 dynes/cm, cRGD-MB exhibited 5-fold higher adhesion to immobilized recombinant αvβ3 integrin relative to nontargeted MB and cRAD-MB controls. Similarly, cRGD-MB showed significantly greater adhesion to bEnd.3 EC compared with nontargeted MB and cRAD-MB. In addition, cRGD-MB, but not nontargeted MB or cRAD-MB, showed significantly enhanced contrast signals with a high tumor-to-background ratio. The adhesion of cRGD-MB to bEnd.3 was reduced by 80% after using anti-αv monoclonal antibody to treat bEnd.3. The normalized image intensity amplitude was ∼0.8, 7 minutes after the administration of cRGD-MB relative to the intensity amplitude at the time of injection, while the spatial variance in image intensity improved the detection of bound agents. The accumulation of cRGD-MB was blocked by preadministration with an anti-αv blocking antibody. The results demonstrate the functionality of a novel MB contrast agent covalently coupled to an RGD peptide for ultrasound molecular imaging of αvβ3 integrin and the feasibility of quantitative molecular ultrasound imaging with a low MI.

State-of-the-art imaging techniques in endoscopic ultrasound

Endoscopic ultrasound (EUS) has recently evolved through technological improvement of equipment, with a major clinical impact in digestive and mediastinal diseases. State-of-the-art EUS equipment now includes real-time sono-elastography, which might be useful for a better characterization of lesions and increased accuracy of differential diagnosis (for e.g. lymph nodes or focal pancreatic lesions). Contrast-enhanced EUS imaging is also available, and is already being used for the differential diagnosis of focal pancreatic masses. The recent development of low mechanical index contrast harmonic EUS imaging offers hope for improved diagnosis, staging and monitoring of anti-angiogenic treatment. Tridimensional EUS (3D-EUS) techniques can be applied to enhance the spatial understanding of EUS anatomy, especially for improved staging of tumors, obtained through a better assessment of the relationship with major surrounding vessels. Despite the progress gained through all these imaging techniques, they cannot replace cytological or histological diagnosis. However, real-time optical histological diagnosis can be achieved through the use of single-fiber confocal laser endomicroscopy techniques placed under real-time EUS-guidance through a 22G needle. Last, but not least, EUS-assisted natural orifice transluminal endoscopic surgery (NOTES) procedures offer a whole new area of imaging applications, used either for combination of NOTES peritoneoscopy and intraperitoneal EUS, but also for access of retroperitoneal organs through posterior EUS guidance.

Detection of Hepatic Metastases from Colorectal Cancer: Prospective Evaluation of Gray Scale US Versus SonoVue® Low Mechanical Index Real Time-Enhanced US as Compared with Multidetector-CT or Gd-BOPTA-MRI

To compare ultrasound (US), low-mechanical index contrast enhanced US (CEUS) and multidetector-CT (MDCT) for the detection of hepatic metastases from colorectal cancer. From January to June 2006, 110 patients (65 males, 45 females; mean age 62 years; range 39-78) with suspected hepatic lesions from colorectal cancer were prospectively evaluated with US, CEUS and MDCT by two independent readers. Intraoperative ultrasonography (IOUS, n = 45) or a follow-up up for at least 6 months by using MDCT or Gd-BOPTA-enhanced MRI was considered the gold standard. McNemar test was employed. Reference standards revealed 430 metastases in 110 patients. On a patient-by-patients analysis, CEUS improved US sensitivity from 67.4-71.6% to 93.4-95.8% (p < 0.05). On a lesion-by-lesion analysis, CEUS improved the sensitivity of US from 60.9-64.9% to 85.3-92.8% (p < 0.001). The specificity increased from 50-60% to 76.7-83.3%. No significant differences in sensitivity or specificity between CEUS and MDCT were found. Contrast-enhanced US was significantly more sensitive than baseline US in the detection of metastases smaller than 1 cm (p < 0.001) with an increase in sensitivity from 29.1-35% to 63.3-76.6% no significant statistical difference was identified when compared with MDCT (sensitivity of 73.3-75.8%). CEUS is significantly more accurate than US and highly comparable with MDCT in the detection of liver metastases from colorectal cancer. Therefore, in the evaluation of patients with suspected hepatic metastases from colorectal tumour, US examination must be performed after contrast administration.

Evidence supportive of impaired myocardial blood flow reserve at high altitude in subjects developing high-altitude pulmonary edema

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.

A fundamental study for quantitative measurement of ultrasound contrast concentration by low mechanical index contrast ultrasonography.

In high mechanical index (MI) contrast ultrasonography it has been shown that the power of contrast signal intensity (CI) has a strong linear correlation with the concentration of the ultrasound contrast agent under conditions of constant applied acoustic pressure. However, it is unclear whether the linearity is preserved in low-MI contrast ultrasonography. Thus, we investigated the relationship between ultrasound contrast concentration and CI in vitro. Solutions of the ultrasound contrast agents Definity and Imagent were prepared at concentrations of 0.5, 2, 8, 32, and 128 μl/l. Placing a jelly block between the transducer and the solution, the solutions were transmitted using pulse subtraction imaging with an MI of 0.05, 0.1, and 0.5. CI was measured in dB in a region of interest 3 mm in height placed just below the border between the jelly and the solution. Data were plotted using double logarithm scales, where the concentration was expressed in dB as 10 × log (concentration). CI in dB had a strong linear correlation with concentration in dB for both agents with any MI. Best fitted slopes were close to 1, indicating that the power of CI is proportional to the concentration. In low-MI contrast ultrasonography, the power of CI is proportional to contrast concentration, and CI in dB is logarithmic to the concentration. Thus, the microbubble concentration can be quantitatively measured even in low-MI contrast ultrasonography.

Giant Mucocele of the Appendix

Clinical and imaging (sonographic and computed tomographic [CT]) findings in 3 cases of giant mucocele of the appendix are described. Clinical records of 3 cases of giant mucocele of the appendix were reviewed. All patients had a basal B-mode sonographic examination and a contrast-enhanced sonographic examination using a second-generation low-mechanical index contrast medium. In all cases, a dual-phase spiral CT examination was carried out. In 2 cases, the abdominal masses were discovered in asymptomatic patients; 1 patient had vague abdominal discomfort. A pathologic diagnosis of benign cystoadenoma was found at pathologic examination in all cases, and malignant pseudomyxoma peritonei was disclosed in 1 patient 1 year later. Common sonographic findings were as follows: (1) a huge abdominal mass with a maximum diameter ranging between 20 and 25 cm; (2) a thin hyperechoic border without either solid vegetations or signs of infiltration of surrounding tissues; (3) a complex internal echo structure with anechoic lacunae interspersed between curvilinear, wavy bands of echogenic material (the so-called sonographic onion skin sign); and (4) avascularity of the masses shown on contrast-enhanced sonography with a low-mechanical index medium. At CT, a well-circumscribed cysticlike mass of low attenuation was displayed in all cases. There was lack of enhancement during a dual-phase examination in 2 cases; in the other, a small peripheral area of faint enhancement was appreciated. Only in the latter case could CT reliably assess the origin of the mass. It is suggested that a combination of sonographic (namely the onion skin sign) and CT findings may aid in the correct preoperative diagnosis of giant mucocele of the appendix.