ICUS Weekly News Monitor 12-19-2008

1. HealthImaging.com, Dec 17, 2008, Large analysis suggests echo contrast agents associated with reduced mortality By Editorial Staff 2. MarketWatch, Dec 15, 2008, Press Release New Study Published in the American Journal of Cardiology Finds Survival Benefit among Hospitalized Patients Undergoing Definity(R)- Enhanced Echocardiography 3. American Journal of Cardiology, Dec 15, 2008 Acute Mortality in Hospitalized Patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent (Multicenter Registry Results in 4,300,966 Consecutive Patients) By Michael L. Main, MD et al 4. Ultrasound, Jan 2009, Induction of Apoptosis in Sonoporation and Ultrasonic Gene Transfer By HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 Douglas L. Miller, Chunyan Dou HealthImaging.com Dec 17, 2008 Large analysis suggests echo contrast agents associated with reduced mortality. By Editorial Staff Compared with patients not receiving a contrast agent, administration of perflutren lipid microsphere (PLM) injectable suspension contrast agent during echocardiography was associated with a 24 percent decreased risk of mortality, according to a retrospective analysis in the December issue of the American Journal of Cardiology.

The authors noted that although the FDA recently relaxed the issued warnings for perflutren-containing ultrasound contrast agents on May 13, concerns still exist regarding the safety of these compounds, particularly in critically ill patients.

Michael L. Main, MD, of Saint Luke's Mid America Heart Institute in Kansas City, Mo., and colleagues examined patients undergoing echocardiography during hospitalization, which were separated into those performed without contrast enhancement and those performed with PLM injectable suspension contrast agent (Definity from Lantheus Medical Imaging of North Billerica, Mass.). Vital status within one day of the echocardiogram was available for all patients using hospital billing data.

Between Jan. 1, 2002 and Oct. 31, 2007, approximately 4.3 million patients underwent transthoracic echocardiography at rest during hospitalization: unenhanced studies were 4,242,712 and contrast-enhanced studies were 58,254.

The researchers used a multivariate logistic regression analysis to compare 24-hour mortality, controlling for case mix and clinical covariates. They found that one-day mortality rates were 1.08 percent (45,789 deaths) for patients undergoing non-contrast enhanced studies and 1.06 percent (616 deaths) for patients undergoing contrast-enhanced exams.

Main and colleagues found that in patients undergoing an echocardiogram, patients receiving PLM injectable suspension contrast agent were 24 percent less likely to die within one-day than patients not receiving a contrast agent. 

They concluded that acute crude mortality was not increased in patients receiving PLM injectable suspension contrast agent.

