ICUS Weekly News Monitor 7-11-17

Science Daily

Tiny bubbles offer sound solution for drug delivery

Noninvasive approach to drug delivery for next generation brain therapies uses ultrasound and bubbles

June 26, 2017

Source: Acoustical Society of America

Cavitation microstreaming generated by a SonoVue microbubble and marked by fluorescent beads. Under ultrasound exposure, microbubbles can produce streaming flows which may contribute to blood-brain barrier opening and will be investigated directly using our in vitro platform.

Credit: Miles M. Aron, courtesy of BUBBL, University of Oxford, England

Your brain is armored. It lives in a box made of bones with a security system of vessels. These vessels protect the brain and central nervous system from harmful chemicals circulating in the blood. Yet this protection system -- known as the blood-brain barrier -- also prevents delivery of drugs that could help treat patients with brain cancers and brain diseases such as Alzheimer's disease. The heavily guarded brain has long frustrated physicians tending patients in need of brain treatments without surgery.

With recent advances in technology, the blood-brain barrier can now be opened safely, noninvasively and in a targeted manner using ultrasound. One of the newest approaches aiming to advance this research will be presented during Acoustics '17 Boston, the third joint meeting of the Acoustical Society of America and the European Acoustics Association being held June 25-29, in Boston, Massachusetts.

Investigators at the University of Oxford in the United Kingdom, collaborating with colleagues at the University of Twente in the Netherlands, have produced a promising in vitro experimental platform to investigate relationships between the way the blood-brain barrier opens, how long it takes to recover, and the sounds emitted during blood-brain barrier opening. Think of it as a blood-brain barrier on-a-chip using cultured cells rather than animal or human models.

"The key advantage of our system is that it uses three modalities -- involving light, sound, and electrical fields -- to simultaneously monitor acoustic emissions, blood-brain barrier disruption and recovery, and the biological response of blood-brain barrier cells in real-time," said Miles M. Aron at the University of Oxford.

Researchers have tried to open the blood-brain barrier using ultrasound since the 1950s. The breakthrough for safely opening the blood-brain barrier was to use tiny bubbles that interact with the ultrasound field known as "cavitation agents." Several cavitation agents are already approved for enhancing contrast in ultrasound imaging by the U.S. Food and Drug Administration. Cavitation agents work by oscillating rapidly or "singing" when exposed to ultrasound.

"The treatment can be monitored externally by 'listening' to the re-radiated sound from the cavitation agents interacting with the ultrasound field. These acoustic emissions provide information regarding the energy of cavitation within the blood vessels and are already being used to adjust ultrasound parameters in real-time to reduce the likelihood of damaging healthy cells during treatment," Aron said.

The team monitors acoustic emissions and the integrity of the blood-brain barrier in real-time throughout the treatment, an improvement compared to other approaches that generally involve blood-brain barrier assessment only after the treatment is completed, Aron said.

In addition, the team uses fluorescent probes to monitor either changes in the cells during treatment, or mechanical and chemical effects from the cavitation agents as they are exposed to ultrasound in real-time.

"By analyzing multiple sources of data during ultrasound exposure and throughout BBB recovery, we aim to better understand this promising new treatment," Aron said. "With the Oxford Centre for Drug Delivery Devices, OxCD3, we are currently working on a non-invasive method to detect and treat brain metastases before they become deadly. Our in vitro system will play a critical role in the development of this and other next-generation approaches to ultrasound-mediated blood brain barrier opening."

 
 
 
 
 
 

Uro Today

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. Contrast-Enhanced Ultrasound Differentiation Between Low and High-Grade Bladder Urothelial Carcinoma and Correlation With Tumor Microvessel Density.

May 27, 2017

By Suping Guo, Pan Xu, Aiyun Zhou, Gongxian Wang, Weimin Chen, Jinhong Mei, Fan Xiao, Juan Liu, Cheng Zhang

Department of Ultrasonography, First Affiliated Hospital of Nanchang University, Nanchang, China., Department of Urology Surgery, First Affiliated Hospital of Nanchang University, Nanchang, China., Department of Pathology, First Affiliated Hospital of Nanchang University, Nanchang, China.

