ICUS Weekly News Monitor 9-18-2015

1.  FierceDrugDelivery,  Sep 15, 2015,  Study finds ultrasound contrast agents can improve delivery of chemotherapy drugs     By Varun Saxena
2.  HealthCareBusiness,  Sep 14, 2015,  Contrast-enhanced ultrasound can predict tumor response to drugs in children     By Lauren Dubinsky
3.  ICUS,  Sep 14, 2015,  Politico Pro: Prescription Pulse: Drug value debate heats up — Pharma IPR carveout iffy — New First Amendment challenge for FDA
4.,  Sep 11, 2015,  ICUS: Ultrasound contrast backers urge new approach
By Erik L. Ridley
5.  Uro Today,  Sep 3, 2015,  Additional Targeted Biopsy in Clinically Suspected Prostate Cancer: Prospective Randomized Comparison between Contrast-Enhanced Ultrasound and Sonoelastography Guidance.     Ultrasound in medicine & biology Aug 19, 2015  [Epub ahead of print]    Authors:  Jieun Koh, et al.

Sep 15, 2015
Study finds ultrasound contrast agents can improve delivery of chemotherapy drugs
By Varun Saxena
Ultrasound sonoporation can improve the delivery of chemotherapy drugs in patients with advanced pancreatic cancer thanks to the presence of gaseous microbubbles in commercially available contrast agents, a study presented at the International Contrast Ultrasound Society conference in Chicago suggests.
Among 10 patients with inoperable cases of the disease, tumors were either reduced size or grew at a slower rate following ultrasound "sonoporation," or a temporary opening and closing of cell membranes that enables delivery and absorption of drugs. Two of the 10 patients are still alive a year after their last treatment cycle, according to a release, which says that the average life expectancy after diagnosis with metastatic pancreatic cancer is 3 to 6 months, with three-fourths of patients dying within one year of diagnosis.
"Our early findings suggested that commercially-available ultrasound microbubbles, combined with a standard chemotherapy drug, might prolong survival in pancreatic cancer patients," said Dr. Odd Helge Gilja of Haukeland University Hospital in Bergen, Norway, in a statement. "The patients treated with ultrasound sonoporation were able to undergo significantly more treatment cycles than those receiving standard chemotherapy. Additional studies are planned to confirm and potentially extend the results."
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In the study, the standard chemotherapy drug gemcitabine (marketed as Gemzar by Eli Lilly) was given to the participants via infusion, followed by commercially available microbubble contrast agents. A customized but commercially available ultrasound scanner was used to identify the microbubbles near the tumor and induce sonoporation.
The three contrast agents used are manufactured by Lantheus Medical Imaging, GE Healthcare ($GE) and Lumason to enhance cardiac images produced via echocardiograms. They are not approved by the FDA for drug delivery purposes.
"If further studies confirm the Bergen findings, ultrasound microbubbles could prove to be an innovative platform option for delivery of drugs and genes to treat other cancers and a wide variety of medical abnormalities throughout the body," said Dr. Steven Feinstein, co-president of the International Contrast Ultrasound Society and a professor of medicine at Rush University in Chicago, in a statement.
Sep 14, 2015
Contrast-enhanced ultrasound can predict tumor response to drugs in children
By Lauren Dubinsky
Contrast-enhanced ultrasound (CEUS) imaging can help determine whether certain drugs are effective at treating cancer in children, according to a new St. Jude Children’s Research Hospital study. CEUS also appears to be more accurate than CT and MR for predicting treatment response, which are the current standards of care.

Anti-angiogenic drugs can be used to try to cut off the blood supply to the tumors. CEUS can then be used to quantify blood flow and determine if the tumors are responding to the treatment.

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“Ultrasound contrast agents are made up of ‘microbubbles’ that are about the same size as red blood cells and are highly visible on ultrasound images,” Dr. Beth McCarville of St. Jude Children’s Research Hospital, told HCB News. “We can use these ‘microbubbles' as an indirect method of measuring tumor blood flow.”

The usual method of assessing tumor response to therapy is to measure the size of the tumor because when conventional chemotherapy is working, the tumors shrink. CT and MR are used to measure the tumor’s size.

“Tumor size is not a reliable method to know if chemotherapy that targets blood vessels is working because these targeted chemotherapies can be very effective without causing tumors to shrink,” said McCarville.

The study included 13 children with metastatic tumors who didn’t respond to earlier therapy and were considered incurable. The researchers had them undergo CEUS to evaluate their response to experimental anti-angiogenic cancer therapy.

The researchers found that CEUS was able to predict which patients would respond to therapy at very early time points. The children who responded to the drugs had longer periods of time before tumors started to get larger and spread compared to the children who didn’t respond to the drugs.

However, larger clinical studies will need to be conducted to prove that CEUS is reliable and reproducible for measuring tumor blood flow and that could take five more years, said McCarville. “Then I think it will become a routine part of monitoring patients who receive therapy that targets blood vessels,” she added.

