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

ICUS Weekly News Monitor 11-28-2008

1. The New England Journal of Medicine, Nov 27, 2008, Ultrasound Imaging of the Thoracic Duct By Marcus Seeger, M.D.; Burkhard Bewig, M.D. 
 2. Journal of Ultrasound in Medicine, Nov, 2008, A Method for Assessing the Microvasculature in a Murine Tumor Model Using Contrast-Enhanced Ultrasonography By: Mary E. Loveless, MS, Xia Li, PhD, et al 3. FDAnews Device Daily Bulletin, Nov 17, 2008, ASE Backs Use of Ultrasound Contrast Agents (Vol 5, No 225)

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