ICUS Weekly News Monitor 10-17-2008

1. DOTmed News, Oct 17, 2008, Philips Combines Ultrasound With Cancer Drug Delivery By Lynn Shapiro 2. Science Centric, Oct 16. 2008 Why contrast-enhanced ultrasound better than intraoperative ultrasound ? 3. The Engineer, Oct 15, 2008, Targeted delivery By Siobhan Wagner 4. 7thSpace Interactive, Oct 13, 2008, The usefulness of contrast during exerciseechocardiography for the assessment of systolic pulmonary pressure By Luis R Lopes & et al 5., Oct 13, 2008, Acusphere's Imagify to get FDA review DOTmed News Oct 17, 2008 Philips Combines Ultrasound With Cancer Drug Delivery By Lynn Shapiro, Writer In its first foray into the pharmaceutical arena, Philips is combining its ultrasound bubble system, now used for the diagnosis of heart failure and liver disease, with a drug delivery system for cancer drugs. "We have found a way to load drugs inside these bubbles while using the contrast agents as well," Steve King, communications manager for research tells DOTmed News. 

"We inject the drug-filled microbubbles in the patient's bloodstream and follow the bubbles with ultrasound imaging. When we see the bubbles reach the tumor, we use a higher energy focused ultrasound wave to burst the bubbles and release the drugs into the tumor." 

Philips is betting that this localized drug delivery system will reduce the side effects of chemotherapy without compromising its efficacy. 

So far, Philips researchers have tested the cancer drug, paciltaxel, in mice. King says while local drug delivery is feasible, Philips is only in the first stage of developing its new chemo technology. He believes it will be five years before clinical studies on human beings can begin. "Philips is not into cancer medicine and cannot enter this field alone," King says. The company is now attempting to find a pharmaceutical partner to help develop research studies. 

"Pre-clinical experiments make us very confident that this system will work," King says. The company is now working with the University of Virginia, where researchers did their preclinical studies. 

Full caption: 
The microbubbles are tiny gas-filled spheres of biodegradable material no bigger than red blood cells. These are to be injected into the patient's bloodstream and carried to the site of a tumor. The arrival of the microbubbles at the tumor can be monitored with ultrasound imaging. Science Centric Oct 16. 2008 Why contrast-enhanced ultrasound better than intraoperative ultrasound ? IOUS is an important tool in the fields of surgery for liver tumours, but it also has some drawbacks such as lacking of specificity to differentiate cirrhotic nodules from small malignant nodules. Contrast-enhanced ultrasound was shown with improved nodule characterisation by recent studies. The research team led by Prof. Yan Luo from West China Hospital found that besides the merits of IOUS, CE-IOUS shows tumour vascularity and tissue microcirculation by applying intravenous ultrasound contrast agents, thus helps to differentiate malignant nodules from benign ones. Therefore it helps surgeons to eradicate malignant nodules and avoid unnecessary intervention of benign ones. Their finding were published on 7 July 2008 in the World Journal of Gastroenterology. Due to the high sensitivity and specificity of CE-IOUS to find malignant liver tumours, this new technique should be used more frequently in surgeries for cirrhotic livers. Although this study includes only a short number of patients, the research is quite interesting and the results are relevant to improve the quality of hepatic surgery. The Engineer Oct 15, 2008 Targeted delivery By Siobhan Wagner A new minimally invasive procedure that attacks cancerous cells only at the site of diseased tissue is claimed to cause patients fewer ill effects.

The treatment, which is being studied by researchers at Philips Research and various academic institutions, involves injecting patients with microscopic polymer bubbles filled with anti-cancer drugs. The bubbles are then tracked in the bloodstream with ultrasound imaging and burst using a focused ultrasound pulse to release the drugs at the desired spot.

'Traditional chemotherapy is administered to every part of the body and is certainly an effective therapy for patients, but it does have side effects,' said Steve Klink, a spokesman for Philips. 'One way to reduce these is to reduce the dose,' he added.

But he added that while this may cut down on the side effects, it will also reduce the effectiveness.

Klink explained that with the new method the drugs are only administered to the region where they are needed. 'Of course, the microbubbles also reach other regions of the body as they travel through the bloodstream, but since the drugs are encapsulated in a microbubble patients will not feel any side effects.' he said.

Philips is working with several academic partners, including the University of Virginia in the US, where pre-clinical experiments are being performed on mice, and the University of Münster in Germany to refine the technology. Clinical trials, said Klink, are no nearer than five years away.