But if CEUS does become the standard of care for measuring tumor blood flow, children will not be exposed to the ionizing radiation that CT emits or have to undergo sedation for an MR exam.

CEUS is not the only technology under investigation for assessing the effect cancer drugs have on tumors. Two separate research teams were funded in part by the National Institutes of Health’s National Cancer Institute to develop devices that test how tumors respond to a variety of drugs.

The Massachusetts Institute of Technology developed a small device that can be implanted in patients through a standard needle biopsy. The device has reservoirs that release small doses of up to 16 different drugs into certain regions.

A second biopsy needle can be used after 24 hours to retrieve the device and a small column of tissue around it, which can be used to evaluate the effects of the drug on the tumor.

The Fred Hutchinson Cancer Research Center created a device called CIVO, which is comprised of an array of up to eight needles that can inject small amounts of drugs directly into the tumors. As the drugs are delivered, the needle is retracted, which leaves column-like tracks through the tumor.

After 24 to 72 hours, tumor samples are retrieved and processed and the tumor’s response to each of the drugs is evaluated with an image analysis system.

Both of the devices were used on mouse models and have shown promising results. They are planning on testing the devices in clinical trials in the near future.

Sep 14, 2015
Politico Pro
Prescription Pulse: Drug value debate heats up — Pharma IPR carveout iffy — New First Amendment challenge for FDA
(Comment - Following the favorable ruling in the Amarin case earlier this month, the pharmaceutical industry appears to continue to look for opportunities to push this First Amendment precedent to allow for manufacturers to proactively market off-label uses of therapeutics.  With the current limited approved label for CEUS in the U.S., this would increase provider education and ultimately patient access.)
SECOND DRUG COMPANY MOUNTS FIRST AMENDMENT CHALLENGE AGAINST FDA - Pacira Pharmaceuticals filed a lawsuit against the FDA last week challenging the agency's efforts to restrict promotion of its postsurgical pain drug Exparel. The company alleges FDA has violated its First Amendment rights by restricting its exchange of "truthful and non-misleading speech." It also says FDA violated the Administrative Procedure Act, the Fifth Amendment, its guidance materials and precedent because it threatened enforcement action against the company for promoting the drug in a manner the company argues is consistent with the indication FDA approved. FDA warned the company in September 2014 for marketing the drug for unapproved uses. Pacira says it has repeatedly tried to address disagreements over the advertising with FDA but has been denied that opportunity.
... The suit was filed in the U.S. District Court for the Southern District of New York, the same district court that is reviewing Amarin Pharma's First Amendment suit against the FDA. The court handed Amarin a victory in August when it issued a preliminary order allowing it to market its prescription fish oil pill for uses not approved by the agency without fear of government prosecution, assuming it engages in truthful and non-misleading speech. Amarin has already begun marketing the drug in this manner. However, FDA and Amarin have announced they are working to reach a settlement agreement.
Sep 11, 2015
ICUS: Ultrasound contrast backers urge new approach
By Erik L. Ridley
Some 15 years after the first ultrasound contrast agents were cleared in the U.S., the technology remains underutilized. It's now time to consider another path toward broader acceptance, according to a Thursday talk at the International Contrast Ultrasound Society (ICUS) Bubble Conference in Chicago.
Advocates for broader ultrasound contrast use in the U.S. are seeing opportunities in a recent defeat handed to the U.S. Food and Drug Administration (FDA) over what kinds of off-label statements vendors can make to physicians about their products.
The FDA legal defeat, coupled with the pursuit of temporary CPT codes for new ultrasound contrast indications, could be used as a stepping-stone to move beyond the current FDA-cleared indications in echocardiography to applications such as liver imaging, according to Dr. Michael Main, medical director of the Echocardiography Laboratory at Saint Luke's Mid America Heart Institute in Kansas City.
Legal setback for the FDA
Last month, the FDA lost a legal challenge by pharmaceutical firm Amarin involving FDA regulations that prohibit pharmaceutical companies from making truthful off-label statements to physicians, Main said. Amarin manufactures Vascepa, which was approved by the FDA for treating patients with very high triglyceride levels.
Amarin had been seeking a broader indication for the drug and thought it could do so as a supplemental indication. But the FDA didn't believe the company had adequate clinical data to support the new use and charged the company with misbranding its product.
The case ended up before a federal judge in New York, who on August 7 ruled in favor of Amarin, stating that the FDA can't prosecute pharmaceutical companies for speech that promotes the lawful off-label use of an FDA-approved drug. The FDA chose not to appeal.
The judge in the case noted that off-label use is the norm in the U.S. rather than the exception, Main said.
"He also went on to say that the 'therapeutic -- indeed sometimes even lifesaving -- value of off-label uses of FDA-approved drugs has been widely recognized,' " he said.
Now that the FDA has been dealt a serious setback in federal court, the question is whether ultrasound contrast developers will take a more aggressive stance in marketing off-label indications for their products, according to Main.
"We will see," he said.
FDA and ultrasound contrast
Although it has been modified since it was initially mandated by the FDA in 2007, the black box safety warning still remains in place for ultrasound contrast agents.
