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1.  Comparative study of thyroid puncture biopsy guided by contrast-enhanced ultrasonography and conventional ultrasound 
The aim of this study was to investigate the application value of thyroid puncture biopsy guided by contrast-enhanced ultrasound (CEUS). A total of 48 patients with 51 solid thyroid nodules (suspected papillary thyroid carcinoma, PTC) were enrolled in the study. Following detection by conventional ultrasonography and CEUS, puncture biopsy of the suspicious lesions guided by conventional ultrasonography and CEUS was conducted, respectively. Then, pathological diagnosis was performed. The number of PTC positive nodules and puncture points detected by the two methods were compared. In 51 nodules with 310 punctures, 44 nodules (86.3%, 44/51) and 240 punctures (77.4%, 240/310) were pathologically diagnosed as PTC. In the 44 nodules diagnosed as PTC, 43 and 34 nodules were detected by CEUS and conventional ultrasound, respectively, with a significant difference between the two methods (P=0.022). Eleven (25%) nodules were independently detected by CEUS. The sensitivity and accuracy of puncture point detection by CEUS (82.9 and 82.6%, respectively) were significantly higher compared with those of conventional ultra-sound (48.3 and 56.5%, respectively; P<0.001). The specificity of puncture points detected by CEUS (81.4%) was significantly lower compared with that by conventional ultrasound (84.3%; P=0.009). Compared with conventional ultrasound, a greater number of PTC-positive nodules were detected by CEUS, with increased sensitivity and accuracy of the puncture points.
doi:10.3892/etm.2013.1016
PMCID: PMC3671767  PMID: 23737884
contrast-enhanced ultrasound; ultrasound; papillary thyroid carcinoma; puncture biopsy
2.  The use of contrast-enhanced ultrasound in the characterisation of focal liver lesions 
The Ulster Medical Journal  2007;76(1):22-25.
Purpose
To determine the potential application of contrast-enhanced ultrasound in the characterisation of focal liver lesions encountered in radiological practice at a district general hospital.
Materials & Methods
Retrospective analysis of 68 sequential patients undergoing contrast-enhanced ultrasound (CEUS) of liver. All patients were referred for CEUS following identification of 1 or more focal liver lesions on conventional ultrasound or CT imaging. After baseline US examination (Acuson), a bolus of 1.0-2.4 ml of SonoVue (Bracco, UK) was administered intravenously. CEUS images were obtained during arterial, portal venous and delayed phases. Patients were followed up for a mean period of 6 months. The CEUS diagnosis was compared to that indicated by other imaging modalities, histopathology, and clinical follow up.
Results
CEUS correctly identified malignant liver lesions in 19 patients, with the final diagnosis confirmed by histopathology in 5 cases and clinico-radiological follow up in 14 cases. 47 patients were correctly identified with benign liver lesions on CEUS imaging, with all these cases confirmed on clinico-radiological follow up. In the detection of malignancy, the sensitivity was 95.0% and the specificity was 97.9%
Conclusions
In our experience to date, contrast-enhanced ultrasound imaging is highly accurate in characterising malignant and benign focal liver lesions. It therefore has significant potential for utilisation in most general radiology departments.
PMCID: PMC1940303  PMID: 17288301
Ultrasound; Liver; Contrast
3.  Novel contrast-enhanced ultrasound imaging in prostate cancer 
World Journal of Urology  2011;29(5):581-587.
Purpose
The purposes of this paper were to present the current status of contrast-enhanced transrectal ultrasound imaging and to discuss the latest achievements and techniques now under preclinical testing.
Objective
Although grayscale transrectal ultrasound is the standard method for prostate imaging, it lacks accuracy in the detection and localization of prostate cancer. With the introduction of contrast-enhanced ultrasound (CEUS), perfusion imaging of the microvascularization became available. By this, cancer-induced neovascularisation can be visualized with the potential to improve ultrasound imaging for prostate cancer detection and localization significantly. For example, several studies have shown that CEUS-guided biopsies have the same or higher PCa detection rate compared with systematic biopsies with less biopsies needed.
Materials and methods
This paper describes the current status of CEUS and discusses novel quantification techniques that can improve the accuracy even further. Furthermore, quantification might decrease the user-dependency, opening the door to use in the routine clinical environment. A new generation of targeted microbubbles is now under pre-clinical testing and showed avidly binding to VEGFR-2, a receptor up-regulated in prostate cancer due to angiogenesis. The first publications regarding a targeted microbubble ready for human use will be discussed.
Conclusion
Ultrasound-assisted drug delivery gives rise to a whole new set of therapeutic options, also for prostate cancer. A major breakthrough in the future can be expected from the clinical use of targeted microbubbles for drug delivery for prostate cancer diagnosis as well as treatment.
doi:10.1007/s00345-011-0747-3
PMCID: PMC3189413  PMID: 21847656
Contrast-enhanced ultrasound; Prostate cancer; TRUS; Targeted microbubbles; Quantification
4.  Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer 
BMC Cancer  2007;7:171.
Background
Contrast enhanced ultrasound (CEUS) is an imaging technique which appeared on the market around the year 2000 and proposed for the detection of liver metastases in gastrointestinal cancer patients, a setting in which accurate staging plays a significant role in the choice of treatment.
Methods
A total of 109 patients with colorectal (n = 92) or gastric cancer prospectively underwent computed tomography (CT) scan and conventional US evaluation followed by real time CEUS. A diagnosis of metastases was made by CT or, for lesions not visibile at CT, the diagnosis was achieved by histopathology or by a malignant behavior during follow-up.
