Ultrasound contrast agents for prostate imaging and biopsy

Transrectal gray scale ultrasound (TRUS)–directed prostate biopsy is the standard technique used to diagnose prostate cancer. While prostate cancer can often be detected as a hypoechoic lesion, the ability to differentiate malignant foci based on TRUS imaging lacks sufficient sensitivity and specificity to use the ultrasound image alone to direct the biopsy. To compensate for these limitations, increasing the numbers of prostate biopsies from the standard six to 10–12 or more has been advocated. Enhanced TRUS techniques such as color Doppler have also been investigated but are not particularly useful in most patients. The use of ultrasound contrast agents is a new approach to identify malignant lesions in the prostate. These agents contain microbubbles that are administered intravenously and can enhance standard gray scale and Doppler images of the prostate. Altered vascular anatomy around malignant lesions is thought to be the reason that these contrast agents enhance the detection of cancer. Ultrasound contrast agents offer the potential to allow more targeted biopsy of the prostate and improve accuracy in the diagnosis of cancer.     

Contrast enhanced color Doppler endorectal sonography of prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure

PURPOSE: We evaluated the accuracy of contrast enhanced color Doppler endorectal ultrasound to guide biopsy for the detection of prostate cancer. MATERIALS AND METHODS: A total of 85 patients were evaluated with gray scale and color Doppler before and during intravenous injection of ultrasound contrast agent made of galactose based air microbubbles. Our biopsy protocol was performed during contrast injection. An additional 18 directed cores were obtained based on contrast enhanced imaging. Diagnostic efficiency with and without contrast medium injection for detecting prostate cancer were compared based on biopsy results. RESULTS: Cancer was identified in a total of 58 biopsy sites in 54 patients. Gray scale imaging revealed 96 abnormal hypoechoic nodules or irregular zones inside the outer gland, of which 48 were malignant on pathological evaluation. Contrast enhanced color Doppler had higher sensitivity (93%) than unenhanced color Doppler (54%), while specificity increased only 79% to 87% for enhanced imaging. Nine of 10 isoechoic suspicious zones were depicted with enhancement, while unenhanced Doppler detected 7 of them. There was no significant difference between the intensity of enhancement and tumor Gleason scores. CONCLUSIONS: Contrast enhanced color Doppler endorectal sonography increases the detection of prostate cancer. Improvement in sensitivity was high, while the difference in specificity was not as pertinent. It is accurate when using a common and routine application ultrasound unit. This technique is easy to perform and not time-consuming. Obtaining additional biopsy cores of suspicious enhancing foci significantly improves the detection rate of cancer.     

The role of transrectal ultrasound in diagnosing prostate cancer

The availability of the prostate-specific antigen test to screen for prostate cancer has caused a significant workload burden for urologists and radiologists alike. Prostate cancer is common in our aging population and most cancers are now definitively detected by transrectal ultrasound (TRUS)-guided prostatic needle biopsy. TRUS alone has limited potential to identify prostatic cancer because of frequent multifocality of cancer within the prostate, the variable sonographic appearance of prostatic tumors, the poor specificity of focal ultrasonic abnormalities, and the substantial percentage of isoechoic prostate cancers (which cannot be differentiated from adjacent benign tissues with imaging). Developments in TRUS equipment over the past decade include the use of color and power Doppler, higher frequencies, broad bandwidth technologies, and harmonic, contrast harmonic, and pulse inversion imaging. All of these improvements may enhance detection of subtle focal sonographic abnormalities within the prostate. Ultrasonic contrast agents can aid the visualization of subtle alterations in prostatic echotexture by highlighting changes in microvasculature. It is possible that Doppler techniques and contrast agents have the potential to reveal prognostic information about cancer in individual patients.     

Three dimensional ultrasound and prostate cancer

Three-dimensional ultrasound (3-D US) is a non-invasive method of producing whole volume images of solid structures. Early work on prostate imaging identified several advantages over 2-D imaging with a good ability to detect intraprostatic lesions. Several 3-D transrectal ultrasound (3-D TRUS) systems are now available for prostate imaging. Initial work using gray scale ultrasound appears promising with reported overall staging accuracies of up to 94%. These results were favourable when compared to other modalities for local staging of prostate cancer. Several adjuncts to 3-D gray scale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents. Further clinical applications for 3-D TRUS include assessing placement of brachytherapy seeds and for cyroablation techniques. Computer enhancement with image registration has shown that 3-D US images can be manipulated to derive more information. Although the results of gray scale imaging alone or with adjuncts and post processing appear promising, these techniques remain largely experimental.     