Lantheus provided funding for this study MarketWatch Dec 15, 2008 Press Release New Study Published in the American Journal of Cardiology Finds Survival Benefit among Hospitalized Patients Undergoing Definity(R)- Enhanced Echocardiography Multicenter Study Results Find No Difference in Acute Mortality Rates for Patients Undergoing Contrast versus Non-Contrast Echocardiograms NORTH BILLERICA, Mass., Dec 15, 2008 (BUSINESS WIRE) -- Lantheus Medical Imaging, Inc. a worldwide leader in diagnostic imaging, announced today new data from a retrospective, multicenter, cohort study of over four million hospitalized patients that shows similar unadjusted mortality rates for patients receiving DEFINITY(R) Vial For (Perflutren Lipid Microsphere) Injectable Suspension enhanced resting echocardiography exams when compared with patients who did not receive DEFINITY(R). Although the patients that received DEFINITY(R) were sicker on average and had a higher baseline mortality risk prior to the exam, following DEFINITY(R) administration these same patients exhibited a 24% reduced risk of mortality over 24 hours compared to the those patients who received only echocardiography without the ultrasound contrast agent. These study findings were published in the December 2008 issue of The American Journal of Cardiology. "As the largest retrospective, observational study to date to examine the short-term safety profile of perflutren-containing ultrasound contrast agents, the data highlight the relatively low incidence of adverse safety reactions associated with DEFINITY(R) and demonstrate a significantly lower risk of acute mortality for patients receiving DEFINITY(R)-enhanced echocardiograms," said Mark Hibberd, M.D., Ph.D., Senior Medical Director, Global Medical Affairs, Lantheus Medical Imaging, Inc. and co-author on the study. "These study findings provide the physician community with essential safety information on the use of DEFINITY(R), especially among hospitalized patients, and provide valuable information on patient outcomes that bear further investigation." The study was designed to assess short-term (one-day) mortality in hospitalized patients undergoing resting transthoracic echocardiography both with and without DEFINITY(R). The study analyzed more than 4.3 million patients undergoing clinically indicated echocardiography from January 1, 2002 through October 31, 2007 using the Premier Perspective Database, the largest U.S. hospital-based, service-level comparative database providing detailed resource utilization data along with patients' primary and secondary diagnosis and procedure codes. Of this population, 4,242,712 patients received non-enhanced echocardiograms and 58,254 received contrast-enhanced studies using DEFINITY(R). One-day mortality rates were 1.08% for patients undergoing non-contrast studies and 1.06% for patients undergoing DEFINITY(R) contrast-enhanced examinations. However, patients receiving DEFINITY(R) were more likely to have an increased baseline severity of illness and a higher pre-study risk of mortality. A multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates. Patients undergoing DEFINITY(R) -enhanced echocardiograms had a 24% lower risk adjusted odds ratio for mortality within one day than those patients who received only echocardiography without the ultrasound contrast agent. These findings build on and corroborate a recently published multicenter retrospective study that also demonstrated no increased mortality in patients undergoing echocardiography with a contrast agent in comparison with patients undergoing non-contrast-enhanced examinations (Journal of the American College of Cardiology, Volume 51, Number 17, 2008).(1) In addition, this multicenter analysis was presented in part at a meeting of the United States Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee in June, 2008. These study findings also confirm the safety profile of ultrasound contrast imaging agents and support the implementation of the recently published American Society of Echocardiography (ASE) Consensus Statement on the Clinical applications of Ultrasound Contrast Agents in echocardiography. "This study is groundbreaking in the echocardiography area, and represents the largest evaluation of resting echocardiography among hospitalized patients," continued Dr. Hibberd of Lantheus. "It is also the first to evaluate the impact of contrast echocardiography on survival among hospitalized patients. The results clearly indicate that there is no additional risk associated with DEFINITY(R)-enhanced studies, while in fact those patients that received DEFINITY(R) had improved short-term survival when compared to those who received only transthoracic echocardiograms without DEFINITY(R). The study did not address the reason for this effect. These data provide the medical community with further clinical evidence of how DEFINITY(R) can significantly improve the standard of care for patients undergoing cardiac evaluations, and we are continuing to explore the role of DEFINITY(R) in specialized patient populations such as those in the ICU and receiving mechanical ventilation." Don Kiepert, President and CEO, Lantheus Medical Imaging added, "We are encouraged by these data that further demonstrate the role and clinical value of DEFINITY(R), and believe these findings will answer any remaining safety questions regarding ultrasound contrast agents. Lantheus continues to remain committed to providing important safety information on the use of DEFINITY(R) in routine clinical practice." About DEFINITY(R) Since its launch in 2001, activated DEFINITY(R) Vial For (Perflutren Lipid Microsphere) Injectable Suspension has been administered to over two million patients.(2) In patients with suboptimal echocardiograms, DEFINITY(R) enables physicians to visualize the borders of the heart more clearly.