This is not the first use of microbubbles with medical ultrasound imaging. In current clinical practice, doctors use gas-filled microbubbles as contrast agents. Microbubbles can be used, for example, to highlight blood in ultrasound images because they reflect ultrasound waves better than blood or soft tissue.

This latest drug delivery technology being developed at Philips continues to use the contrast-enhancing capabilities of microbubbles so that ultrasound operators can locate tumours, which appear as dense masses surrounded by a network of small blood vessels.

The new part of the technology involves shattering the microbubble shells in the blood vessels using a focused high-energy ultrasound pulse. As a result of this, the drugs in the microbubbles are released directly inside the tumour.

Klink said the microbubbles are typically less than five microns across, which is about the size of a red blood cell, and their shell is made of polylactic acid - a biodegradable, thermoplastic polyester derived from renewable sources such as corn starch.

'We have developed a way to incorporate a liquid that contains the anti-cancer drug inside the microbubble,' he said, adding that the bubbles are only partly filled. 'We want to maintain air in them so the bubbles still retain their contrast agent capabilities. The air also allows the bubbles to burst easier.'

The bubbles are created by mixing a solution consisting of a carrier solvent, an oil that can be removed after freeze-drying, another oil with an anti-cancer drug dissolved in it and a polymer.

Inkjet droplets of this solution are dropped into water where they form into polymer capsules. The capsules are then freeze-dried, which results in polymer microbubbles filled with anti-cancer drugs and air.

Klink said the other innovation involved in the research is a computer-controlled ultrasound device that can steer and focus the microbubble-rupturing ultrasound pulses.

Philips researchers developed a special phased-array transducer that can focus ultrasound pulses into a small ellipsoidal volume up to 10cm deep in the target tissue.

In the experimental prototype developed by Philips, the phased array transducer is co-aligned with a standard clinical imaging transducer so that the ultrasound imaging and drug delivery could be performed simultaneously.

The researchers believe they may be able to make use of the way microbubbles generate their own acoustic signal when they burst. This information could help doctors tell how many microbubbles have ruptured, which could allow them to quantify and control drug dosage.

Beyond this drug delivery application, Philips researchers believe their transducer might also be optimised to produce other bio-effects such as thrombolysis (clot busting). The microbubble payload delivery system could also have applications in gene therapy.

 7thSpace Interactive Oct 13, 2008 The usefulness of contrast during exerciseechocardiography for the assessment of systolic pulmonary pressure By Luis R Lopes, Maria J Loureiro, Rita Miranda, Sofia Almeida, Ana R Almeida, Ana Cordeiro, Carlos Cotrim and Manuel Carrageta
 The systolic pulmonary artery pressure (PAPs) can be accurately estimated, non-invasively, using continuous-wave Doppler (CWD) ultrasound measurement of the peak velocity of a tricuspid regurgitant (TR) jet.However, it is often difficult to obtain adequate tricuspid regurgitation signals for measurement of PAPs, what could lead to its underestimation. Therefore, utilization of air-blood-saline contrast has been implemented for the improvement of Doppler signal in several clinical contexts.

It is now recommended in the evaluation of patients with pulmonary hypertension. Physical activity is severely restricted in patients with PAH, being exertional dypnea the most typical symptom.

Exercise stress echo-Doppler imaging allows assessment of the response to exercise. It is an excellent screening test for patients with suspected PAH.

Our purpose was to evaluate the value and accuracy of agitated saline with blood contrast echocardiography, in the improvement of the Doppler signal, to quantify PAPs during treadmill exercise-echocardiography.Purpose: To evaluate the value of contrast echocardiography, using agitated saline with blood, in the improvement of the Doppler signal used to quantify the pulmonary artery systolic pressure during exercise. 

Methods: From a total of 41 patients (pts), we studied 38 pts (93%), 35 women, aged 54 +/- 12 years-old.

27 with the diagnosis of systemic sclerosis, 10 with history of pulmonary embolism and one patient with a suspected idiopathic PAH, who were referred to the Unity of Heart Failure and Pulmonary Hypertension for screening of PAH. According to the Unity protocol, a transthoracic echocardiogram was made, in left decubitus (LD), with evaluation of right ventricle-right atria gradient (RV/RAg).

