ICUS Weekly News Monitor 4-2-2015

1.  The Scientist,  Apr 1, 2015,  Bursting Cancer’s Bubble; Scientists make oxygen-filled microbubbles designed to increase tumor sensitivity to radiation     By Ruth Williams
2.  Medical Physics Web,  Mar 19, 2015,  ECR 2015: Advanced ultrasound applications
By Cynthia E. Keen
The Scientist
Apr 1, 2015
Bursting Cancer’s Bubble
Scientists make oxygen-filled microbubbles designed to increase tumor sensitivity to radiation
By Ruth Williams
The rapid growth and high metabolic activity of a tumor can cause its cells to become hypoxic due to an insufficient blood supply. Somewhat counterintuitively, however, these sickly, oxygen-starved cells are actually harder to kill with radiation treatment than healthy tissue. Researchers are thus investigating ways to boost oxygen levels in tumors so the cells can be nuked more effectively.
One idea has been to inject tiny oxygen-filled bubbles into a patient’s bloodstream. The bubbles would then enter the tumor—where blood vessel walls tend to be leaky—and burst to locally release the oxygen, explains John Eisenbrey of Thomas Jefferson University in Philadelphia.
Such bubble-based treatment is not as strange as it might sound. Indeed, the ultrasound community has been using gas-filled microbubbles as a contrast agent to improve imaging for some time. And local rupturing of these bubbles by high-intensity ultrasound is being investigated as a drug-delivery method.
With ultrasound, “you can see where these [microbubbles] go and then you can disrupt them at the site you want,” explains Steve Feinstein of Rush University Medical Center in Chicago.
Eisenbrey and others are thus co-opting the technique for oxygen delivery to tumors. In a recent experiment on two mice with breast tumors, Eisenbrey showed that oxygen-containing microbubbles were visible in the tumors and, upon rupture, were capable of increasing detectable oxygen by up to 30 mmHg. That’s a significant amount, explains Eisenbrey, because “if you can just deliver between 10 and 15 mmHg of oxygen to cells, you can make them twice as sensitive to radiation.” Eisenbrey’s next step, he says, will be to see whether the oxygen boost does indeed improve the effectiveness of radiation therapy. (See below:  Int J Pharm, 478:361-67, 2015)
International Journal of Pharmaceutics
Volume 478, Issue 1, 15 January 2015, Pages 361–367
Jan 15, 2015
Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue
Authors: John R. Eisenbrey; Lorenzo Albala; Michael R. Kramer; Nick Daroshefski; David Brown; Ji-Bin Liu; Maria Stanczak; Patrick O’Kane; Flemming Forsberg; Margaret A. Wheatley
Radiation therapy is frequently used in the treatment of malignancies, but tumors are often more resistant than the surrounding normal tissue to radiation effects, because the tumor microenvironment is hypoxic. This manuscript details the fabrication and characterization of an ultrasound-sensitive, injectable oxygen microbubble platform (SE61O2) for overcoming tumor hypoxia. SE61O2 was fabricated by first sonicating a mixture of Span 60 and water-soluble vitamin E purged with perfluorocarbon gas. SE61O2 microbubbles were separated from the foam by flotation, then freeze dried under vacuum to remove all perfluorocarbon, and reconstituted with oxygen. Visually, SE61O2 microbubbles were smooth, spherical, with an average diameter of 3.1 μm and were reconstituted to a concentration of 6.5 E7 microbubbles/ml. Oxygen-filled SE61O2 provides 16.9 ± 1.0 dB of enhancement at a dose of 880 μl/l (5.7 E7 microbubbles/l) with a half-life under insonation of approximately 15 min. In in vitro release experiments, 2 ml of SE61O2 (1.3 E8 microbubbles) triggered with ultrasound was found to elevate oxygen partial pressures of 100 ml of degassed saline 13.8 mmHg more than untriggered bubbles and 20.6 mmHg more than ultrasound triggered nitrogen-filled bubbles. In preliminary in vivo delivery experiments, triggered SE61O2 resulted in a 30.4 mmHg and 27.4 mmHg increase in oxygen partial pressures in two breast tumor mouse xenografts.
Graphical abstract
O2, oxygen;
pO2, partial pressure of oxygen;
SE6102, experimental oxygen microbubble consisting of a Span60 and vitamin E shell;
UCA, ultrasound contrast agents
Medical Physics Web
Mar 19, 2015
ECR 2015: Advanced ultrasound applications
By Cynthia E. Keen
An ultrasound exam may not immediately be thought of as sophisticated as advanced imaging technologies like CT, MRI or PET. But at the recent European Congress of Radiology (ECR 2015) in Vienna, Austria, a special focus session looking at new sonographic techniques impressed the attendees.