Results
Of 109 patients, 65 were found to have metastases at presentation. CEUS improved sensitivity in metastatic livers from 76.9% of patients (US) to 95.4% (p <0.01), while CT scan reached 90.8% (p = n.s. vs CEUS, p < 0.01 vs US). CEUS and CT were more sensitive than US also for detection of single lesions (87 with US, 122 with CEUS, 113 with CT). In 15 patients (13.8%), CEUS revealed more metastases than CT, while CT revealed more metastases than CEUS in 9 patients (8.2%) (p = n.s.).
Conclusion
CEUS is more sensitive than conventional US in the detection of liver metastases and could be usefully employed in the staging of patients with gastrointestinal cancer. Findings at CEUS and CT appear to be complementary in achieving maximum sensitivity.
doi:10.1186/1471-2407-7-171
PMCID: PMC2000899  PMID: 17767722
5.  Does 3D Ultrasound Enhance the Diagnosis of Bladder Tumours in Patients with Haematuria? 
ISRN Urology  2012;2012:158437.
Purpose. Bladder cancer is a frequent cause of haematuria in elderly patients, and bladder ultrasound (US) is a valuable tool in diagnosing these malignancies. We examined the accuracy of 3D bladder US in diagnosing bladder tumors in patients with haematuria. Patients and Methods. Twenty-one patients observed in the emergency department for haematuria underwent a kidney and bladder US. Patients with normal or uncertain bladder US findings underwent a 3D US and a cystoscopy. Results. In 5 (23.8%) patients, the 3D US detected bladder tumours not seen in 2D US. All these patients were found to have bladder tumours on cystoscopy. Another 5 (23.8%) patients with uncertain findings on 2D US had normal 3D US and cystoscopy. 3D US showed a sensitivity of 83.3% and a specificity of 100% with a positive predicted value and negative predictive values of 100% and 93.8%, respectively. Conclusion. 3D US was more sensitive than 2D US in diagnosing bladder tumours in patients with haematuria.
doi:10.5402/2012/158437
PMCID: PMC3329719  PMID: 22550603
6.  New ultrasound techniques for lymph node evaluation 
Conventional ultrasound (US) is the recommended imaging method for lymph node (LN) diseases with the advantages of high resolution, real time evaluation and relative low costs. Current indications of transcutaneous ultrasound and endoscopic ultrasound include the detection and characterization of lymph nodes and the guidance for LN biopsy. Recent advances in US technology, such as contrast enhanced ultrasound (CEUS), contrast enhanced endoscopic ultrasound (CE-EUS), and real time elastography show potential to improve the accuracy of US for the differential diagnosis of benign and malignant lymph nodes. In addition, CEUS and CE-EUS have been also used for the guidance of fine needle aspiration and assessment of treatment response. Complementary to size criteria, CEUS could also be used to evaluate response of tumor angiogenesis to anti-angiogenic therapies. In this paper we review current literature regarding evaluation of lymphadenopathy by new and innovative US techniques.
doi:10.3748/wjg.v19.i30.4850
PMCID: PMC3740414  PMID: 23946589
Lymph nodes; Ultrasound; Endoscopic ultrasound; Lymph node metastasis; Lymphoma
7.  Contrast-enhanced ultrasonographic findings of hepatic paragonimiasis 
AIM: To investigate the features of hepatic paragonimiasis on contrast-enhanced ultrasound (CEUS) imaging.
METHODS: Fifteen patients with hepatic paragonimiasis who were admitted to our hospital between March 2008 and August 2012 were enrolled to this study. The conventional ultrasound and CEUS examinations were performed with a Philips IU22 scanner with a 1-5-MHz convex transducer. After conventional ultrasound scanning was completed, the CEUS study was performed. Pulse inversion harmonic imaging was used for CEUS. A bolus injection of 2.4 mL of a sulfur hexafluoride-filled microbubble contrast agent (SonoVue) was administered. CEUS features were retrospectively reviewed and correlated with pathological findings.
RESULTS: In total, 16 lesions were detected on CEUS. The mean size of the lesions was 4.4 ± 1.6 cm (range, 1.7-6.6 cm). Subcapsular location was found in 12 lesions (75%). All the lesions were hypoechoic. Six lesions (37.5%) were of mixed content, seven (43.8%) were solid with small cystic areas, and the other three (18.8%) were completely solid. Ten lesions (62.5%) were rim enhanced with irregular tract-like nonenhanced internal areas. Transient wedge-shaped hyperenhancement of the surrounding liver parenchyma was seen in seven lesions (43.8%). Areas with hyper- or iso-enhancement in the arterial phase showed contrast wash-out and appeared hypoenhanced in the late phase. The main pathological findings included: (1) coagulative or liquefactive necrosis within the lesion, infiltration of a large number of eosinophils with the formation of chronic eosinophilic abscesses and sporadic distribution of Charcot-Leyden crystals; and (2) hyperplasia of granulomatous and fibrous tissue around the lesion.
CONCLUSION: Subcapsular location, hypoechogenicity, rim enhancement and tract-like nonenhanced areas could be seen as the main CEUS features of hepatic paragonimiasis.
doi:10.3748/wjg.v19.i13.2087
PMCID: PMC3623987  PMID: 23599629
Paragonimiasis; Liver; Infection; Contrast-enhanced ultrasonography
8.  CEUS in the differentiation between low and high-grade bladder carcinoma 
Journal of Ultrasound  2012;15(4):247-251.