A peripheral venous access was obtained, with a 3-way stopcock and the patients were placed in orthostatism (O), with a new evaluation of RV/RAg. Exercise echocardiography (EE) was begun, with evaluation of RV/RAg at peak exercise (P) and afterwards agitated saline (8cc with 1cc of air and 1cc of blood) was injected, followed by a new evaluation of RV/RAg (PC) and then the interruption of the EE.

Pulmonary Hypertension was diagnosed when RV/RAg at the end of the exercise was superior to 40 mmHg. 

Results: The quality of Doppler signal was deteriorated in 5 pts, maintained in 6 pts and improved in 26 pts, with the use of contrast.

In one patient, an interventricular septal defect was diagnosed. In 6 pts, a Doppler signal was only obtained with the use of contrast.

In 15 pts, a RV/RAg superior to 40 mmHg was only obtained with the use of contrast. Of these, 9 have already been submitted to right heart cathetherism, that confirmed the diagnosis of pulmonary hypertension in 5 of them (56%).RV/RAg (P) was 44+/-11 mmHg and RV/RAg (PC) was 54+/-11 mmHg, p<0,001.

Conclusions: 1. The method is applicable in a large number of patients.

2. RV/RA gradients obtained at peak exercise are higher with the use of contrast, and the clinical meaning of this difference should be evaluated in a larger number of pts submitted to right heart cathetherism.

The high number of false positives should lead to a higher diagnostic threshold. 3.

This method seems to have relevant clinical value in the diagnosis of pulmonary arterial hypertension. Oct 13, 2008 Acusphere's Imagify to get FDA review 
Ultrasound contrast developer Acusphere said that its Imagify contrast agent will be reviewed during a planned public meeting of the U.S. Food and Drug Administration (FDA)'s Cardiovascular and Renal Drugs Advisory Committee on December 10. 
(Full article available by subscription)