(3,4) In May 2008, Lantheus announced the initiation of CaRES (Contrast Echocardiography REgistry for Safety Surveillance), the first multi-center Phase IV observational registry that will further evaluate the safety profile of DEFINITY(R) in patients with suboptimal echocardiograms and provide safety information on the use of ultrasound contrast agents in routine clinical practice. The open-label, non-randomized registry is being conducted in more than 10 clinical sites in the United States and include at least 1,000 patients. The study will gather data on patient characteristics and demographics, indication for DEFINITY(R)'s use, results of safety monitoring of patients during and after DEFINITY(R) administration, and the nature and frequency of any adverse events that may occur. Important Safety Information about DEFINITY(R) Activated DEFINITY(R) Vial for (Perflutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. The safety and efficacy of DEFINITY(R) with exercise stress or pharmacologic stress testing have not been established. WARNING: Serious Cardiopulmonary Reactions Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration. Assess all patients for the presence of any condition that precludes DEFINITY(R) administration (see CONTRAINDICATIONS). In patients with pulmonary hypertension or unstable cardiopulmonary conditions, monitor vital sign measurements, electrocardiography and cutaneous oxygen saturation during and for at least 30 minutes after DEFINITY(R) administration (see WARNINGS). Always have resuscitation equipment and trained personnel readily available. Activated DEFINITY(R) should not be administered to patients with known or suspected cardiac shunts (right-to-left, bi-directional or transient right-to-left), or hypersensitivity to perflutren. Do not administer DEFINITY(R) by intra-arterial injection. In postmarketing use, uncommon but serious reactions observed during or shortly following perflutren-containing microsphere administration included fatal cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia or fibrillation), hypotension, respiratory distress or cardiac ischemia (see ADVERSE REACTIONS). The risk for these reactions may be increased among patients with pulmonary hypertension or unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, serious ventricular arrhythmias or respiratory failure, including patients receiving mechanical ventilation). In the absence of these underlying conditions, observe patients closely during and following DEFINITY(R) administration. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY(R) administration and monitor all patients for acute reactions. For full prescribing information, please visit www.lantheus.com. American Journal of Cardiology Dec 15, 2008 Acute Mortality in Hospitalized Patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent (Multicenter Registry Results in 4,300,966 Consecutive Patients) (This study was presented in part at a meeting of the United States Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee on June 24, 2008.) Michael L. Main, MDa Amy C. Ryan, MS, Teresa E. Davis, BS, Maureen P. Albano, RN, Lisa L. Kusnetzky, BA, Mark Hibberd, MD We sought to define acute mortality in a large multicenter cohort of hospitalized patients undergoing clinically indicated echocardiography with and without use of an ultrasound contrast agent. Although the United States Food and Drug Administration recently relaxed the issued warnings for perflutren-containing ultrasound contrast agents on May 13, 2008, concerns still exist regarding the safety of these compounds, particularly in critically ill patients. A retrospective analysis was performed using the Premier Perspective Database. Patients undergoing echocardiography during hospitalization were separated into those performed without contrast enhancement and those performed with perflutren lipid microsphere (PLM) injectable suspension contrast agent (Definity, Lantheus Medical Imaging, North Billerica, Massachusetts). Vital status within 1 day of the echocardiogram was available for all patients using hospital billing data. Between January 1, 2002 and October 31, 2007, 4,300,966 patients underwent transthoracic echocardiography at rest during hospitalization (unenhanced studies n = 4,242,712 and contrast-enhanced studies n = 58,254). Multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates; 1-day mortality rates were 1.08% (n = 45,789 deaths) for patients undergoing noncontrast studies and 1.06% (n = 616 deaths) for patients undergoing contrast-enhanced examinations (p = 0.613). Multivariate logistic regression analysis revealed that, in patients undergoing an echocardiogram, patients receiving PLM injectable suspension contrast agent were 24% less likely to die within 1-day than patients not receiving a contrast agent (adjusted odds ratio = 0.76, 95% confidence interval 0.70 to 0.82). In conclusion, acute crude mortality was not increased in patients receiving PLM injectable suspension contrast agent. Multivariate logistic regression analysis revealed that, compared with patients not receiving a contrast agent, administration of PLM injectable suspension contrast agent during echocardiography was associated with a 24% decreased risk of mortality. Ultrasound Jan 2009 Induction of Apoptosis in Sonoporation and Ultrasonic Gene Transfer HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 Douglas L. Miller, Chunyan Dou Abstract  The role of apoptosis in sonoporation and ultrasound-enhanced gene transfection of cell suspensions was examined in vitro. Suspensions of HL-60 and of CHO-K1 cells were exposed to 2.25-MHz continuous ultrasound for 1 min in a 60-rpm rotating-tube exposure system, with ultrasound contrast media added to ensure nucleation of cavitation. Cell necrosis was measured by trypan blue dye exclusion (using a hemacytometer) and by propidium iodide nuclear staining (using flow cytometry). Apoptosis was detected by the annexin V method with Alexa Fluor 350 as the fluorescent label, and confirmed by Hoechst 33342 nuclear staining. Sonoporation cell loading was assessed by uptake of large fluorescent-dextran molecules from the medium. Transfection was demonstrated by expression of green fluorescent protein (GFP) from plasmids transferred into the cells by the treatment. Cell scoring was performed by flow cytometry, with necrotic cell events excluded. For HL-60 cells at 0.4 MPa, cell loading and transfection was significantly increased relative to shams at 2, 6 and 24 h post exposure, peaking at 19.0 ± 5.5% and 9.6 ± 4.2% of non-necrotic cells, respectively, at 6 h. However, about one third of the treatment-positive cells were identified as apoptotic. The cell loading and gene transfer effects increased for increasing peak rarefactional pressure amplitude, reaching 24.4 ± 7.7% and 12.7 ± 5.1% of non-necrotic cells, respectively, for 0.6-MPa exposure. However, the lethal cellular injury caused by cavitation in the rotating tube system reduced the overall apparent efficacy of cell loading and gene transfer to 5.1 ± 2.1% and 2.1 ± 0.9%, respectively, after accounting for necrosis and apoptosis. Similar tests with CHO cells showed increased sonoporation but mostly cell death by necrosis, rather than apoptosis. The induction of apoptosis by cavitation treatments should be considered as a possible confounding factor, in addition to necrosis, in sonoporation and ultrasonic gene transfer research. (E-mail This email address is being protected from spambots. You need JavaScript enabled to view it. )