Introduction
Bladder cancer ranks 4th overall in the number of newly diagnosed cancers and 10th in causes of cancer deaths. More than 90% of all cases of bladder cancer are transitional cell carcinoma (TCC). The goal of this study is to confirm the usefulness of low mechanical index contrast-enhanced ultrasonography (CEUS), also in association with time–intensity curves, in the differentiation between high- and low-grade bladder malignant lesions.
Materials and methods
From February 2006 to February 2012 we recruited 144 patients. All patients underwent grayscale ultrasonography (US), color-Doppler ultrasonography (CDUS) and contrast-enhanced ultrasonography (CEUS). Subsequently all patients underwent cystoscopy and TURB.
Results
Histological diagnoses were: 88 high-grade carcinomas (61.1%), and 56 low-grade carcinomas (38.9%). Sensitivity and specificity of CDUS were 87.5% (126/144) and 60%, respectively. Sensitivity and specificity of CEUS were 90.9% and 85.7%, respectively. Sensitivity and specificity of TIC were 91.6% (132/144) and 85.7%, respectively.
Discussion and conclusions
CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves.
doi:10.1016/j.jus.2012.09.002
PMCID: PMC3558094  PMID: 23730389
Contrast-enhanced ultrasonography, CEUS; Bladder cancer; Time-intensity curves; Color-Doppler ultrasonography, CDUS
9.  Detection Of Focal Liver Lesions In Cirrhotic Liver Using Contrast-Enhanced Ultrasound 
World Journal of Radiology  2009;1(1):25-36.
Patients with liver cirrhosis are at increased risk of hepatocellular carcinoma (HCC). Conventional or baseline ultrasound (BUS) is often used as the first-line tool for HCC surveillance or detection, but the accuracy of BUS in HCC detection or differentiation from other focal liver lesions (FLLs) is limited. Contrast-enhanced ultrasound (CEUS) represents a recent revolution in the field of ultrasonography and it has become increasingly important in the detection and evaluation of FLLs. In CEUS, HCC typically exhibits arterial hyper-enhancement and portal-venous washout represented by hypo-enhanced lesions in the portal venous and late phases. The detection rate of HCC was significantly higher with CEUS compared with BUS. Even regenerative or some dysplastic nodules may exhibit arterial hyper-enhancement as they are differentiated from HCC by its iso-enhancing pattern in portal and late phases. The contrast-enhancement patterns of other different types of benign and malignant FLLs, as well as their detection rates with CEUS, were also discussed.
doi:10.4329/wjr.v1.i1.25
PMCID: PMC2998885  PMID: 21160718
Contrast-enhanced ultrasound; Cirrhosis; Focal liver lesions; Metastatic liver cancer; Hepatocellular carcinoma
10.  Response evaluation of chemotherapy in metastatic colorectal cancer by contrast enhanced ultrasound 
AIM: To evaluate whether contrast enhanced ultrasound (CEUS) might also be used for response prediction and early response evaluation in patients receiving bevacizumab based chemotherapy for metastasized colorectal cancer.
METHODS: Thirty consecutive patients with non primary resectable liver metastases from colorectal cancer underwent CEUS before treatment (CEUS date 1) and before the second (CEUS date 2) and fourth (CEUS date 3) cycle of bevacizumab based chemotherapy. Three parameters [PEAK, Time to peak (TTP) and RISE RATE]were correlated with radiological response.
RESULTS: For neoadjuvant purpose a reduction of tumour mass was required to assume clinical response. Based on these response criteria there was a significant (P < 0.001) correlation in TTP between metastases of responders (9.08 s) and non-responders (14.76 s) archived on CEUS date 1. By calculating a standardized quotient (metastases divided by normal liver tissue) we were able to define a cut off, predicting response with a sensitivity of 92.3 % and a specificity of 100 %. To reflect a palliative intention only those patients with progressive disease were classified as non-responders. In this stetting TTP was also significantly (P < 0.01) different between responders and non-responders. In contrast, Peak and Rise rate did not show any significant difference between responder and non-responder.
CONCLUSION: CEUS might serve as a surrogate marker to predict treatment response in patients with metastasized colorectal cancer who receive antiangiogenic therapy.
doi:10.3748/wjg.v18.i6.541
PMCID: PMC3280399  PMID: 22363120
Colorectal cancer; Liver metastases; Response prediction to chemotherapy; Contrast-enhanced ultrasound; Bevacizumab
11.  Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound 
The British Journal of Radiology  2010;83(989):411-418.
The aim of this study was to evaluate the imaging features of hepatic angiomyolipoma (AML) on contrast-enhanced ultrasound (CEUS). The imaging features of 12 pathologically proven hepatic AML lesions in 10 patients who had undergone baseline ultrasound (BUS) and CEUS examinations were evaluated retrospectively. The enhancement extent, pattern and dynamic change, along with the enhancement process, on CEUS were analysed. The diagnostic results of BUS and CEUS before pathological examination were also recorded. The results showed that 75% (9/12) of the AML lesions exhibited mixed echogenicity on BUS and most showed remarkable hyperechogenicity in combination with a hypoechoic or anechoic portion. Arterial flow signals were detected in 75% (9/12) of the lesions on colour Doppler imaging. On CEUS, 66.7% (n = 8) of the 12 lesions exhibited hyperenhancement in the arterial phase, slight hyperenhancement (n = 2) or isoenhancement (n = 6) in the portal phase, and slight hyperenhancement (n = 1) or isoenhancement (n = 7) in the late phase. Three (25%) lesions exhibited hyperenhancement in the arterial phase and hypoenhancement in both portal and late phases. One (8.3%) lesion exhibited hypoenhancement throughout the CEUS process. Before pathological examination with BUS, only 3 (25%) lesions were correctly diagnosed as hepatic AML. Conversely, on CEUS, correct diagnoses were made for 66.8% (8/12) of hepatic AMLs. Therefore, arterial hyperenhancement and subsequent sustained enhancement on CEUS were found in the majority of hepatic AMLs. The combination of BUS and CEUS leads to the correct diagnosis in the majority of hepatic AMLs, and is higher than the success rate achieved by BUS alone.
