ICUS Weekly News Monitor 9-22-2016

ICUS Weekly News Monitor
9/22/16 - 9am Eastern
1.  Aunt Minnie,  Sep 22, 2016,  Contrast US clears up indeterminate HCC cases on MRI
By Erik L. Ridley
2.  ICUS,  Sep 15, 2016,  SonoVue Approved in Mexico!
*To view presentations live-streamed from the 31st Annual Advances in Contrast Ultrasound Bubble Conference held in Chicago, 8/9 September 2016, go to:
Aunt Minnie
Sep 22, 2016
Contrast US clears up indeterminate HCC cases on MRI
By Erik L. Ridley, AuntMinnie staff writer

Contrast-enhanced ultrasound (CEUS) is highly effective for characterizing tumors thought to be hepatocellular carcinoma (HCC) but indeterminate on MRI, according to a presentation at the 2016 Advances in Contrast Ultrasound - Bubble Conference earlier this month in Chicago.
Sharing preliminary findings from an ongoing study, senior author Dr. Stephanie Wilson of the University of Calgary reported on her institution's experience using CEUS to resolve more than 50 cases so far with suspicion for HCC and indeterminate findings on MRI. Wilson said she hopes that such studies will facilitate the integration of CEUS into existing imaging guidelines for liver imaging.
"I hope that after every place on the guidelines that currently says, '[after an] indeterminate MR, do a CT scan' or 'do biopsy,' it will say instead, 'do CEUS,' " she said.
MRI as a mainstay
MRI remains the mainstay of imaging for hepatocellular carcinoma in 2016, both in North America and in other parts of the world, Wilson said. However, MRI can also produce an indeterminate result due, for example, to the absence of the required contrast-enhancement features for an HCC diagnosis: arterial phase hyperenhancement (APHE) and slow contrast washout.
An indeterminate result may also occur due to the lack of baseline observations on T1-, T2-, and diffusion-weighted imaging (DWI), Wilson said. The American Association for the Study of Liver Diseases (AASLD) recommended in 2011 that indeterminate results on MRI be considered for biopsy.
CEUS can help, however. The University of Calgary research team, which included first author and medical student Jingui Hui, PhD, performed a prospective study, recruiting all patients who were considered to be at risk for HCC and had temporally related CEUS and MRI exams. In a six-month period from July 2015 to January 2016, 102 patients were enrolled in the study, which is ongoing. Data analysis is still in progress for the initial six-month period, but Wilson shared preliminary results in her talk in Chicago.
Of the 102 patients, 52 (51%) had an MRI report that suggested an indeterminate result. This included 49 patients with an abnormal parenchymal observation; 35 of these had a total of 41 mass-like observations, including 26 mass-like observations that showed arterial phase contrast hyperenhancement but not portal venous-phase washout on MRI.
In addition, 14 patients with an abnormal parenchymal observation had arterial phase hyperenhancement only, without a baseline T1, T2, or DWI abnormality and without contrast washout; these observations were suspected to be arterial portal shunts due to their appearance, Wilson said. The remaining three patients with indeterminate results on MRI had an indeterminate thrombus in the portal vein.
Resolution with CEUS
Of the 26 patients with MR findings of a mass-like area with arterial phase hyperenhancement only, 12 had a nodule on the baseline ultrasound scan that was not seen on MRI. Eleven of the 12 had classic HCC features on CEUS: arterial phase hyperenhancement and weak late contrast washout, she said. The other patient had classic nonhepatocellular carcinoma features on CEUS: arterial phase hyperenhancement and rapid contrast washout.
Five cases are biopsy-proven for HCC, including four of HCC and the one case of nonhepatocellular carcinoma, which was confirmed as cholangiocellular carcinoma (CCC).
"All of these [12 cases] have been treated as cancer," she said.
CEUS can also be an excellent method for resolving cases of suspected arterial portal shunts, according to Wilson.
Among the 14 cases with suspected arterial portal shunts, 13 had completely negative findings on CEUS, with no baseline nodule, hyperenhancement, or washout.
"So this would support that these are correctly identified as arterial portal shunts," she said.
However, CEUS did show a nodule in one case that had classic enhancement features for HCC, Wilson said.
Above, small superficial hypoechoic mass (marked by calipers) in the cirrhotic liver of a 64-year-old man. Below, at 17 seconds after contrast injection, the mass is hypervascular relative to the remainder of the liver and appears brighter on this image. All images courtesy of Dr. Stephanie Wilson.
Above, at one minute and 36 seconds after contrast injection, the mass (marked by calipers) shows very faint reduction in enhancement and washout. Below, at four minutes and 35 seconds after contrast injection, the mass is now showing more marked washout. The arterial phase hyperenhancement and slow washout shown in this CEUS study are classic features of HCC.
CEUS can also differentiate between bland and tumor thrombus. This is very important, as the presence of tumor thrombus significantly changes cancer staging, treatment options, and prognosis, she said. Of the three patients in the study with an indeterminate thrombus in the portal vein, CEUS found that one patient had two bland thrombi and two patients each had a tumor thrombus.
"[CEUS] has been shown to be the most sensitive modality for detecting neovascularity within a tumor thrombus," she said.
Adding CEUS to guidelines
Wilson also hopes that the imminent release of new AASLD guidelines will incorporate CEUS, which had been removed in 2011. In other positive developments, the initial publication in June of the American College of Radiology's Liver Imaging Reporting and Data System (LI-RADS) for CEUS now accompanies the already existing LI-RADS publication for CT and MRI, she said.
"This is a huge advantage for CEUS and will pave the way for CEUS advancement in the U.S. and elsewhere," she said.
*View the original presentation delivered by Dr Stephanie Wilson at the 31st Annual Advances in Contrast Ultrasound Bubble Conference by going to:
Sep 15, 2016
SonoVue Approved in Mexico!
(Website news)
ICUS is pleased to note that the Mexican Federal Commission for Protection Against Sanitary Risk (COFEPRIS) has approved the contrast agent SonoVue in Mexico for use in echocardiography and Doppler ultrasonography. SonoVue is produced by Bracco and will be marketed in Mexico by Justesa Imagen Mexicana, S.A. de C.V.
ICUS applauds this action. We have long advocated for broader acceptance and appropriate use of ultrasound contrast agents, which have strong safety profiles and reduce overall health care costs without exposing patients to ionizing radiation.