ICUS Weekly News Monitor 12-12-2008

1. Auntminnie.com, Dec 11, 2008, FDA panel rejects Acusphere contrast agent By AuntMinnie.com staff writers 2. 7th Space Interactive, Dec 10, 2008 Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: rationale and design of the Sonolysis study By Jeroen Slikkerveer, et al 3. Reuters, Dec 10, 2008, US FDA panel rejects Acusphere heart imaging agent By Susan Heavey 4. Reuters, Dec 8, 2008, FDA staff cites Acusphere drug risks, shares sink By Susan Heavey 5. Academic Radiology, Jan 2009, Vol 16, Issue 1, Delta-projection Imaging on Contrast-enhanced Ultrasound to Quantify Tumor Microvasculature and Perfusion By Chandra M. Sehgal, PhD, et al 6. Dow Jones, Dec 8, 2008, FDA: Concerned About Safety Of Acusphere's Proposed Drug By Jared A. Favole 7. MarketWatch, Dec 5, 2008, Cryoablation of Early Invasive Ductal Breast Cancer With MRI Confirmation Shows Promising Clinical Benefits Press Release (Sanarus medical) Auntminnie.com Dec 11, 2008 FDA panel rejects Acusphere contrast agent By AuntMinnie.com staff writers A U.S. Food and Drug Administration (FDA) panel rejected the regulatory application for the Imagify ultrasound contrast agent from Acusphere of Watertown, MA. In a meeting on December 10, the FDA's Cardiovascular and Renal Drugs Advisory Committee voted by a 16-1 margin with one abstention that the risks of the product do not justify the diagnostic benefits. The committee also discussed concerns that it would like addressed to support approval of the product for the detection of coronary artery disease. The FDA said prior to the committee meeting that it had concerns about the safety of the agent based on results from clinical trials. The FDA in 2007 required black box warnings for the two ultrasound contrast products on the U.S. market: Definity from Lantheus Medical Imaging of North Billerica, MA, and Optison from GE Healthcare of Chalfont St. Giles, U.K. The committee's vote is not binding, but it will be considered by the FDA in its review of Imagify's new drug application (NDA). The target date for FDA action on the NDA is February 28, 2009. Acusphere said that it plans to work with the FDA to determine what additional information might be required for approval of the agent. 7th Space Interactive Dec 10, 2008 Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: rationale and design of the Sonolysis study By Jeroen Slikkerveer, Pieter A. Dijkmans, Gertjan T. Sieswerda, Pieter A.F.M. Doevendans, Arie P.J. van Dijk, Freek W.A. Verheugt, Thomas R. Porter and Otto Kamp
 Experimental studies have shown that ultrasound contrast agents enhance the effectiveness of thrombolytic agents in the presence of ultrasound in vitro and in vivo. Recently, we have launched a clinical pilot study, called "Sonolysis", to study this effect in patients with ST-elevation myocardial infarction based on proximal lesions of the infarct-related artery.DesignIn our multicenter, randomized, placebo controlled clinical trial we will include patients between 18 and 80 years of age with their first ST-elevation myocardial infarction based on a proximal lesion of the infarct-related artery.