ICUS Weekly News Monitor 10-8-2008

1. MarketWatch, Oct 8, 2008, Toshiba Installs Vantage Titan MR System at Health Scan Imaging 2. The, Oct 7, 2008, Ultrasound-based strategies comparable for DVT diagnosis, treatment guidance By Steve Stiles MarketWatch Oct 8, 2008 Toshiba Installs Vantage Titan MR System at Health Scan Imaging Significant Noise Reduction and High Image Quality Led to Purchase of the Titan The quietness and open design of the Toshiba Vantage Titan(TM) is dramatically improving the MR experience for patients. Health Scan Imaging has installed the Vantage Titan as the flagship MR machine at its new 5,000-square-foot location in Temecula, Calif. The system boasts a 71-centimeter opening, the largest in the industry, and patented noise reduction technology. The Vantage Titan's patient-focused features significantly improve patient comfort and increase the range of patients who can undergo a MR exam. Claustrophobic and obese patients are now able to be imaged with MR because the open bore provides a greater feeling of openness. Toshiba's patented Pianissimo(TM) technology dramatically reduces acoustic noise, the most significant cause of patient discomfort during a MR exam. Finally, patients sensitive to contrast agents now have an option for a contrast-free MRA exam. "The quietness of the Vantage Titan is dramatic when compared to other MRI systems on the market," said Dr. Bill Kelly, founder and medical director of Health Scan Imaging, a medical imaging network with nine locations throughout Southern California. "Our radiologists, employees and especially patients have all noticed the distinct reduction in noise. Additionally, our patients really appreciate the more comfortable, wider bore. In fact, both of these features have led referring physicians and patients to recommend our site." The open bore of the 1.5T Vantage Titan MRI system is 18 percent larger than other 1.5T systems on the market and features a large 71-centimeter patient aperture, outstanding homogeneity, and the largest available clinical field-of-view (FOV) of 55 x 55 x 50 cm, providing the highest level of patient care and diagnostic capability available. The 30/130 gradient platform of the Vantage Titan provides unparalleled power. It also has a guaranteed homogeneity specification of two parts per million over a 50 x 50 x 50 cm DSV and a 1.4-meter magnet length, producing exceptional image quality. "Maintaining our reputation for high levels of patient care due to outstanding image quality was paramount in our purchasing decision," explained Dr. Kelly. "Alternative short bore systems on the market did not meet our needs because of limitations in z-axis field-of-view and excessive noise. The Titan's 50 cm z-axis field-of-view for abdominal, pelvic and spine studies was a main factor in acquiring the system." The Vantage Titan MR system also takes advantage of Toshiba's proprietary contrast-free MRA techniques -- Fresh Blood Imaging (FBI), Contrast-free Improved Angiography (CIA), Time-Spatial Labeling Inversion Pulse (Time-SLIP) and Time and Space Angiography (TSA). Contrast-free imaging is particularly important because gadolinium, the most common contrast agent used for MR exams, has been directly linked to a potentially fatal disease that has occurred in patients with renal insufficiency, called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD). These contrast-free protocols allow physicians to perform scans on patients with known renal compromise and diabetes. "Health Scan Imaging's purchase of the Titan is a testament to the system's patient-friendly features," said Bob Giegerich, director, MR Business Unit, Toshiba. "The large, wide bore and significant reduction in noise create a better imaging experience for all patients. Also, the Vantage Titan's large clinical FOV is unique for this bore size and produces high-quality images without compromising homogeneity or overall imaging performance." About Health Scan Imaging Health Scan Imaging is an out patient imaging center network with nine locations throughout Southern California. Established in 1998, Health Scan Imaging has propelled its growth and has rapidly gained market share at each location by steadfastly maintaining its founding principles of quality, professional expertise and service. Health Scan Imaging provides its customers access to the industry's most advanced technology, including high-resolution multislice 3D CT, high-field open concept multichannel MRI, ultrasound and digital X-ray. All locations are linked by a wide-band-width T1 PACS network that provides instant distribution of imaging examinations to appropriate sub-specialists among its team of fellowship-trained radiologists. Health Scan Imaging especially caters to the needs of patients with complex and challenging conditions referred by specialty physicians in the fields of neuroscience, orthopedics, sports medicine, oncology, ENT and pain management. For more information visit The Oct 7, 2008 Ultrasound-based strategies comparable for DVT diagnosis, treatment guidance By Steve Stiles Two ultrasound-based evaluations, both with their advantages and disadvantages, are about equally effective at guiding the management of patients with suspected lower-extremity deep-vein thrombosis (DVT), conclude the authors of a randomized trial reported in the October 8, 2008 issue of Journal of the American Medical Association [ HYPERLINK "" \l "bib_1" 1]. But the writer of an accompanying editorial [ HYPERLINK "" \l "bib_2" 2] gives the edge to one of the techniques, the one that's been around longer and is simpler and probably more widely available, and notes that a clinical prediction rule not evaluated in the study can also play a role in the initial evaluation of DVT. The study of more than 2000 patients with suspected DVT found comparably low three-month rates of confirmed venous thromboembolism (VTE) among those who were spared the burdens of anticoagulation therapy based on the results of either two-point compression ultrasonography with provisional D-dimer testing or whole-leg color-coded Doppler ultrasonography. Compression ultrasonography, typically performed on proximal leg veins, plus D-dimer testing "is simple, convenient, and widely available but requires repeat testing in one-fourth of the patients," according to the authors, led by Dr Enrico Bernardi (Civic Hospital, Conegliano, Italy). The Doppler method "offers a one-day answer [and is] desirable for patients with severe calf complaints, for travelers, and for those living far from the diagnostic service but is cumbersome, possibly more expensive, and may expose patients to the risk of (unnecessary) anticoagulation," they write. Whole-leg color-coded Doppler ultrasonography, unlike the other method, will disclose DVT of the calf, they explain; its clinical importance, and therefore the value of anticoagulation directed at it, has been questioned. Still, both methods are "reliable diagnostic options," Bernardi et al conclude. "Either strategy may be chosen based on the clinical context, on the patients' needs, and on the available resources." The study was very well done and sheds light on a common clinical problem, according to Dr C Seth Landefeld (University of California, San Francisco), who wrote the accompanying editorial. "It finds, basically, that the nice, standard test we've been using for 20 years, compression ultrasonography, works very well compared with the newer, more bells-and-whistles, color-coded Doppler ultrasound," he told heartwire. The Doppler method, Landefeld said, is at least noninvasive and, unlike the gold standard, venography, doesn't involve the use of contrast agents. But he echoed Bernardi et al in observing that the Doppler method, compared with compression ultrasonography, "is probably more expensive and less widely available and takes more expertise, and it will diagnose DVT that's limited to the calf and distal leg, which may lead to unnecessary treatment." The trial's patients had been referred to one of 14 ultrasound laboratories in Italy with a first episode of suspected symptomatic DVT. Of the 1045 randomized to the two-point ultrasonography strategy, 217 had abnormal findings at the initial workup and were classified as having proximal DVT; 828 had normal findings and underwent D-dimer testing. That test was abnormal in 256, who were scheduled for repeat ultrasonography a week later. Repeat ultrasound yielded abnormal findings in 14 patients. So, 814 patients were spared anticoagulation therapy and were followed for the prespecified three months; they included the 572 with normal findings at ultrasonography and D-dimer testing plus 242 with repeatedly normal ultrasonography despite a positive D-dimer result. Whole-leg color-Doppler ultrasonography yielded abnormal findings in 278 of the 1053 assigned to it. Those patients received anticoagulation therapy while the 775 with a negative test were followed. Venous thromboembolism was confirmed in seven of the 801 patients in the two-point ultrasonography group (0.9%) and in nine of the 763 in the whole-leg ultrasonography group (1.2%) who hadn't been anticoagulated and were available for the three-month follow-up. The difference met the trial's criteria for equivalence, the authors write. In his editorial, Landefeld recommends that patients with a suspected first instance of DVT be initially evaluated using two of three methods: the clinical prediction rule, two-point ultrasonography, and D-dimer testing. "If both tests are negative, DVT is effectively ruled out, and anticoagulation can be withheld safely," he said. "If the clinical evaluation using the Wells criteria [ HYPERLINK "" \l "bib_3" 3] suggests low [DVT] probability, and if the [two-point] ultrasound or the D-dimer test is negative, you've essentially ruled out DVT," Landefeld explained to heartwire. "If the compression ultrasound is positive for proximal DVT, you've made the diagnosis. If the clinical evaluation suggests intermediate or high [DVT probability] and the compression ultrasound is negative, then you have to do something more. And that could be to do another test in a week or a more definitive one right then, which would be venography or color-coded Doppler." That's not a strategy tested by Bernardi et al, he observed, "but it would be a reasonable way to go."