Molecular imaging and ultrasound-assisted drug delivery

Ultrasound imaging is undergoing a major revolution, about to bring this modality well beyond its established role as a low-cost noninvasive real-time imaging modality. Particularly important has been the commercial availability of microbubble-based contrast agents. Several new indications for contrast ultrasound have been developed and have entered clinical practice. The characterization of focal liver lesions and the follow-up of antiangiogenic therapy are two applications that will have a major impact in medical practice. Others, such as prostate cancer diagnosis, are still under investigation and need to be clinically validated. Thanks to its outstanding sensitivity, contrast-enhanced ultrasound is also geared to become the preferred modality for molecular imaging of diseases occurring at the vascular level. Angiogenesis, inflammation, and other endothelial dysfunctions are important targets that can be imaged and investigated with targeted microbubbles. In the field of prostate cancer, targeted agents will facilitate detection and provide additional information on tumor size, and hopefully on aggressiveness as well. Ultrasound can also play a role to deliver drugs or genes locally. This is an exciting area that has become an important field of research. Imaging and drug delivery can be performed simultaneously, thereby achieving the release of a drug, at the site where it is needed, in a most efficient way.     

A Review of Breast Ultrasound

Frequent advances in transducer design, electronics, computers, and signal processing have improved the quality of ultrasound images to the extent that sonography is now a major mode of imaging for the clinical diagnosis of breast cancer. Breast ultrasound is routinely used for differentiating cysts and solid nodules with high specificity. In combination with mammography, ultrasound is used to characterize solid masses as benign or malignant. There is growing interest in using Doppler ultrasound and contrast agents for measuring tumor blood flow and for imaging tumor vascularity. Ease of use and real-time imaging capability make breast ultrasound a method of choice for guiding breast biopsies and other interventional procedures. Breast ultrasound is used in many forms. B-mode is the most common form of imaging for the breast, although compound imaging and harmonic imaging are being increasingly applied to better visualize breast lesions and to reduce image artifacts. These developments, together with the formulation of a standardized lexicon of solid mass features, have improved the diagnostic performance of breast ultrasound. Several approaches that are currently being investigated to further improve performance include: (1) computer-aided-diagnosis; (2) the assessment of tumor vascularity and tumor blood flow with Doppler ultrasound and contrast agents; and (3) tissue elasticity imaging. In the future, ultrasound will play a greater role in differentiating benign from malignant masses and in the diagnosis of breast cancer.     

Contrast-enhanced ultrasound for myocardial perfusion imaging

Ultrasound contrast agents are gas-filled microbubbles that enhance visualization of cardiac structures, function and blood flow during contrast-enhanced ultrasound (CEUS). An interesting cardiovascular application of CEUS is myocardial contrast echocardiography, which allows real-time myocardial perfusion imaging. The intraoperative use of this technically challenging imaging method is limited at present, although several studies have examined its clinical utility during cardiac surgery in the past. In the present review we provide general information on the basic principles of CEUS and discuss the methodology and technical aspects of myocardial perfusion imaging.     

How does endorectal MRI, PET-CT and transrectal ultrasound contribute to diagnosis and management of localized prostate cancer

We analyze the main imaging techniques (transrectal ultrasound, Magnetic Resonance Imaging and Position Emission Tomography) that are currently used in the diagnosis and management of localised prostate cancer patients. We analyze the results that may be obtained with transrectal US and describe the latest advances in this technique (Doppler, power doppler and contrast media). With Magnetic Resonance Imaging, we describe the underlying principles, results and indications as well as some new applications (diffusion, perfusion, spectroscopy and the use of lymphotrophic nanoparticles). Finally we will describe the current state of positron emission tomography in diagnosis, follow up and recurrence detection using the different radiomarkers that are available.     

How to improve prostate biopsy detection of prostate cancer

The combination of serum prostate-specific antigen (PSA) testing and transrectal ultrasonography is a highly effective strategy to diagnose prostate cancer at an early curable stage. Even though PSA is the most useful serum biomarker to aid in prostate cancer detection, it has limited specificity: as many as 75% of men who undergo prostate biopsy because of an elevated PSA do not have prostate cancer. Additionally, sextant prostate biopsies miss prostate cancer at least 20% of the time. To reduce the number of false-negative biopsies, many have advocated obtaining 12 or more cores in a single biopsy session. Studies have shown that this practice is safe and can enhance cancer detection modestly. Although it is unlikely that prostate cancer imaging will replace prostate biopsy in the near future, many exciting new imaging technologies should eventually improve targeting of prostate needle biopsy and reduce false-negative biopsies. Some of the most exciting areas include power Doppler sonography, microbubble intravenous ultrasound contrast agents, and magnetic resonance spectroscopy. These functional imaging modalities can assess tumor blood flow and metabolic activity at a cellular level and can detect malignant changes that may not be detected by standard anatomic imaging.     