ICUS Weekly News Monitor 9-16-2016

1.  American College of Radiology,  Sep 1, 2016,  ACR CEUS LI-RADS 2016 - The ACR announces the official release of CEUS LI-RADS.
2.  International Contrast Ultrasound Society (ICUS),  Sep 9, 2016,  Contrast Ultrasound Identifies Deadly Liver Cancers     (Business Wire)
3.  International Contrast Ultrasound Society (ICUS),  Sep 8, 2016,  CEUS Liver and Kidney  Tests Produce Big Savings in Testing Time and Cost     (Business Wire)
*To view presentations live-streamed from the 31st Annual Advances in Contrast Ultrasound Bubble Conference held in Chicago, 8/9 September 2016, go to:
American College of Radiology
Sep 1, 2016
The ACR announces the official release of CEUS LI-RADS.
ACR CEUS LI-RADS, or CEUS LI-RADS for short, is a standardized system for technique, interpretation, reporting, and data collection for contrast-enhanced ultrasound (CEUS) exams in patients at risk for developing HCC. The system currently includes a lexicon of controlled terminology, schematic illustrations, and a categorization algorithm. A complete illustrative atlas, reporting guidelines, and educational material are in development. CEUS LI-RADS will be updated as experience accrues, as knowledge add technology advance, and in response to user feedback.
ACR CEUS LI-RADS was developed by working group of national and international experts. The group is Chaired by Dr. Yuko Kono, MD, of the University of California, San Diego. Members include radiologists and hepatologists from the United States, Canada, Europe, and Asia. The group was convened in April 2014. Beta versions of the CEUS LI-RADS algorithm were presented at national and international conferences in 2015 and 2016. Feedback was solicited. Based on the feedback and iterative consensus, the working group refined and in 5-21-16 finalized the CEUS LI-RADS algorithm. The algorithm was officially approved by the ACR LI-RADS Steering Committee on 6-24-16 and submitted to the ACR for public release on 6-24-16.
Please click here to view the complete CEUS LI-RADS 2016 Presentation »
International Contrast Ultrasound Society (ICUS)
Sep 9, 2016
Contrast Ultrasound Identifies Deadly Liver Cancers
CHICAGO -- (Business Wire) -- Tiny microbubbles are being used to more effectively identify liver tumors, according to a study described today at the 31st annual Advances in Contrast Ultrasound conference in Chicago.
Patients with hepatocellular carcinoma, the third leading cause of cancer deaths worldwide, were found to benefit from contrast-enhanced ultrasound (CEUS) imaging when MRI imaging was inconclusive, according to Dr. Stephanie Wilson, a professor of medicine at the University of Calgary in Canada and Co-President of the International Contrast Ultrasound Society.   She said that inconclusive MRIs occur frequently.
"This is an exciting option because hepatocellular carcinoma is the most common form of liver cancer, and standard imaging with MRI is often an insufficient option for characterizing the tumor," Dr .Wilson said.
CEUS uses liquid suspensions of tiny gas microbubbles  to improve the clarity and reliability of an ultrasound image without exposing patients to ionizing radiation.  The microbubbles are smaller than red blood cells and, when they are injected into a patient's arm vein, they improve the accuracy of diagnostic ultrasound exams. The microbubbles are expelled from the body within minutes.