doi:10.1259/bjr/81174247
PMCID: PMC3473573  PMID: 19723766
12.  Noninvasive Electromagnetic Detection of Bladder Cancer 
ISRN Urology  2014;2014:802328.
Objectives. Normal and neoplastic human tissues have different electromagnetic properties. This study aimed to determine the diagnostic accuracy of noninvasive electromagnetic detection of bladder cancer (BC) by the tissue-resonance interaction method (TRIM-prob). Patients and Methods. Consecutive patients were referred for cystoscopy because of (i) microscopic or gross hematuria and/or irritative voiding symptoms and (ii) bladder ultrasounds and urinary cytology findings negative or just suspicious of malignancy. Patients were first submitted to TRIM-prob bladder scanning by a single investigator and then to cystoscopy by another investigator blind to TRIM-prob data. Results. In 125 evaluated patients cystoscopy was positive for BC in 47 and negative in the remaining 78; conversely, TRIM-prob bladder scanning was positive for BC in 53 and negative in 72. In particular, TRIM-prob scanning yielded 7 false positives and only one false negative; therefore, its overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.9%, 89.9%, 86.8%, 98.6%, and 93.6%, respectively. Conclusions. TRIM-prob bladder scanning was a simple and quite accurate method for non-invasive electromagnetic detection of BC. If the elevated positive and negative predictive values will be replicated in further well-designed studies, it could be used to screen asymptomatic patients at high risk of BC.
doi:10.1155/2014/802328
PMCID: PMC3915748  PMID: 24563795
13.  Contrast-enhanced ultrasonography for real-time monitoring of interstitial laser thermal therapy in the focal treatment of prostate cancer 
Introduction
We report a case study of the application of contrast-enhanced ultrasonography (CEUS) for intraoperative monitoring of thermal ablation of a single focus of prostate cancer.
Methods
A patient presented with biopsy-proven, solitary-focus, low-risk prostate cancer and was recruited into a clinical trial of interstitial laser thermal focal therapy. Multiparametric magnetic resonance imaging (MRI) was used to locate the single dominant focus, and photothermal ablation was performed at the tumour site under the guidance of transrectal ultrasonography. Transrectal CEUS using systemic bolus injections of the intravascular contrast agent Definity was performed immediately before, several times during and on completion of therapy. Lesions observed on CEUS were compared with treatment effect as measured by tissue devascularization on 1-week gadolinium (Gd)–enhanced MRI.
Results
Baseline images showed CEUS contrast-agent signal throughout the prostate. During and after treatment, large hypocontrast regions were observed surrounding the treatment fibres, indicating the presence of an avascular lesion resulting from photothermal therapy. Lesion size was found to increase during the delivery of thermal energy. Lesion size measured using CEUS (16 × 11 mm) was similar to the 7-day lesion measured using Gd-enhanced T1-weighted MRI.
Conclusion
Focal therapy for prostate cancer requires both complete treatment of the dominant tumour focus and minimal morbidity. The application of CEUS during therapy appears to provide an excellent measure of the actual treatment effect. Hence, it can be used to ensure that the therapy encompasses the whole target but does not extend to surrounding critical structures. Future clinical studies are planned with comparisons of intraoperative CEUS to Gd-enhanced MRI at 7 days and whole-mount pathology samples.
PMCID: PMC2666908  PMID: 19424466
14.  Contrast-enhanced US and MRI for assessing the response of breast cancer to neoadjuvant chemotherapy☆ 
Journal of Ultrasound  2008;11(4):143-150.
Purpose
To evaluate the response of breast cancers to neoadjuvant chemotherapy (NAC) with second-generation contrast-enhanced ultrasound (CEUS) and magnetic resonance (MR).
Materials and Methods
We studied 16 women aged 33–74 years (mean, 53 years; median, 38 years) with locally advanced breast carcinoma or large operable breast cancer (>2 cm; T2–T4, N0–N3, M0) that had been detected by mammography, conventional ultrasonography, and biopsy. CEUS (with SonoVue, 5 ml) and MR (with Gd-DTPA; 0.2 mM/kg) were performed under blinded conditions before, during, and after 6–8 cycles of NAC. Lesions were measured and time/signal intensity (T/SI) curves were calculated during both the examinations. The data obtained were analyzed in light of the results of surgical pathology.