New imaging techniques in prostate cancer

Correct staging of prostate cancer at initial diagnosis, as well as accurate staging and tumor localization with biochemical recurrence, remains generally inaccurate with current imaging techniques. Newer modalities are being investigated to accurately identify patients with prostate cancer at different stages of disease. Identification of locally recurrent disease or distant metastasis at the time of biochemical failure after local therapy will help guide treatment options and avoid potentially toxic salvage therapies in patients who will not benefit. A review of prostate cancer imaging literature over the past 12 months was performed to identify emerging imaging modalities that may be beneficial in the management of prostate cancer. Enhanced transrectal ultrasonography modalities, including ultrasound contrast agents, color and power Doppler, and elastrography, have demonstrated incremental benefit when combined with standard grayscale ultrasonography to accurately target and diagnose prostate cancer. Endorectal MRI, with contrast enhancement and spectroscopic imaging, shows promise in the initial staging of prostate cancer prior to local therapy. The use of positron-emission tomography scan for prostate cancer remains to be defined, but may help delineate the site of recurrence with biochemical failure after local therapy. Several new imaging modalities show promise for the evaluation of the patient with prostate cancer. Enhanced ultrasonography techniques may prove to be more accurate in diagnosing prostate cancer over standard gray-scale ultrasonography. Accumulating evidence supports the use of endorectal MRI and spectroscopy to help treatment planning with either surgical or radiotherapeutic approaches. Although intriguing, the available data for positron-emission tomography in prostate cancer remains too shallow to advocate routine use.     

Urologic imaging for localized prostate cancer in 2007

Increasing numbers of systematic random biopsies have virtually replaced urologic imaging as a detection and staging tool in prostate cancer. TRUS as the most commonly utilized urologic imaging is now mainly utilized to guide the biopsy needle into the correct anatomical or topographic region of the prostate. But even multiple systematic random biopsies have been shown to overlook a large number of clinically significant carcinoma. This fact has led to a dramatic increase in the number of biopsies taken in the detection of localized prostate cancer. There are some centers where 6, 10, 12, even up to 143 biopsies are taken in one sitting. This increasingly invasive and heterogeneous strategy underlines the need for an improvement in diagnostic imaging. New modalities and innovative techniques are currently being investigated in order to identify prostate cancer more accurately. The purpose of this paper is to review innovative urologic imaging techniques to identify emerging modalities that may be beneficial in the management of prostate cancer. Enhanced transrectal ultrasonography modalities, including ultrasound contrast agents, color and power doppler, elastography and computerized (C)-TRUS with artificial neural network analysis (ANNA) promise benefits in comparison to standard gray-scale ultrasonography to accurately target and diagnose prostate cancer.     

Multiparametric magnetic resonance imaging: Current role in prostate cancer management

Digital rectal examination, serum prostate‐specific antigen screening and transrectal ultrasound‐guided biopsy are conventionally used as screening, diagnostic and surveillance tools for prostate cancer. However, they have limited sensitivity and specificity. In recent years, the role of multiparametric magnetic resonance imaging has steadily grown, and is now part of the standard clinical management in many institutions. In multiparametric magnetic resonance imaging, the morphological assessment of T2‐weighted imaging is correlated with diffusion‐weighted imaging, dynamic contrast‐enhanced imaging perfusion and/or magnetic resonance spectroscopic imaging. Multiparametric magnetic resonance imaging is currently regarded as the most sensitive and specific imaging technique for the evaluation of prostate cancer, including detection, staging, localization and aggressiveness evaluation. This article presents an overview of multiparametric magnetic resonance imaging, and discusses the current role of multiparametric magnetic resonance imaging in the different fields of prostate cancer management.     