Multi-parametric imaging
Jean-Michel Correas, from Necker University Hospital in Paris, France, discussed in depth how multi-parametric ultrasound imaging – which combines techniques associated with B-mode anatomic imaging, vascular imaging, functional ultrasound imaging, tissue elastography and 3D/4D fusion imaging – improves diagnostic performance. The approach can also provide better guidance for interventional procedures such as biopsy and tumour ablation.
Multi-parametric ultrasound imaging (click to zoom)
Multi-parametric ultrasound integrates anatomical information provided by B-mode imaging, which Correas noted considerably improved over recent years, with information about vascularity inside the target tissue. "We are used to evaluating the vascularity of an organ with colour and power Doppler," he said. "But now new micro-Doppler techniques are becoming available. These include ultrafast Doppler, ultrasensitive Doppler and superb microvascular imaging, which employs an advanced Doppler algorithm and does not require contrast enhancement. We should also not forget that contrast-enhanced ultrasound is a good vascular imaging modality."
The third step in multi-parametric ultrasound imaging is incorporating information about the stiffness of the tissue or lesion being characterized. This can be achieved using strain elastography, which is based on the analysis of tissue deformation. During a prostate exam, for example, the transrectal transducer is used as a compression device to apply external stress on the rectal wall. Tissue stiffness is estimated by visualizing the differences in strain between adjacent regions, but this approach does not provide quantitative information.
Another approach is shear-wave elastography (SWE), which is based on the measurement of shear wave propagating through tissue. SWE combines the use of a shear wave that provides stiffness information and an ultrasonic wave that provides high spatial information. It enables local measurements of prostate stiffness with true quantitative values. Due to its high negative predictive values, SWE can increase positive predictive biopsy rates, and help ensure that few cancers will be missed.
When vascular imaging, B-mode anatomical imaging and elastography are combined with 3D/4D approaches and fusion imaging, detection and characterization of suspicious lesions are improved further. "These should also be incorporated with functional ultrasound imaging, including perfusion, parametric and molecular imaging," Correas added. He noted that it should be possible to integrate multiparametric information, for example from B-mode imaging, colour flow imaging, micro-Doppler and SWE, and use contrast only when there is a high suspicion of a lesion.
Correas urged ECR attendees to continue to promote education regarding these advanced ultrasound applications. "We are getting more and more tools for improving diagnoses, but the major limitation is how we can share the capabilities needed to perform these exams and use these tools in the most adequate scenarios, because it takes time to do SWE and micro-Doppler. We need to develop teaching programmes about how to integrate these different techniques to improve diagnoses."
Correas concluded by saying that at the start of his radiology career, colleagues said that colour Doppler would only be used by highly academic teaching centres and would never reach the level of being used in routine practice. The same may be said now about state-of-the-art ultrasound technologies, but education and training are required to integrate these into routine clinical use.
Standardizing and validating new techniques
Establishing standards of measurement and clinical validation is one step in this process. Nathalie Lassau of Gustave Roussy in France has been working to validate how dynamic contrast-enhanced ultrasound (DCE-US) can be effectively used to predict the outcomes of anti-angiogenic therapy for solid tumours.
DCE-US enables a quantitative assessment of solid tumour perfusion using a mathematical model to analyse raw linear ultrasound data, and provides an earlier evaluation of tumour response than can be achieved with CT and MRI. In her presentation, Lassau explained the necessity of conducting preclinical, monocentric and, most importantly, multicentric studies to achieve the best level of validation.
"The problem for functional imaging is standardization," Lassau explained. "There is no consensus about the parameters or the timing for the early evaluation of anti-angiogenic drugs. With DCE-US, we are able to analyse the blood volume, the blood flow and the mean transit time."
DCE-US displays the enhancement of a lesion with a high frame-rate after bolus contrast administration, by comparing profiles between normal and abnormal tissue. Quantification of DCE-US is not only useful to quantify tumour enhancement, but also limits intra- and inter-observer variability.
Lassau described the process that she and her colleagues used to develop standardized techniques. These ultimately culminated in use for a large French multicentre clinical trial that proved a validated criterion – the area under the time-intensity curve – to predict tumour progression. This led to its adoption in EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) guidelines for use of DCE-US to assess response to biologic therapy in metastatic gastrointestinal tumours.
"More multicentric studies are needed," she said, turning to her co-presenters. "It is your turn now."

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