"There are continued product label 'warnings' against the use of ultrasound contrast agents in sick patients -- the ones who derive the greatest benefit -- and there is a continued shunt contraindication," Main said.
In addition, the FDA hasn't cleared any new ultrasound contrast indications in more than 15 years, despite the successful completion of two large stress perfusion trials and the demonstrated efficacy of ultrasound contrast in many other disease states as well.
"The question I would ask is: Is it time to pursue another path?" he said.
Once a drug or device is approved, it's acceptable for physicians to use it off-label, he noted. The FDA also doesn't determine which services are reimbursed; procedural codes, relative values, and ultimately reimbursement are determined through a process governed by the American Medical Association (AMA) and the U.S. Centers for Medicare and Medicaid Services (CMS), and also separately by private carriers.
CPT add-on codes
A recent initiative to implement a new CPT add-on code for myocardial strain imaging could serve as a template to get reimbursement for new ultrasound contrast indications, Main said.
A code change proposal (CCP) for myocardial strain imaging was submitted last year to the AMA CPT panel and was presented at the February 2015 CPT meeting, he said. That led to the establishment of a category III add-on code (+0399T) for imaging myocardial strain to assess myocardial deformation. Published on July 1, the code will be active on January 1, 2016.
Category III codes are temporary CPT codes issued for emerging technology and are not reimbursed by CMS. However, they may be reimbursed by private payors, Main said.
There's also an opportunity for category III codes to progress to category I status (reimbursable by CMS) in one to two years, provided that the code has demonstrated significant utilization and additional peer-reviewed literature substantiates clinical utility.
Myocardial perfusion imaging
Following that strategy, an add-on CPT code is in the works for myocardial perfusion imaging. In July, the American Society of Echocardiography (ASE) submitted a code change proposal that describes myocardial contrast perfusion echocardiography at rest or with stress for assessing myocardial ischemia or viability, Main said.
If approved, that add-on CPT code could potentially be reportable along with CPT codes 93306, 93307, 93308, 93350, and 93351, he said. If category III status is conferred by the CPT panel in October, the code will be published on January 1, 2016, and go live on July 1, 2016.
"Of course, there would be opportunities then to pursue reimbursement from private carriers and local Medicare contractors, and also, importantly, to track utilization of this service, which at the current time we really just can't do," Main said.
In response to an audience question, Main said he would "absolutely" suggest that this pathway be used to pursue liver imaging applications for contrast-enhanced ultrasound.
"Some people kind of discount the value of an emerging technology code, but it is a marker and gets you on the map," he said. "It allows you to track currently for all of these services. Right now, nobody really knows how frequently they are being performed."
The end of the beginning
Market research firm Arlington Medical Resources projected in June that contrast echocardiography will make up 4.5% of total echocardiography studies in 2015, up from 2.5% in 2005 and from less than 1% in 2008, after the FDA mandated the black box warning, according to Main.
"Utilization continues to climb, although I think it remains far short of all of our targets," he said.
With respect to finally reaching targets for contrast-enhanced ultrasound, Main cited British Prime Minister Winston Churchill's famous 1942 quote after the defeat of the Axis armies in North Africa during World War II.
"Now is not the end," he said. "It is not even the beginning of the end. But it is, perhaps, the end of the beginning."
Uro Today
Sep 3, 2015
Additional Targeted Biopsy in Clinically Suspected Prostate Cancer: Prospective Randomized Comparison between Contrast-Enhanced Ultrasound and Sonoelastography Guidance.
Ultrasound in medicine & biology Aug 19, 2015 [Epub ahead of print]
Authors:  Jieun Koh, Dae Chul Jung, Young Taik Oh, Moon Gyu Yoo, Songmi Noh, Kyung Hwa Han, Koon-Ho Rha, Young Deuk Choi, Sung Joon Hong
Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea , Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea  , Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea , Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea , Department of Pathology, Cha Medical College, Gang-Nam Cha Hospital, Seoul, Korea , Avison Biomedical Research Center, Department of Radiology; Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea , Department of Urology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea , Department of Urology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea , Department of Urology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
Our aim was to improve the detection of prostate cancer by evaluating whether contrast-enhanced ultrasound (CEUS) or sonoelastography (SE) is more helpful in guiding targeted biopsy (TB) performed before systematic biopsy (SB).
A total of 52 patients suspected of having prostate cancer were prospectively included and randomly assigned to either the CEUS or SE group. Different, independent radiologists performed TB and twelve-core SB. Within each group, cancer detection rates based on core number were compared between SB and TB. We evaluated the effect of TB on core-based cancer detection rates between the CEUS and SE groups. Cancer detection was higher in overall TB cores 16.4% (28/171) than SB cores 11.4% (71/624) in both groups. In the SE group, TB cores revealed higher cancer detection than did SB cores from 4.49% (14/312) to 12.86% (9/70) (p = 0.01). Compared with CEUS, SE may improve detection rates when considering additional TB guidance methods.

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