Value of contrast-enhanced ultrasound and elastography in imaging of prostate cancer

PURPOSE OF REVIEW: Prostate cancer is the most commonly diagnosed malignancy in men. Gray-scale ultrasound-guided systematic biopsy is the standard of care for prostate cancer detection in men with an elevated prostate-specific antigen or an abnormal digital rectal examination. Systematic biopsy may miss up to 35% of clinically relevant cancers. Color and power Doppler ultrasound, ultrasound contrast agents, and elastography have and will dramatically change the role of ultrasound in prostate cancer diagnosis. RECENT FINDINGS: Several reports have demonstrated that contrast-enhanced ultrasound investigations of the blood flow of the prostate allow for prostate cancer visualization and therefore, for targeted biopsies. Comparisons between systematic and contrast-enhanced ultrasound-targeted biopsies have shown that the targeted approach detects more cancers with a lower number of biopsy cores. Furthermore, contrast-enhanced ultrasound has been shown to detect cancers with higher Gleason scores compared with the systematic approach, which seems to improve prostate cancer grading. In addition, elastography is a new ultrasound technique that allows for the assessment of tissue elasticity. SUMMARY: Contrast-enhanced ultrasound and elastography improve prostate cancer detection and may be useful for prostate cancer grading and staging. Future clinical trials will be needed to determine the promise of these new advances for ultrasound of the prostate evolving into clinical applications.     

超声造影微泡非线性声学特性与成像研究进展

超声造影微泡在声场中会发生非线性散射,在基频超声波激励下,会产生次谐波、超谐波及高次谐波,这意味着可利用超声造影微泡进行非线性成像,从而大幅度提高超声成像的临床诊断能力。本文概述了当前国内外对于超声造影微泡的非线性声学特性的研究和发展现状,重点介绍了微泡在不同频率、声压条件下的非线性行为,总结了目前国内外对于超声造影微泡非线性成像的应用研究成果,并对今后的研究和应用进行了展望。     

Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biopsy: impact on Gleason score

PURPOSE: Prostate cancer grading with Gleason score is an important prognostic factor. This prospective randomized study compares ultrasound systematic biopsy vs contrast enhanced color Doppler targeted biopsy for the impact on Gleason score findings. MATERIALS AND METHODS: We examined 690 men (mean age 56 years, range 41 to 77) with a serum total prostate specific antigen of 1.25 ng/ml or greater, a free-to-total prostate specific antigen ratio less than 18% and/or a suspicious digital rectal examination. Contrast enhanced color Doppler targeted biopsies with a limited number of cores (5 or less) were performed in hypervascular areas of the peripheral zone during administration of the ultrasound contrast agent Sonovuetrade mark (Bracco, Milano, Italy). Ten systematic biopsies were obtained in a standard spatial distribution. Cancer detection rates and Gleason score were compared. RESULTS: Prostate cancer was identified in 221 of 690 subjects (32%) with a mean prostate specific antigen of 4.6 ng/ml (range 1.4 to 35.0). Prostate cancer was detected in 180 of 690 subjects (26%) with contrast enhanced color Doppler targeted biopsy and in 166 of 690 patients (24%) with systematic ultrasound biopsy. The Gleason score of all 180 cancers detected on contrast enhanced color Doppler targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected on systematic biopsy ranged from 4 to 6 and mean Gleason score was 5.4. Contrast enhanced color Doppler targeted biopsy detected significantly higher Gleason scores compared to systematic biopsy (Wilcoxon rank sum test p <0.003). CONCLUSIONS: Contrast enhanced color Doppler targeted biopsy detected cancers with higher Gleason scores and more cancer than systematic biopsy. Therefore, contrast enhanced color Doppler seems to be helpful in the grading of prostate cancer, which is important for defining prognosis and deciding treatment.     

Update of staging and risk assessment for prostate cancer patients

PURPOSE OF REVIEW: This paper will review the current staging system for prostate adenocarcinoma patients, and will also review new information that can be combined with clinical and pathological staging in order to assess a patient's risk of success or failure of treatment. RECENT FINDINGS: There has been significant stage migration of prostate cancer patients in the past 15 years, such that patients are currently being diagnosed younger, with lower clinical stages and serum prostate-specific antigen levels, and a lower risk of metastatic disease than previously. The incorporation of the results of extended prostate biopsy schemes, with stage, grade and serum prostate-specific antigen levels, improves the risk assessment of newly diagnosed prostate cancer patients. New imaging techniques, such as transrectal ultrasound Doppler flow and magnetic resonance spectroscopy hold promise for improving risk assessment. Molecular biomarkers may improve risk assessment in the future, although none are currently approved by the US Food and Drug Administration for this indication. Gene chip arrays may further refine risk assessment and assist with the identification of therapeutic targets. SUMMARY: There has been significant stage migration of prostate cancer patients in the prostate-specific antigen era. Incorporating biopsy information into nomograms and risk assessment equations improves upon clinical staging and risk assessment. New imaging techniques, molecular markers and gene chip arrays hold promise for future risk assessment.     