After receiving a single bolus alteplase 50 mg IV (Actilyse(R) Boehringer Ingelheim GmbH), a loading dose of aspirin 500 mg, and heparin 5000 IU in the ambulance according to the prehospital thrombolysis protocol, patients, following oral informed consent, are randomized to undergo 15 minutes of pulsatile ultrasound with intravenous administration of ultrasound contrast agent or placebo without ultrasound. Afterwards coronary angiography and, if indicated, percutaneous coronary intervention will take place.

A total of 60 patients will be enrolled in approximately 1 year. The primary endpoints are based on the coronary angiogram and consist of TIMI flow, corrected TIMI frame count, and myocardial blush grade.

Follow-up includes 12-lead ECG, 2D-echocardiography, cardiac MRI, and enzyme markers to obtain our secondary endpoints, including the infarct size, wall motion abnormalities, and the global left ventricular function. Discussion The Sonolysis study is the first multicenter, randomized, placebo controlled clinical trial investigating the therapeutic application of ultrasound and microbubbles in acute ST-elevation myocardial infarction patients.

A positive finding may stimulate further research and technical innovations to implement the treatment in the ambulance and maybe obtain even more patency at an earlier stage. Trial registration - Trialregister NTR161

Author: Jeroen Slikkerveer, Pieter A. Dijkmans, Gertjan T. Sieswerda, Pieter A.F.M. Doevendans, Arie P.J. van Dijk, Freek W.A. Verheugt, Thomas R. Porter and Otto Kamp
Credits/Source: Trials 2008, 9:72
 Reuters Dec 10, 2008 US FDA panel rejects Acusphere heart imaging agent By Susan Heavey A U.S. Food and Drug Administration advisory panel rejected Acusphere Inc's (ACUS.O: Quote, Profile, Research, Stock Buzz) imaging contrast agent on Wednesday, saying possible risks outweighed its potential for screening heart patients. In a 16-1 vote, the FDA's panel of outside advisers said there was not consistent data to prove the product worked, and expressed concern about potential side effects, including low blood pressure. One panelist abstained. "How it actually performed was disappointing in light of the risks," said panel member Tal Geva, a Harvard Medical School pediatrician. Acusphere wants FDA approval to market Imagify, also known as AI-700, for use with cardiac ultrasound scans to screen patients with chest pain to see if they have heart disease and if they need more tests. Cardiac ultrasounds, also known as echocardiograms, use sound waves to create images of the heart, which can be enhanced by contrast products. FDA has been concerned about side effects with contrast imaging agents and earlier called for warnings after hundreds of reports of complications, including deaths. In June, it sought advice from an advisory panel, which called on companies to collect additional data for those already on the market. FDA officials have said it is unclear whether Imagify's risks are worth it since it helps diagnose heart issues but does not treat them, and are seeking the panel's advice. It usually follows its panel's recommendations. Acusphere said its product is not the same as other "microbubble" contrast agents that contain gas within a molecular shell. Imagify is a "microsphere" agent that holds gas within a porous material, it said. But FDA officials said safety issues were a top worry, and that Imagify would likely qualify for the same cautions that its competitors carry. "There are some class effects here," said Dwaine Rieves, head of the FDA's imaging products division. Acusphere said the side effects were manageable and using its contrast agent with cardiac ultrasounds gave doctors necessary information while avoiding radiation from alternative tests at a lower cost. Panel members were not convinced, saying the company's clinical trial data was not strong enough to show it would clearly offer doctors any advantages over other available tests. "It was not persuasive largely because of inconsistency," said panelist Ruth Day, who directs Duke University's Medical Cognition Laboratory. They also cited safety concerns, although FDA staff told the panel it was difficult to tell whether the agent or the underlying heart problems caused patient complications. Company studies of Imagify found that some patients who were given the agent experienced dangerously low blood pressure and lack of oxygen in the blood. Some experienced heart attacks, chest pain, flushing and other side effects. The panel recommended that the company conduct