Results
Six patients had complete responses manifested by the disappearance of enhancement at both CEUS and MR. Six others had partial responses (reduction of lesion enhancement >50%). In 5/6, T/SI curves obtained with CEUS and MR were both indicative of malignancy (flat curves at CEUS, type I curves at MR); the sixth had a discontinuous curve at CEUS and a type II curve at MR. Four patients had lesional enhancement reductions of <50%. In 3, concordant pictures emerged from the analysis of T/SI curves (discontinuous curves in CEUS, type II and III curves in MR); the fourth had a flat CEUS curve and a type I MR curve. Responses to NAC classified on the basis of MR and CEUS findings showed good correlation with the pathological response.
Conclusions
T/SI curves recorded during CEUS correlate with those obtained during MR and may be a valid index of response to the therapy.
doi:10.1016/j.jus.2008.09.007
PMCID: PMC3553156  PMID: 23396645
Breast ultrasonography; Breast cancer; Contrast media; Contrast-enhanced US; MRI
15.  Intraprocedural contrast-enhanced ultrasound (CEUS) in liver percutaneous radiofrequency ablation: clinical impact and health technology assessment 
Insights into Imaging  2014;5(2):209-216.
Objectives
To assess the clinical and the economic impacts of intraprocedural use of contrast-enhanced ultrasound (CEUS) in patients undergoing percutaneous radiofrequency ablation for small (<2.5 cm) hepatocellular carcinomas.
Methods
One hundred and forty-eight hepatocellular carcinomas in 93 patients were treated by percutaneous radiofrequency ablation and immediate assessment by intraprocedural CEUS. Clinical impact, cost effectiveness, and budget, organisational and equity impacts were evaluated and compared with standard treatment without intraprocedural CEUS using the health technology assessment approach.
Results
Intraprocedural CEUS detected incomplete ablation in 34/93 (36.5 %) patients, who underwent additional treatment during the same session. At 24-h, complete ablation was found in 88/93 (94.6 %) patients. Thus, a second session of treatment was spared in 29/93 (31.1 %) patients. Cost-effectiveness analysis revealed an advantage for the use of intraprocedural CEUS in comparison with standard treatment (4,639 vs 6,592) with a 21.9 % reduction of the costs to treat the whole sample. Cost per patient for complete treatment was € 4,609 versus € 5,872 respectively. The introduction of intraprocedural CEUS resulted in a low organisational impact, and in a positive impact on equity
Conclusions
Intraprocedural use of CEUS has a relevant clinical impact, reducing the number of re-treatments and the related costs per patient.
Teaching Points
• CEUS allows to immediately asses the result of ablation.
• Intraprocedural CEUS decreases the number of second ablative sessions.
• Intraprocedural CEUS may reduce cost per patient for complete treatment.
• Use of intraprocedural CEUS may reduce hospital budget.
• Its introduction has low organisational impact, and relevant impact on equity.
doi:10.1007/s13244-014-0315-7
PMCID: PMC3999370  PMID: 24563244
Radiofrequency ablation; Hepatocellular carcinoma; Cost-effectiveness; Clinical impact; Budget impact; Health technology assessment; Intraprocedural contrast-enhanced ultrasound
16.  Narrow-band imaging cystoscopy in non-muscle-invasive bladder cancer: a prospective comparison to the standard approach 
Therapeutic Advances in Urology  2012;4(5):211-217.
Objectives:
A single-centre, prospective trial was performed aiming to assess the impact of narrow-band imaging (NBI) cystoscopy in cases of non-muscle-invasive bladder cancer (NMIBC) in comparison to standard white light cystoscopy (WLC).
Materials and methods:
A total of 95 NMIBC-suspected consecutive cases were enrolled. The inclusion criteria were hematuria, positive urinary cytology or ultrasound suspicion of bladder tumors. All patients underwent WLC and NBI cystoscopy. Standard resection was performed for all lesions visible in white light and NBI transurethral resection of bladder tumors for only NBI-observed tumors.
Results:
The overall detection rates of NMIBC and carcinoma in situ (CIS) were significantly improved for NBI (96.2% versus 87.2% and 100% versus 66.7% respectively). Also, NBI cystoscopy showed significantly superior detection for CIS, pTa and overall tumors (95.2% versus 61.9%, 93.9% versus 85.2% and 94.8% versus 83.9% respectively). Additional tumors were diagnosed by NBI in a significant proportion of patients with CIS, pTa, pT1 and NMIBC (55.5% versus 11.1%, 26.5% versus 10.2%, 30% versus 10% and 30.8% versus 10.3%). Postoperative treatment was significantly improved due to NBI results (16.7% versus 5.1%).
Conclusions:
NBI cystoscopy represents a valuable diagnostic alternative in patients with NMIBC, with significant improvement in tumor visual accuracy as well as detection. This approach provides a substantial improvement to bladder cancer therapeutic management.
doi:10.1177/1756287212454181
PMCID: PMC3441134  PMID: 23024703
narrow-band imaging cystoscopy; non-muscle-invasive bladder cancer; transurethral resection of bladder tumors; white light cystoscopy
17.  Pitfalls of contrast-enhanced ultrasound (CEUS) in the diagnosis of splenic sarcoidosis 
Journal of Ultrasound  2013;16(2):75-80.