  1. PubMed http://www.ncbi.nlm.nih.gov/pubmed/28556470

Time-intensity curves (TICs) of contrast-enhanced ultrasound (CEUS) were analyzed retrospectively to differentiate between low-grade and high-grade bladder urothelial carcinoma, and to investigate correlation with tumor microvessel density (MVD).

The data of 105 patients with pathologically confirmed bladder urothelial carcinoma (55 low-grade and 50 high-grade) were reviewed. Lesions were examined before surgery using conventional ultrasound and CEUS with TIC analysis. The TIC parameters time from peak to one-half the signal intensity (TPH) and the corresponding descending slope (DS) of the low-grade and high-grade groups were compared, and receiver operating characteristic curves constructed. The MVDs of the resectioned tissue specimens were quantified via immunohistochemistry for CD34.

Based on conventional ultrasound, the low-grade and high-grade groups were similar in tumor shape, number, topography, internal echo, height, width, and vascularity. The TPH of the high-grade group was significantly longer than that of the low-grade group, and the DS was lower. The cutoff points of TPH and DS for differentiating low-grade and high-grade bladder urothelial carcinoma were 48.06 seconds and 0.15 dB/seconds, respectively (area under the receiver operating characteristic curve = 0.79 for both). The mean MVDs per high-power field of the low-grade and high-grade groups were 41.39 16.65 and 51.03 20.16, respectively (P = .009). The TPH correlated linearly with MVD (P < .01), as did the DS (P < .01).

Contrast-enhanced ultrasound can be used to differentiate low from high-grade bladder urothelial carcinoma. The TIC parameters of CEUS reflect the MVD of bladder urothelial tumors and may be helpful for evaluating tumor angiogenesis, with implications for clinical diagnosis, treatment, and prognosis.

ICUS Weekly News Monitor 6-29-17

European Medicines Agency

Committee for Medicinal Products for Human Use (CHMP)

Summary of opinion (post authorisation)

22 June 2017

EMA/CHMP/347620/2017

SonoVue (sulphur hexafluoride)

On 22 June 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for the medicinal product SonoVue. The marketing authorisation holder for this medicinal product is Bracco International B.V.

The CHMP adopted a new indication associated with a new route of administration for intravesical use as follows:

“Ultrasonography of excretory urinary tract

SonoVue is indicated for use in ultrasonography of the excretory tract in paediatric patients from newborn to 18 years to detect vesicoureteral reflux. For the limitation in the interpretation of a negative urosonography, see section 4.4 and 5.1.”

For information, the full indications for SonoVue will be as follows:

Intravenous use:

“This medicinal product is for diagnostic use only.

SonoVue is for use with ultrasound imaging to enhance the echogenicity of the blood, or of fluids in the urinary tract which results in an improved signal to noise ratio.

SonoVue should only be used in patients where study without contrast enhancement is inconclusive.

Echocardiography

SonoVue is a transpulmonary echocardiographic contrast agent for use in adult patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers and enhance left ventricular endocardial border delineation.

Doppler of macrovasculature

SonoVue increases the accuracy in detection or exclusion of abnormalities in cerebral arteries and extracranial carotid or peripheral arteries in adult patients by improving the Doppler signal to noise ratio.

SonoVue increases the quality of the Doppler flow image and the duration of clinically-useful signal enhancement in portal vein assessment in adult patients.

Doppler of microvasculature

SonoVue improves display of the vascularity of liver and breast lesions during Doppler sonography in adult patients leading to more specific lesion characterisation.

Intravesical use:

Ultrasonography of excretory urinary tract

SonoVue is indicated for use in ultrasonography of the excretory tract in paediatric patients from newborn to 18 years to detect vesicoureteral reflux. For the limitation in the interpretation of a negative urosonography, see section 4.4 and 5.1.”

Detailed recommendations for the use of this product will be described in the updated summary of product characteristics (SmPC), which will be published in the revised European public assessment report (EPAR), and will be available in all official European Union languages after a decision on this change to the marketing authorisation has been granted by the European Commission.

 
 
 
 
 
 

Health Imaging

Brain ultrasound during tumor surgery matches pre-op MRI guidance and then some

Jun 05, 2017

By Dave Pearson

Italian researchers have shown how surgeons resecting glioblastomas, the most common and aggressive brain tumors, can use contrast-enhanced ultrasound to guide their view of tumor location, morphologic features, margins and dimensions in real time and for the duration of the entire surgery.