Evaluation of transrectal power-Doppler ultrasonography and effect of contrast-enhancement for detecting prostate cancer

PURPOSE: There are many reports about the usefulness of transrectal power-Doppler ultrasonography (PDUS) for detecting prostate cancer because of the high microvessel density in cancerous tissue in the prostate. The purpose of this study was to assess the role of PDUS and contrast-enhanced transrectal power-Doppler ultrasonography (enhanced PDUS) in the identification of prostate cancer. MATERIALS AND METHODS: One hundred forty-two cases (90 cases without enhancement, 52 cases with enhancement) of suspected prostate cancer found with digital rectal examination (DRE), transrectal ultrasound (TRUS) abnormal or prostate specific antigen (PSA) elevation were evaluated by PDUS and enhanced PDUS. RESULTS: Forty-three (30.3%) cases of cancer were detected, and there was a significant difference (p < 0.05) between PDUS group (22 cases, 24.4%) and enhanced PDUS (21 cases, 40.0%). However, there were no significant statistical results about the usefulness of enhancement to detect prostate cancer although imaging was clear with contrast agent. The results of statistical analysis of PDUS use were almost the same as for PSA of more than 10.1 ng/ml. Combination with PDUS was very helpful to detect prostate cancers. The positive predictive value of the combination with DRE, TRUS and PSA improved from 68.0% to 81.0% with the addition of PDUS. In particular, cancer was revealed frequently (65.8%) in peripheral hypoechoic lesions on gray-scale TRUS with hypervascular areas on PDUS. CONCLUSIONS: We conclude that enhancement with contrast agent is not especially useful in the identification of prostate cancer although imaging was clear with contrast agent. However, PDUS is useful especially for hypoechoic peripheral areas. It is suggested that we should add PDUS to DRE, TRUS and PSA examinations.     

TRUS and Biopsy: Practical Aspects

Transrectal ultrasonography (TRUS) has become a standard imaging technique for prostatic diseases and ultrasound guided biopsies are the golden standard for the early detection of prostate cancer. Newly developed TRUS modalities, such as computer assisted automated detection, neural networks, colour Doppler ultrasound (CDU), power Doppler ultrasound (PDU), contrast ultrasound and three-dimensional imaging cannot replace systemic biopsies in the diagnosis of prostate cancer. However, such modalities will be able to improve biopsy yield and increase sensitivity and specificity of traditional grayscale TRUS. Their use in non-surgical treatment of localised prostate cancer may also improve outcome and reduce side-effects, such as erectile dysfunction. Nevertheless, because the improvements made so far are limited and the fact that these modalities are expensive, they do not yet have a place in routine practice.     

Transrectal ultrasound in the diagnosis of prostate cancer: state of the art and perspectives.

OBJECTIVES: Transrectal ultrasound (TRUS) is an important tool in diagnosing prostate cancer. However, specificity and sensitivity of conventional grey-scale TRUS for the detection of prostate cancer are disappointingly low. New ultrasound modalities are designed to overcome the disappointing results and improve the use of ultrasound in the diagnosis of prostate cancer. This work is a review of the recent literature, combined with own experiences. METHODS: The papers were collected using a Medline search, combined with some papers by author selection. The terms used for the Medline search included among other things: transrectal ultrasound, prostate, prostate cancer, prostate biopsies, colour Doppler ultrasound, power Doppler ultrasound, contrast ultrasound. The authors used their own experiences for illustrations of various techniques. RESULTS AND CONCLUSIONS: Although several modalities show a significant improvement in sensitivity and specificity for the detection of prostate cancer, none of the TRUS modalities discussed can replace prostate biopsies as a definitive diagnostic. Several techniques, especially contrast ultrasound, show definitive promise. However, two valid conclusions can be made from the data presented. First: with today's technology, none of the TRUS modalities discussed can replace systemic biopsies in the early detection of prostate cancer. Second: none of the discussed TRUS modalities has found a definitive place in routine clinical practice.     

Ultrasound-assisted thrombolysis in acute ischemic stroke

Numerous experimental studies,in vitro and in animal models, have demonstrated that ultrasound can accelerate clot lysis. This effect is probably related to the cavitation of microbubbles contained in the medium exposed to ultrasound. Clinical studies show that transcranial application of low-intensity, low-frequency ultrasound identical to that routinely used for diagnostic purposes can improve recanalization rates in patients with acute ischemic stroke. These promising findings should be confirmed in larger studies and using MR or CT angiography to assess recanalization independently. The optimal method of ultrasound-assisted thrombolysis has not been determined yet. Experimental data suggest that it may be enhanced by coadministration of microbubbles used as contrast agents.