By observing the real-time behavior of focal liver lesions at three vascular phases (arterial, portal-venous, and late), contrast-enhanced ultrasound (CEUS) has been successfully applied to differentiate benign from malignant hepatic nodules. In recent years, numerous studies highlighted the usefulness of CEUS also for other applications such as abdominal trauma, renal, pancreatic, thyroid, and inflammatory bowel diseases, supporting its role even in differentiating benign from malignant splenic nodules. Therefore, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) recently updated the guidelines for the use of ultrasound contrast agents in clinical practice, pointing out the indication to characterize splenic parenchymal inhomogeneity or suspected lesions found on conventional ultrasound (BUS). We describe the case of a patient with a history of colon cancer and finding, at BUS and CEUS, of hypoechoic lesions with a highly suggestive pattern for metastases, subsequently histologically proved to be splenic localizations of a benign and multisystemic granulomatous disease such as sarcoidosis. We therefore reviewed the current literature focusing on the role of CEUS in differentiating benign from malignant splenic lesions, emphasizing on the lack of data and numerical shortage of sarcoidosis derived-lesions in the available studies. We conclude that sarcoidosis remains a diagnosis of exclusion and new studies are needed before defining precise indications of CEUS in these patients.
doi:10.1007/s40477-013-0013-1
PMCID: PMC3774908  PMID: 24294346
Sarcoidosis; CEUS; Spleen; Guidelines
18.  Comparison of Diagnostic Efficacy of Contrast-Enhanced Ultrasound, Acoustic Radiation Force Impulse Imaging, and Their Combined Use in Differentiating Focal Solid Thyroid Nodules 
PLoS ONE  2014;9(3):e90674.
Background
A key limitation of conventional ultrasound (US) includes poor differentiation of benign from malignant thyroid nodules. Contrast-enhanced US (CEUS) and acoustic radiation force impulse (ARFI) could provide better characterization of focal thyroid nodules; however, no studies have compared their efficacies.
Objective
To evaluate the diagnostic efficacy of conventional US,CEUS, ARFI, and their combined use in differentiating focal solid thyroid nodules.
Methods
One-hundred-forty-six Chinese patients with 175 thyroid nodules (119 benign and 56 malignant) were prospectively enrolled. Each patients underwent conventional US, CEUS and ARFI, respectively. The diagnostic performance of the conventional US, CEUS, ARFI, combined use of either CEUS or ARFI and combined use of the three modalities were assessed and compared using Pathological diagnosis (histological/cytological) as the reference method.
Results
There were no significant differences between individual groups (CEUS vs US, P = 0.279, ARFI vs US, P = 0.372, CEUS vs ARFI, P = 0.849), combined use of US and CEUS or combined use of US and ARFI yielded significant difference compared to US. (combination of US & CEUS vs US, P = 0.021; combination of US & ARFI vs US, P = 0.036). The combination of three modalities significantly improved the diagnostic accuracy compared with either combination of conventional US and CEUS or combination of conventional US and ARFI (P = 0.045 and P  = 0.027, respectively).
Conclusions
CEUS and ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules. The combination of CEUS with ARFI can significantly improve the diagnostic accuracy.
doi:10.1371/journal.pone.0090674
PMCID: PMC3940946  PMID: 24594879
19.  Contrast Enhanced Ultrasound of the Kidneys: What Is It Capable of? 
BioMed Research International  2013;2013:595873.
One of the many imaging uses of contrast enhanced ultrasound (CEUS) is studying a wide variety of kidney pathology, due to its ability to detect microvascular blood flow in real time without affecting renal function. CEUS enables dynamic assessment and quantification of microvascularisation up to capillary perfusion. The objective of this paper is to briefly refresh basic knowledge of ultrasound (US) contrast agents' physical properties, to study technical details of CEUS scanning in the kidneys, and to review the commonest renal indications for CEUS, with imaging examples in comparison to baseline unenhanced US and computed tomography when performed. Safety matters and limitations of CEUS of the kidneys are also discussed.
doi:10.1155/2013/595873
PMCID: PMC3884609  PMID: 24455707
20.  Contrast-enhanced US of the prostate with time/intensity curves: Preliminary results 
Journal of Ultrasound  2008;11(1):8-11.
Purpose
To evaluate the diagnostic performance of ultrasonography using second-generation contrast agent in the study of patients with focal prostate lesions and increased serum prostate-specific antigen (PSA) level.
Materials and methods
Six consecutive patients (age range: 72–87 years) with increased PSA (≥4 ng/ml) underwent transrectal ultrasonography (TRUS) followed by contrast-enhanced ultrasonography (CEUS) with injection of second-generation contrast agent. All patients showed areas of abnormal echostructure suspicious for neoplastic lesions. On the basis of CEUS, a time/intensity curve of the suspected area was compared to that of a normal-appearing distant area of the gland and to the results of biopsy of the hypoechoic area.
Results
At CEUS two different patterns of enhancement were identified and considered to be significant: pattern 1 characterized by a rapid rise in the time/intensity curve of the suspected area compared with the normal gland. Two out of six patients had this pattern and biopsy showed cancer in the biopsied area. Pattern 2 was characterized by a similar rise in the time/intensity curve of the suspected area compared with the normal gland. Four out of six patients had this pattern and biopsy showed prostatitis in the biopsied area.
Conclusions
CEUS using second-generation contrast agent can on the basis of time/intensity curves show differences in vascularization in normal and pathological tissue. Evaluation of the two patterns seems to be useful for identifying areas requiring biopsy, particularly when peripheral hypoechoic areas are observed at TRUS. Our data need to be confirmed in a larger patient population.
doi:10.1016/j.jus.2007.10.004
PMCID: PMC3553197  PMID: 23396763
Prostate; Ultrasonography; Contrast media
21.  Detection of vascularity in wrist tenosynovitis: power doppler ultrasound compared with contrast-enhanced grey-scale ultrasound 
Arthritis Research & Therapy  2010;12(6):R209.