David Cosgrove, Emeritus Professor at Imperial and Kings Colleges London, said the findings demonstrate the vast potential benefits of using microbubble ultrasound contrast agents as a safe, convenient and effective diagnostic imaging tool that improves patient care without exposing individuals to ionizing radiation. "CEUS is an excellent modality that can help differentiate benign from malignant tumors," he added.
*View the original presentation delivered by Dr Stephanie Wilson at the 31st Annual Advances in Contrast Ultrasound Bubble Conference by going to:
International Contrast Ultrasound Society (ICUS)
Sep 8, 2016
CEUS Liver and Kidney  Tests Produce Big Savings in Testing Time and Cost
CHICAGO -- (Business Wire) - Contrast-enhanced ultrasound (CEUS) can speed up the diagnosis of patients with liver and kidney diseases, reduce the need for more expensive downstream MR and CT imaging, and reduce overall imaging costs, according to a new study described today at the 31st annual Advances in Ultrasound conference in Chicago.
According to Dr. Edward Grant, a professor of medicine at the University of Southern California Keck School of Medicine, patients with liver and kidney masses identified on routine ultrasound scans were examined with CEUS at Los Angeles County General Hospital.  He and his colleagues determined that the hospital could anticipate a reduction of 339 CT and 53 MRIs annually by using contrast ultrasound tests first - a potential $132,000 cost reduction each year.
CEUS "is comparable to CT and MRI exams in its capacity to characterize liver and kidney lesions, such as hepatocellular carcinoma and hemangiomas," Dr. Grant said. "But what is remarkable is that CEUS results were usually added to the patient chart the same day, with over 72% done within 24 hours."
By comparison, the mean time to diagnosis and study completion was up to 52 days for CT exams and up to 123 days for an MRI, Dr. Grant added.
The study also found that CEUS reduced the need for CT and MRI follow up exams in the liver and kidney.  Dr. Grant noted that "66.7 percent of the CEUS exams were deemed of sufficient quality to not require further evaluation with CT or MRI."
"Ultrasound contrast agents are safe, low cost, and completely radiation-free imaging tools that can improve the clarity and reliability of front-line ultrasound scans of the heart and enhance the ability of routine CEUS scans to characterize tumors in the liver and kidneys.  They avoid unnecessary downstream testing, save lives and lower overall health care costs," according to Dr. Steven Feinstein, Co-President of the International Contrast Ultrasound Society (ICUS), who is an expert in cardiac CEUS and professor of medicine at Rush University Medical Center in Chicago.
He noted that previous studies in cardiac patients showed that CEUS could also cut costs and help avoid downstream testing in those populations.
"This is an outstanding example of patient-centered care, since CEUS provided same day diagnoses and avoided lengthy diagnostic delays associated with CT or MRI,"  according to Dr. Stephanie Wilson, Co-President of ICUS.  Dr. Wilson is an expert in abdominal CEUS and a professor of medicine at the University of Calgary in Canada.
"Coupled with the significant cost savings, CEUS offers an enormous improvement in patient management and care." she added.
Three ultrasound contrast agents, Definity (Lantheus Medical Imaging), Optison (GE Healthcare), and Lumason (Bracco Diagnostics) are available in the United States.  Definity and Optison  are approved by the Food and Drug Administration for cardiac imaging only, while Lumason is approved for both cardiac and liver imaging.
*View the original presentation delivered by Dr Ed Grant at the 31st Annual Advances in Contrast Ultrasound Bubble Conference by going to:

ICUS Weekly News Monitor 8-18-2016

1.  Dove Medical Press,  Aug 12,2016,  Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles      Authors:  Xiaozhou Fan, et al
2.  Science Daily,  Aug 9, 2016,  Researchers immobilize underwater bubbles
Source: American Institute of Physics, Authors: Zoubida Hammadi, et al
Dove Medical Press
Volume 2016:11 Pages 3939—3950
Aug 12,2016
Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles
Authors:  Xiaozhou Fan,1 Yanli Guo,1 Luofu Wang,2 Xingyu Xiong,1 Lianhua Zhu,1 Kejing Fang1
1Department of Ultrasound, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 2Department of Urology, Daping Hospital, Institute of Surgery Research, Third Military Medical University, Chongqing, People’s Republic of China
In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times (P>0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different (P<0.05). In PC-3 xenografts, there were no differences in these four indicators. Fluorescent imaging indicated that targeted nanobubbles had an aggregation ability in C4-2 xenograft tumors. In conclusion, targeted nanobubbles carrying the anti-PSMA A10-3.2 aptamer have a targeted imaging effect in prostate cancer.
Science Daily
Aug 9, 2016
Researchers immobilize underwater bubbles
New technique to 'freeze' newly created microbubbles in their tracks could lead to new applications in medicine and the nuclear industry
Source: American Institute of Physics
Authors: Zoubida Hammadi, Laurent Lapena, Roger Morin, Juan Olives.
Immobilization of a bubble in water by nanoelectrolysis;  Applied Physics Letters, 2016; 109 (6): 064101 DOI: 10.1063/1.4960098
Controlling bubbles is a difficult process and one that many of us experienced in a simplistic form as young children wielding a bubble wand, trying to create bigger bubbles without popping them. A research team in CINaM-CNRS Aix-Marseille Université in France has turned child's play into serious business.
They demonstrated they could immobilize a microbubble created from water electrolysis as if the Archimedes' buoyant force that would normally push it to the surface didn't exist. This new and surprising phenomenon described this week in Applied Physics Letters, from AIP Publishing, could lead to applications in medicine, the nuclear industry or micromanipulation technology.
While bubbles are observed frequently in nature, it is not easy to control their diameter, position or time of formation. Previous work by the French research team explored how to control the hydrogen and oxygen gas bubbles formed by the breakdown of water using electricity. They showed that if one of the electrodes is tip-shaped -- with a curvature radius at its apex ranging from 1 nanometer to 1 micrometer -- and an alternating electric current with defnite values of amplitude and frequency was used, microbubbles could be produced at a single point at the apex of the nanoelectrode.
In the current work, the team has demonstrated a new and surprising phenomenon: the immobilization of a single microbubble in water. After a bubble is produced (at the apex of the nanoelectrode), it is immobilized by rapidly increasing the frequency of the electric current. It is a stable situation: No matter which direction the electrode moves, the bubble remains above and at the same distance from the electrode.
The scientists propose that the hydrogen or oxygen molecules enter the immobilized bubble through the lower surface and exit the bubble through the upper surface. The gas molecules are only produced at a single point at the apex of the nanoelectrode.
The team from CINaM-CNRS worked with researchers in acoustics who use ultrasounds for the detection and the characterization of microbubbles. They needed highly calibrated bubbles and the team proposed producing such bubbles using water electrolysis. The team incorporated a number of new ideas and methods in their approach. "While it is usual to consider that electrolysis is controlled by the electric potential, we show that the fundamental quantity is in fact the electric field which is why we use a tip-shaped electrode with a very small curvature radius at the apex," said Juan Olives, a member of the research team. The use of an alternating current of sufficient frequency then produces "nanoelectrolysis," which is the nanolocalization of the electrolysis reactions at a single point.
The greatest surprise in the findings was that, although nothing seems to move when you observe the experiment, in fact, all is moving in an apparent steady state, Olives said. Hydrogen and oxygen molecules are continually produced at the apex of the nanoelectrode, they move in the solution and in the bubble, they enter and leave the bubble, and there is a convection velocity in the solution and in the bubble. Everything is moving, except the surface of the bubble, Olives said.
Controlling microbubbles is critical to numerous applications in medicine including as ultrasound contrast agents, for breaking up blood clots, and for gas embolotherapy, which is the intentional blocking of an artery to prevent excessive blood loss. Controlling microbubbles is also important in the nuclear industry, where microbubbles in liquid sodium coolant can cause problems.

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