Radiology has published their findings online, ahead of print.

Francesco Prada, MD, of the Carlo Besta Neurological Institute in Milan and colleagues reviewed the cases of 10 patients who had glioblastoma multiforme and underwent tumor resection surgery with fusion guidance, which allowed the team to combine and then compare intraoperative ultrasound imaging against gadolinium-enhanced T1-weighted MR images obtained preoperatively.

The researchers found that, in all cases, the two sets of images were superimposable with correct scaling and a positional discrepancy of less than two millimeters.

In one patient, the imaging did differ meaningfully between the two modalities: The ultrasound showed the full bulk of the tumor while the MRI supplied peripheral contrast enhancement.

The authors conclude that intraoperative contrast-enhanced ultrasound enables surgeons to access, in real time, key tumor information that compares favorably with targeting information from preoperative gadolinium MRI—and therefore “can be used as an intraoperative guidance tool.”

They note that, compared with neuro navigation guided by static pre-op images, the ultrasound technique is “dynamic, economic and repeatable” throughout the surgery.

“Future studies should investigate the role of intraoperative ultrasound in the evaluation of residual tumor, usually a great challenge for neurosurgeons,” Prada et al. write. “The synergistic use of contrast-enhanced ultrasound with navigation systems and other imaging modalities, such as intraoperative MR imaging, fluorescence imaging and optical imaging, might help maximize resection of glioblastoma multiforme, thereby minimizing the risks for our patients.”

ICUS Weekly News Monitor 5-26-17

ICUS Weekly News Monitor

26 May 2017 - 9 am Eastern

 
 
 
  1. 1.Health Imaging, May 22, 2017, High-end ultrasound with contrast superior for managing abdominal aneurysms By Dave Pearson
  2. 2.Aunt Minnie, May 16, 2017, Contrast US helps assess breast cancer treatment response By Erik L. Ridley

Health Imaging

High-end ultrasound with contrast superior for managing abdominal aneurysms

May 22, 2017

By Dave Pearson

Patients with abdominal aortic aneurysms are better served by contrast-enhanced ultrasound (CEUS) than by color Doppler for follow-up care after receiving endovascular aortic repair (EVAR), according to a study published online May 18 in Clinical Hemorheology and Microcirculation.

Researchers from Ludwig-Maximilian University of Munich in Germany and Sapienza University of Rome in Italy reviewed the cases of 41 patients. Most of them, 38 (93 percent) were male to correspond to the incidence of the often-asymptomatic problem in the population, and ages ranged from 58 to 100.

Using CEUS as the gold standard, the team found endoleaks could be detected using a high-end system in 28 patients (68 percent) with 13 patients not showing an endoleak after EVAR.

Color Doppler showed a sensitivity of 32.1 percent, a specificity of 92.3 percent, a positive predictive value of 90 percent and a negative predictive value of 38.7 percent compared to CEUS being the gold standard.

"CEUS after EVAR using a modern high-end ultrasound system is a fast and cost-effective imaging modality for the detection and follow-up of endoleaks with superior benefits compared to color Doppler," the authors conclude. "CEUS remains the initial standard-of-care examination for follow-up."

 
 
 
 
 
 

Aunt Minnie

Contrast US helps assess breast cancer treatment response

By Erik L. Ridley

May 16, 2017

Yielding comparable tumor measurements and accuracy, contrast-enhanced ultrasound (CEUS) can be a viable alternative to contrast-enhanced MRI for assessing breast cancer response to neoadjuvant chemotherapy, according to research published in the May issue of the Journal of Ultrasound in Medicine.

In a pilot study, a research team led by Dr. Sandy Lee of the University of Southern California's Keck School of Medicine found that CEUS measurements of tumor size correlated well with MRI, and both modalities produced the same accuracy for predicting how the tumors were responding to therapy. What's more, CEUS tumor measurements correlated better with pathologic tumor size than did MRI tumor measurements.

"CEUS may be a good alternative exam when MRI cannot be performed in the neoadjuvant chemotherapy setting," Lee toldAuntMinnie.com.

An alternative to MRI?