additional larger studies that included a broader range of patients. Shares of Acusphere were halted ahead of the panel's meeting. Reuters Dec 8, 2008 FDA staff cites Acusphere drug risks, shares sink By Susan Heavey Safety risks with Acusphere Inc's Imagify may be "inappropriate" for use in diagnosing patients with heart problems, U.S. Food and Drug Administration staff said in documents released on Monday, sending the company's shares down 60 percent. "FDA is particularly concerned about the safety ... because of signals evidenced in animal and clinical studies," the staff said. "FDA is also concerned that the safety risks associated with the product are inappropriate for the product's proposed clinical use." Acusphere is seeking FDA approval to market the injectable suspension for use in ultrasound imaging tests to help diagnose coronary artery disease. The FDA staff documents were released ahead of an advisory panel meeting on Wednesday to discuss whether the agency should approve the product. The FDA usually follows the recommendation from its panel of outside advisers. Imagify is a type of imaging contrast agent known as a "microsphere" drug with small, gas-containing particles. It is injected into the bloodstream to make the body's vascular system easier to see. FDA officials earlier this year expressed concern about the safety of contrast imaging agents overall. In their analysis released on Monday, FDA staff said many complications were reported in patients given Imagify, including abnormally low blood pressure, blue discoloration of the skin and shaking, but it was difficult to tell whether they were caused by the drug or the accompanying test. Agency staff also said they were concerned about inconsistent findings on how well the ultrasound imaging agent works, calling the data "not sufficient." Acusphere, in separate documents also released on Monday, said most side effects were not serious and were treatable. Use of Imagify appears to work as well as another imaging tests and "will be an effective clinical tool in the triage of patients" who may need more invasive procedures," the company said. Acusphere's shares fell 45 cents to 31 cents in morning trading on the Nasdaq. (Reporting by Susan Heavey, editing by Maureen Bavdek 
 Academic Radiology Jan 2009 Vol 16, Issue 1 Delta-projection Imaging on Contrast-enhanced Ultrasound to Quantify Tumor Microvasculature and Perfusion By Chandra M. Sehgal, PhD; Theodore W. Cary, BA; Peter H. Arger, MD; Andrew KW Wood, DVSc, PhD The aim of this study was to assess the Δ-projection image processing technique for visualizing tumor microvessels and for quantifying the area of tissue perfused by them on contrast-enhanced ultrasound images. Materials and Methods The Δ-projection algorithm was implemented to quantify perfusion by tracking the running maximum of the difference (Δ) between the contrast-enhanced ultrasound image sequence and a baseline image. Twenty-five mice with subcutaneous K1735 melanomas were first imaged with contrast-enhanced grayscale and then with minimum-exposure contrast-enhanced power Doppler (minexCPD) ultrasound. Delta-projection images were reconstructed from the grayscale images and then used to evaluate the evolution of tumor vascularity during the course of contrast enhancement. The extent of vascularity (ratio of the perfused area to the tumor area) for each tumor was determined quantitatively from Δ-projection images and compared to the extent of vascularity determined from contrast-enhanced power Doppler images. Delta-projection and minexCPD measurements were compared using linear regression analysis. Results Delta-projection was successfully performed in all 25 cases. The technique allowed the dynamic visualization of individual blood vessels as they filled in real time. Individual tumor blood vessels were distinctly visible during early image enhancement. Later, as an increasing number of blood vessels were filled with the contrast agent, clusters of vessels appeared as regions of perfusion, and the identification of individual vessels became difficult. Comparisons were made between the perfused area of tumors in Δ-projections and in minexCPD images. The Δ-projection perfusion measurements were correlated linearly with minexCPD. Conclusion Delta-projection visualized tumor vessels and enabled the quantitative assessment of the tumor area perfused by the contrast agent. Dow Jones Dec 8, 2008 FDA: Concerned About Safety Of Acusphere's Proposed Drug By Jared A. Favole, Dow Jones Newswires; 202.862.9207; jared.favole@ dowjones.com HYPERLINK "http://www.dj.com/" Federal regulators said Monday safety risks associated with Acusphere Inc.'s (ACUS) ultrasound heart-imaging agent are inappropriate for the product's proposed clinical use. Acusphere, a specialty pharmaceutical company based in Watertown, Mass., is seeking Food and Drug Administration approval for Imagify to help identify blood-flow problems in patients with stable chest pain. The proposed drug belongs to a class of products called ultrasound heart-imaging agents. These agents, also called contrasting agents, enhance images of the heart. Clinical studies with Acusphere suggest Imagify may result in acute inflammation and abnormally low blood pressure, the FDA said in briefing documents posted on its Web site Monday. Seventeen patients taking Imagify during clinical studies experienced adverse events that were serious enough to cause them to permanently stop taking the product. Such adverse events include vertigo and hypertension. Acupshere said in its own briefing documents that the decreases in blood pressure and other problems were mild in intensity and reversible. The FDA added that Imagify's performance isn't sufficient for the proposed diagnostic use of the product. The FDA released its briefing information ahead of a panel meeting Wednesday, where outside medical experts will discuss the safety and efficacy of Imagify. Contrasting agents came under increased scrutiny last year after post- marketing reports associated several of the products with hundreds of adverse events, including more than a dozen deaths. These reports were associated with GE Healthcare's Optison and Lantheus Medical Imaging's Definity. GE Healthcare is a unit of General Electric Co (GE). Those reports prompted the FDA to update the drugs' labels in October with strong warnings. Doctors have decried the warnings as too strong, saying they deter physicians from using the agents even though they help save lives. Doctors have argued that most of the adverse events reported to the FDA about Optison and Definity were the result of underlying problems with patients, not the drugs. Many patients who receive contrast agents are suffering from severe heart problems. Optison and Definity are "microbubble" contrast agents, meaning they consist of a gas core encased within a molecular shell. Imagify is a "microsphere" drug consisting of a mechanically rigid particle that contains pores filled with gas. The gas contained within the products enhances the acoustic signal of ultrasound waves and provides a contrast between the blood vessels and surrounding structures. Acusphere said the inflexibility of Imagify allows physicians to see images of the heart for a longer period of time than microbubble agents. This increased time frame is essential for helping diagnose coronary artery disease, which if left untreated can lead to heart attacks. MarketWatch Dec 5, 2008 Cryoablation of Early Invasive Ductal Breast Cancer With MRI Confirmation Shows Promising Clinical Benefits Press Release (Sanarus medical) Cryoablation of Early Invasive Ductal Breast Cancer With MRI Confirmation Shows Promising Clinical Benefits, According to Study Presented at RSNA Researcher Says, Sanarus' Visica 2(TM) Treatment System May Offer Same Therapeutic Benefits as Lumpectomy with Improved Cosmesis and Lower Costs Early clinical experience with the FDA cleared Visica 2(TM) Treatment System from Sanarus Medical confirms the effectiveness of ultrasound guided cryoablation to completely eradicate small, unifocal Invasive Ductal Breast Cancer (IDC). Initial data from this multi-center study was presented at the 94th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA), November 29 - December 5, 2008. The study, "New Findings on Contrast-enhanced Magnetic Resonance Imaging, the "Black Hole" and "Cryohalo" are Markers for the Efficacy of Ultrasound-guided Cryoablation of Small Unifocal Invasive Ductal Breast Cancer," presented by Gary Levine, MD, Director of Breast Imaging at Hoag Breast Care Center in Newport Beach, Calif., was designed to evaluate the ability of breast contrast enhanced MRI to assess the effectiveness of ultrasound guided cryoablation for the local treatment of small, unifocal IDC. "With a large body of evidence demonstrating the ability of cryoablation to destroy cancerous and noncancerous tumors of the liver, prostate, kidney and breast, the gating factor for the treatment of breast cancer tumors was the ability to visualize the extent of the tumor in advance and confirm target destruction