Introduction
We sought to assess vascularity in wrist tenosynovitis by using power Doppler ultrasound (PDUS) and to compare detection of intra- and peritendinous vascularity with that of contrast-enhanced grey-scale ultrasound (CEUS).
Methods
Twenty-six tendons of 24 patients (nine men, 15 women; mean age ± SD, 54.4 ± 11.8 years) with a clinical diagnosis of tenosynovitis were examined with B-mode ultrasonography, PDUS, and CEUS by using a second-generation contrast agent, SonoVue (Bracco Diagnostics, Milan, Italy) and a low-mechanical-index ultrasound technique. Thickness of synovitis, extent of vascularized pannus, intensity of peritendinous vascularisation, and detection of intratendinous vessels was incorporated in a 3-score grading system (grade 0 to 2). Interobserver variability was calculated.
Results
With CEUS, a significantly greater extent of vascularity could be detected than by using PDUS (P < 0.001). In terms of peri- and intratendinous vessels, CEUS was significantly more sensitive in the detection of vascularization compared with PDUS (P < 0.001). No significant correlation between synovial thickening and extent of vascularity could be found (P = 0.089 to 0.097). Interobserver reliability was calculated to be excellent when evaluating the grading score (κ = 0.811 to 1.00).
Conclusions
CEUS is a promising tool to detect tendon vascularity with higher sensitivity than PDUS by improved detection of intra- and peritendinous vascularity.
doi:10.1186/ar3185
PMCID: PMC3046516  PMID: 21062450
22.  Optical coherence tomography for bladder cancer - ready as a surrogate for optical biopsy? - Results of a prospective mono-centre study 
Introduction
New modalities like Optical Coherence Tomography (OCT) allow non-invasive examination of the internal structure of biological tissue in vivo. The potential benefits and limitations of this new technology for the detection and evaluation of bladder cancer were examined in this study.
Materials and methods
Between January 2007 and January 2008, 52 patients who underwent transurethral bladder biopsy or TUR-BT for surveillance or due to initial suspicion of urothelial carcinoma of the bladder were enrolled in this study. In total, 166 lesions were suspicious for malignancy according to standard white light cystoscopy. All suspicious lesions were scanned and interpreted during perioperative cystoscopy using OCT. Cold cup biopsies and/or TUR-B was performed for all these lesions. For this study we used an OCT-device (Niris®, Imalux®, Cleveland, US), that utilizes near-infrared light guided through a flexible fibre-based applicator, which is placed into the bladder via the working channel of the cystoscope. The technology provides high spatial resolution on the order of about 10-20 μm, and a visualization of tissue to a depth of about 2 mm across a lateral span of about 2 mm in width. The device used received market clearance from the FDA and CE approval in Germany. The diagnostic and surgical procedure was videotaped and analyzed afterwards for definitive matching of scanned and biopsied lesion. The primary aim of this study was to determine the level of correlation between OCT interpretation and final histological result.
Results
Of 166 scanned OCT images, 102 lesions (61.4%) matched to the same site where the biopsy/TUR-BT was taken according to videoanalysis. Only these video-verified lesions were used for further analysis. Of all analyzed lesions 88 were benign (inflammation, edema, hyperplasia etc.) and 14 were malignant (CIS, Ta, T1, T2) as shown by final histo pathology.
All 14 malignant lesions were detected correctly by OCT. Furthermore all invasive tumors were staged correctly by OCT regarding tumor growth beyond the lamina propria. There were no false negative lesions detected by OCT. Sensitivity of OCT for detecting the presence of a malignant lesion was 100% and sensitivity for detection of tumor growth beyond the lamina propria was 100% as well. Specificity of OCT for presence of malignancy was 65%, due to the fact that a number of lesions were interpreted as false positive by OCT.
Conclusion
As a minimally invasive technique, OCT proved to have extremely high sensitivity for detection of malignant lesions as well as estimation of whether a tumor has invaded beyond the lamina propria. However, specificity of OCT within the bladder was impaired (65%), possibly due to a learning curve and/or the relatively low spatial resolution and visualization depth of the OCT technology. Further studies and technical development are needed to establish an adequate surrogate for optical biopsy.
doi:10.1186/2047-783X-15-3-131
PMCID: PMC3352220  PMID: 20452899
Bladder cancer; diagnosis; minimally invasive; optical biopsy; optical coherence tomography
23.  Contrast-enhanced ultrasound: The evolving applications 
World Journal of Radiology  2009;1(1):15-24.
Contrast-enhanced ultrasound (CEUS) is a major breakthrough for ultrasound imaging in recent years. By using a microbubble contrast agent and contrast-specific imaging software, CEUS is able to depict the micro- and macro-circulation of the targeted organ, which in turn leads to improved performance in diagnosis. Due to the special dual blood supply system in the liver, CEUS is particularly suitable for liver imaging. It is evident that CEUS facilitates improvement for characterization of focal liver lesions (FLLs), detection of liver malignancy, guidance for interventional procedures, and evaluation of treatment response after local therapies. CEUS has been demonstrated to be equal to contrast-enhanced computed tomography or magnetic resonance imaging for the characterization of FLLs. In addition, the applicability of CEUS has expanded to non-liver structures such as gallbladder, bile duct, pancreas, kidney, spleen, breast, thyroid, and prostate. The usefulness of CEUS in these applications is confirmed by extensive literature production. Novel applications include detecting bleeding sites and hematomas in patients with abdominal trauma, guiding percutaneous injection therapy and therefore achieving the goal of using interventional ultrasonography in managing splenic trauma, assessing the activity of Crohn’s disease, and detecting suspected endoleaks after endovascular abdominal aneurysm repair. Contrast-enhanced intraoperative ultrasound (US) and intracavitary use of CEUS have been developed and clinically studied. The potential use of CEUS involves sentinel lymph node detection, drug or gene delivery, and molecular imaging. In conclusion, the advent of CEUS has greatly enhanced the usefulness of US and even changed the status of US in clinical practice. The application of CEUS in the clinic is continuously evolving and it is expected that its use will be expanded further in the future.