MRI is commonly used to evaluate treatment response in breast cancer patients undergoing neoadjuvant chemotherapy. Although MRI is a great tool for this job, the modality can't be used in certain patients, such as those with renal disease, a pacemaker, or an allergy to gadolinium contrast agents, according to Lee

The researchers sought to investigate the use of contrast ultrasound because it's easy to perform, has no radiation, and can be used in patients with contraindications for MRI. In addition, microbubble contrast agents have a relatively safe profile, Lee said.

In the prospective pilot study, CEUS and contrast-enhanced MRI were performed on 30 patients with invasive breast cancer lesions larger than 2 cm. Of the 30 patients, 29 had invasive ductal carcinoma and one had metaplastic carcinoma. Both imaging studies were performed before neoadjuvant chemotherapy and afterward prior to surgery (J Ultrasound Med, May 2017, Vol. 36:5, pp. 901-911).

All contrast ultrasound exams were performed using the Definity ultrasound contrast agent (Lantheus Medical Imaging) on an Epiq ultrasound system (Philips Healthcare) with a 12-MHz linear transducer or a 9-MHz curvilinear transducer, depending on the tumor size and depth. Postprocessing analysis of the CEUS data was performed at a later time using Qlab software (Philips). Blinded to the MRI results and surgical data, a dedicated breast imager with more than 15 years of experience compiled the tumor measurements.

When possible, the MRI and CEUS studies were performed on the same day. However, sometimes the exams were performed on different days due to patient scheduling limitations, according to the researchers.

Patients received dynamic contrast-enhanced MRI using a gadolinium-based contrast agent and either an Excite HD 1.5-tesla scanner (GE Healthcare) or a Symphony 1.5-tesla system (Siemens Healthineers) with a dedicated breast coil. The MRI protocol included axial and coronal short-tau inversion recovery images, a precontrast T1-weighted acquisition, and additional postcontrast T1-weighted acquisitions obtained five to seven minutes after contrast administration.

Postprocessing was performed with CADstream software (Merge Healthcare) to generate subtractions and dynamic time/signal intensity curves. Two dedicated breast imagers -- blinded to the CEUS and surgical data -- then calculated tumor measurements.

The researchers compared the CEUS and MRI results with the pathologic tissue specimens that were obtained from definitive surgical treatment, which is usually performed at their institution four to six weeks after the completion of neoadjuvant chemotherapy. Spearman coefficients (r values) were calculated to quantify the correlation between imaging and pathologic findings. The higher the r value, the higher the level of agreement.

Strong agreement

At baseline prior to treatment, contrast ultrasound and MRI both yielded a 3.1-cm median tumor size; the modalities had strong correlation (r = 0.88, p < 0.001) in tumor size measurements. The researchers noted that one patient had a deep tumor that did not enhance on baseline CEUS, but it was visible on conventional ultrasound and displayed subthreshold enhancement on MRI.

"The deep location and low vascularity of the tumor likely contributed to its lack of enhancement on the contrast-enhanced US scan," the authors wrote.

After neoadjuvant chemotherapy, agreement on tumor size dropped (r = 0.66, p = 0.004) but was still comparable. The researchers observed, however, that in a subset of 15 patients who had both CEUS and MRI studies that could be compared with tumor size at surgery, CEUS (r = 0.75, p < 0.001) correlated better with tumor size at surgery than MRI did (r = 0.42, p = 0.095).

"Contrast-enhanced US findings correlate well with MRI findings and may be even more accurate in predicting residual tumor size after [neoadjuvant chemotherapy]," the authors wrote.

In addition, contrast ultrasound and MRI were equally effective in predicting pathologic response to treatment. The modalities both accurately predicted three (75%) of the four patients who had a complete pathologic response, and eight (72.7%) of the 11 patients with a noncomplete pathological response.

While CEUS performed well in the study, the researchers noted that MRI has its own advantages.

"It can evaluate the remainder of the same breast and the contralateral breast at the same time, while CEUS is more limited to evaluating the known tumor," Lee said.

CEUS may also not be a good exam for evaluating small or deep tumors in the breast, she said.

Future work

The researchers acknowledged that their study was limited by the small number of patients. Studies with a larger patient cohort are now needed to further investigate the use of CEUS in the neoadjuvant chemotherapy setting, according to Lee.

The group is also exploring the possibility of using CEUS to determine when ultrasound-guided breast biopsies may be necessary, she said.

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