post-procedure," said Dr. Levine. "We are very encouraged that our preliminary results demonstrate that in selected early IDC breast cancers, cryoablation with MRI confirmation may offer the same therapeutic benefit as lumpectomy with less morbidity, improved cosmesis and less cost." Patients with newly diagnosed IDC underwent an "early" pre-ablation CEMRI to establish its MR enhancement pattern. Ultrasound-guided cryoablation was then performed using a Visica Treatment System to ablate the malignant tumor and a margin of surrounding tissue. A "delayed" CEMRI was performed approximately four weeks post-ablation followed by a standard surgical lumpectomy. The early and delayed CEMRI findings were correlated with the surgical histopathology. In all 15 cases, the post-ablation MRI's showed no suspicious contrast enhancement remaining at the targeted tumor site and histopathology confirmed complete tumor kill within the intended ablation zone. In three cases histopathology confirmed residual DCIS and/or small satellite lesions outside the cryoablation zone. At delayed CEMRI, previously unreported characteristic and reproducible findings of signal void on post-contrast subtraction images ("black hole") correlates with an area of coagulation necrosis at the cryoablation site and a surrounding uniform thin rim enhancement ("cryohalo") corresponds to a zone of inflammation at the cryoablation margin. "Lack of residual suspicious enhancement on post-cryoablation CEMRI appears to correlate with complete tumor kill within the targeted ablation zone. We believe the novel MR findings termed "black hole" and "cryohalo" serve as markers for successful ablation, giving us a noninvasive and reproducible method to verify clinical results," added Dr. Levine. The study conducted by Dr. Levine and Steven Poplack, MD, Co-Director of Breast Imaging at Dartmouth Hitchcock Medical Center is similar to the National Cancer Institute (NCI) funded clinical trial recently initiated by the American College of Surgeons Oncology Group (ACOSOG). Titled, "A Phase II Trial Exploring the Success of Cryoablation Therapy in the Treatment of Invasive Breast Carcinoma," the ACOSOG study will also evaluate cryoablation as well as the ability of MRI to evaluate post-cryoablation efficacy. The Visica 2 System was selected as the exclusive cryoablation technology to be utilized in the ACOSOG study. Cryoablation is a minimally invasive non-surgical procedure that uses extreme cold to destroy tumors. The Sanarus Visica System has predominately been used in the cryoablation of non-cancerous tumors called fibroadenomas since its initial FDA market clearance in March of 2002. This office-based procedure, which usually takes less than 20 minutes, involves placing a small needle into the center of the fibroadenoma using ultrasound guidance and subsequently freezing and killing the tumor. The safety and efficacy of cryoablation have been well established in over 2,000 fibroadenomas that have been treated with the System to date. This study was presented at RSNA as part of the Breast Imaging (Interventional) Session, #SST01-05, Friday, December 5 at 11:10am in Room E253CD: New Findings on Contrast-enhanced Magnetic Resonance Imaging (CEMRI), the "Black Hole" and "Cryohalo" are Markers for the Efficacy of Ultrasound (US)-guided Cryoablation of Small (less than or equal to 15mm) Unifocal Invasive Ductal Breast Cancer

ICUS Weekly News Monitor 12-5-2008

1. Otolaryngology Journal, Dec 2008, Lymphosonographic sentinel node biopsy of the supraglottis in a swine model 2. US Radiology, Vol 1, Issue 1, Safety and Risk–Benefit Profile of Microbubble Contrast Agents in Echocardiography By Tayeb M. Khumri, MD and Michael L/. Main, MD 3. US Radiology, Vol 1, Issue 1, Microbubble Contrast Agents for Ultrasound Imaging— Safety and Efficacy in Abdominal and Vascular Imaging By Tae Kyoung Kim, MD; Hyun-Jung Jang, MD; Stephanie R. Wilson, MD

4. US Radiology, Vol 1, Issue 1, Cardiovascular Applications of Ultrasound Contrast Agents By Sanjiv Kaul, MD 5. Nature Clinical Practice Gastroenterology & Hepatology, Oct 2008, Contrast-enhanced endoscopic ultrasound for diagnosis of pancreatic malignancy—a visual aid or a distraction? By William R Brugge

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    Washington, DC 20006-1102, USA
  • Telephone: 202-408-6199

About ICUS

ICUS is the world’s only professional society exclusively devoted to contrast-enhanced ultrasound (CEUS) medical imaging technology.

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