ICUS Weekly News Monitor 10-3-2008

1. HealthImaging & IT, Sep 26, 2008, Ultrasound contrast gains a champion with new society HealthImaging & IT Sep 26, 2008 Ultrasound contrast gains a champion with new society A new international and cross-disciplinary professional society, the International Contrast Ultrasound Society (ICUS), has been formed, devoted to overcoming challenges in field of contrast ultrasound and increasing its role in improving patient care worldwide.

The society was formed last week at the Advances in Contrast Ultrasound: Enhanced Atherosclerotic Imaging and Intervention conference in Chicago. 

Its formation follows the controversial decision by the FDA to impose new limitations on the use of contrast ultrasound - a decision that was largely reversed in May following opposition from contrast ultrasound experts, who marshaled new scientific data relating to the life-saving potential of improved contrast ultrasound diagnoses.

Contrast agents are approved in more than 70 countries for use in diagnosing a wide variety of medical abnormalities; however, only four contrast agents are available for approved indications in various countries: Definity (Lantheus Medical Imaging), Levovist (Schering AG), Optison (GE Healthcare), and Sonovue (Bracco Diagnostics). 

While usage of the agents in echocardiograms has declined in the last two years, ongoing clinical trials and pending regulatory applications are aimed at expanding the uses of ultrasound contrast agents.

“There is growing interest worldwide in expanding the approved uses of contrast ultrasound – not just for imaging the heart, but also for diagnosing abnormalities of the liver, carotid arteries, gastro-intestinal system, kidneys, and other organ systems throughout the body,” according to according to Steven Feinstein, MD, co-president of ICUS and director of echocardiography at Rush University Medical Center in Chicago.

Barry Goldberg, MD, co-president of ICUS and past president of the American Institute of Ultrasound in Medicine and the World Federation of Ultrasound in Medicine and Biology, added that the organization will provide a forum for cross-specialty communication and collaboration among contrast ultrasound professionals worldwide. “Collaboration and inclusiveness are key to the growth of the field and, ultimately, will significantly improve patient care,” he said.

Founding ICUS board members include contrast ultrasound experts from North America, Europe, Asia and Latin America. 

The recent FDA controversy has helped cardiologists appreciate “the vital importance of our colleagues in radiology, vascular imaging, and related imaging fields who also are working to develop contrast ultrasound applications -- for the liver, gynecological uses, whole body scans,” according to Feinstein. “The more we learned of their parallel universe, the more we became convinced that we need to foster more cross-specialty dialogue and collaboration.”

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