doi:10.4329/wjr.v1.i1.15
PMCID: PMC2999308  PMID: 21160717
Bile duct; Breast; Gallbladder; Pancreas; Kidney; Liver; Contrast-enhanced ultrasound; Prostate; Spleen; Thyroid
24.  Role of contrast-enhanced ultrasound in follow-up assessment after ablation for hepatocellular carcinoma 
AIM: To assess the usefulness of contrast-enhanced ultrasound (CEUS) during follow-up after percutaneous ablation therapy for hepatocellular carcinoma (HCC).
METHODS: A total of 141 patients with HCCs who received percutaneous ablation therapy were assessed by paired follow-up CEUS and contrast-enhanced computed tomography (CECT). The follow-up scheme was designed prospectively and the intervals between CEUS and CECT examinations were less than 14 d. Both images of follow-up CEUS and CECT were reviewed by radiologists. The ablated lesions were evaluated and classified as local tumor progression (LTP) and LTP-free. LTP was defined as regrowth of tumor inside or adjacent to the successfully treated nodule. The detected new intrahepatic recurrences were also evaluated and defined as presence of intrahepatic new foci. On CEUS and CECT, LTP and new intrahepatic recurrence both were displayed as typical enhancement pattern of HCC (i.e., hyper-enhancing during the arterial phase and washout in the late phase). With CECT as the reference standard, the ability of CEUS in detecting LTP or new intrahepatic recurrence during follow-up was evaluated.
RESULTS: During a follow-up period of 1-31 mo (median, 4 mo), 169 paired CEUS and CECT examinations were carried out for the 141 patients. For a total of 221 ablated lesions, 266 comparisons between CEUS and CECT findings were performed. Thirty-three LTPs were detected on CEUS whereas 40 LTPs were detected on CECT, there was significant difference (P < 0.001). In comparison with CECT, the numbers of false positive and false negative LTPs detected on CEUS were 6 and 13, respectively; the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy of CEUS in detecting LTPs were 67.5%, 97.4%, 81.8%, 94.4% and 92.3%, respectively. Meanwhile, 131 new intrahepatic recurrent foci were detected on CEUS whereas 183 were detected on CECT, there was also significant difference (P < 0.05). In comparison with CECT, the numbers of false positive and false negative intrahepatic recurrences detected on CEUS were 13 and 65, respectively; the sensitivity, specificity, PPV, NPV and overall accuracy of CEUS in detecting new intrahepatic recurrent foci were 77.7%, 92.0%, 92.4%, 76.7% and 84.0%, respectively.
CONCLUSION: The sensitivity of CEUS in detecting LTP and new intrahepatic recurrence after percutaneous ablation therapy is relatively low in comparison with CECT.
doi:10.3748/wjg.v19.i6.855
PMCID: PMC3574882  PMID: 23430451
Contrast-enhanced ultrasound; Contrast-enhanced computed tomography; Hepatocellular carcinoma; Radiofrequency ablation; Microwave ablation
25.  Clinically Useful Diagnostic Tool of Contrast Enhanced Ultrasonography for Focal Liver Masses: Comparison to Computed Tomography and Magnetic Resonance Imaging 
Gut and Liver  2014;8(3):292-297.
Background/Aims
To evaluate the diagnostic value of contrast (SonoVue®) enhancement ultrasonography (CEUS) and to compare this method with computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating liver masses.
Methods
CEUS (n=50), CT (n=47), and MRI (n=43) were performed on 50 liver masses in 48 patients for baseline mass characterization. The most likely impression for each modality and the final diagnosis, based on the combined biopsy results (n=14), angiography findings (n=36), and clinical course, were determined. The diagnostic value of CEUS was compared to those of CT and MRI.
Results
The final diagnosis of the masses was hepatocellular carcinoma (n=43), hemangioma (n=3), benign adenoma (n=2), eosinophilic abscess (n=1), and liver metastasis (n=1). The overall diagnostic agreement with the final diagnosis was substantial for CEUS, CT, and MRI, with κ values of 0.621, 0.763, and 0.784, respectively. The sensitivity, specificity, and accuracy were 83.3%, 87.5%, and 84.0%, respectively, for CEUS; 95.0%, 87.5%, and 93.8%, respectively, for CT; and 94.6%, 83.3%, and 93.0%, respectively for MRI. After excluding the lesions with poor acoustic sonographic windows, the sensitivity, specificity, and accuracy for CEUS were 94.6%, 87.5%, and 93.3%, respectively, with a κ value of 0.765.
Conclusions
If an appropriate acoustic window is available, CEUS is comparable to CT and MRI for the diagnosis of liver masses.
doi:10.5009/gnl.2014.8.3.292
PMCID: PMC4026647  PMID: 24827626
Contrast enhanced ultrasonography; Liver masses

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