New Developments in Ultrasound Imaging - SD

Introduction

I am Dr. Barry Goldberg, director of the Jefferson Ultrasound Research in Education Institute here in Philadelphia, Thomas Jefferson University.

I'm very excited about doing this lecture. Many people ask me about the future directions of ultrasound and while I've started doing ultrasound back in the mid sixties, I've seen many advances, but I can really, honestly tell you that the advances that are on the horizon have just started to come on board and will be coming on board, will really have the potential to revolutionize ultrasound as we know it today.

What I want to talk about are some of the new developments in ultrasound imaging, and I'm gonna divide it into several areas, one in diagnosis. And we're gonna be looking at contrast agents at elastography at computer assisted diagnosis, and then therapy at therapeutic contrast agents, ultrasound guided tumor therapy and monitoring treatment effectiveness.

Diagnosis

Contrast Agents

Let's just try to understand what I mean when we talk about microbubble based ultrasound contrast. Research has been going on for more than a decade and a half with researchers and institutions and in pharmaceutical companies who have been able to produce a variety of ultrasound contrast agents in which there are bubbles of gas, often perfluorocarbons, at least at this point, that can be coated in a variety of different ways to keep the bubbles in solution and small enough, smaller or equal to the size of red blood cells so that they can pass through the capillary system.

Now each bubble is at least a thousand more times reflective than a single red blood cell. So it's a very effective method of identifying smaller and smaller vessels.

Here is an example, where we injected in an animal model into a vein, and we're looking at the kidney. And I think you can clearly see the contrast filling the smaller vessels, the brighter areas like here, and here obviously are the bigger vessels where there's a greater concentration of contrast.

So one can imagine you can use conscience very simply for profusion. If there are areas of infarction, whether they're within the kidney or spleen or elsewhere, you should be able to see the difference quite readily with ultrasound contrast.

Now, in addition to be able to see vessels with contrast in two dimensions, there is a big advantage to see it in three dimensions as we see here, because in three dimensions we can really follow vessels. Remember, vessels are not always in one plane. And so this really is where we would like to go in the future. For ultrasound contrast 3D ultrasound imaging.

Now, ultrasound contrast is being used around the world, not so much here in the United States because it hasn't yet been approved for non-cardiac use. But we're using it to detect small lesions, to improve differential diagnosis, to obtain hemodynamic information, to show tissue profusion status and to guide interventional procedures.

And here we see two examples of a benign lesion, a fibro nodule hyperplasia, and look at the difference in the vessels when compared to the more irregular jumbo vessels with a cancer cellular carcinoma.

Here are some dynamic images, real time contrast, where we see very high vascularity within the pat cellular carcinoma and here, where over time what looks like a normal liver eventually fills with contrast. And now you're seeing many, many dark areas here and here and here where there is no contrast. And these areas represent areas of tumor metastasis filling up the entire liver.

And here I can just demonstrate running through this in real time. You can see with a primary carcinoma you tend to get immediate filling on the arterial phase. And then on the lay phase, the area remains becomes dark. And here also on metastasis, which don't have as much blood flow, we can really identify the area of interest.

And here's an example of three dimensional ultrasound contrast showing normal vessels, and then a jumbo vessels right over here where it was the tumor.

Lympho Sonography

Now what else can we do? We're doing research and hopefully soon we'll have human experience in lympho sonography where we're working with animals to look at the lymphatic channels and to detect sentinel lymph nodes.

And so here is a contrast within a lymphatic channel going to a lymph node and normal lymph nodes will tend to fill with the contrast and stay within those nodes for literally hours. And you don't have to inject the lymphatic channel, you just have to inject wherever there are lymphatics, and in this case, around the tumor, in this case a melanoma.

And so here we can see a correlation between a blue dye injection. You can see the very fine lymphatic channels, which we can easily demonstrate here on ultrasound and finding a relatively normal send on lymph node. Over here. Right now we're using nuclear scanning or blue dye. We really can't easily define the node non-invasively, but with ultrasound, we will be able to.

Now, what happens when a node fills, if it's normal, as we see here, and we've seen nodes even as small as two to three millimeters nail, it fills uniformly. But if there is tumor present, the tumor destroys or what displaces the normal lymphatic tissue. And the contrast, wherever it's white, the contrast is being ized by the macrophages and the normal lymphatic tissue. And so we can easily see any significant tumor and we were able to correlate that.

So here is a whole node that we're demonstrating here filled with tumor except for the white area, which is normal. We see the pathologic correlation, the same thing here, with minimal tumor, you can see the dark area and the normal node over here.

Now we are also finding new things, and that's what's exciting about doing research. We find that in cases that are in the upper chest and lower neck, sometimes the contrast goes right into the lymphatic channels, the bypasses, lymph nodes, and goes right into the thoracic duct. Of course, this is not good for the patient. This will lead to diffuse metastasis throughout the body very early in the stage of a tumor. And here we're actually able to demonstrate that. We can see the lymphatic channel over here and filling the main duct and going into the vein over here.

So you can imagine the tumor cells flowing, bypassing, and not being trapped in the lymph nodes. In this case, this is in about three to 5% of the cases in our animal studies.

Elastography

Now, what else are we looking at? Well, there's a lot of excitement now in elastography, and that's based on the property of tissue structure, the strain modulus and essentially tumors that are harder and tumors that are softer can be differentiated. And we can identify in this case areas that are more firm and areas that are not as firm compared to just imaging with standard ultrasound.

Although the instrument uses that are used are the same, the way we look at the information is different. And that's been made possible by increased power of the instruments, the computers.

A lot of exciting work is being done in the breast and the elastography where we appear to be able to see differences in a what tumor, for instance, in which the area of rigidity appears to be often larger than the actual tumor. And one can imagine the tumor is spreading into tissues, making them more rigid. Whereas benign lesions elastography tend not to be as extensive in terms of their hardness. And so we're excited about that potential.

There are a number of manufacturers. Here's another example in color. A benign tumor would tend to have a more greenish to reddish color. Being softer, where is a blue tumor here would be harder and helps us to differentiate benign from malignant.

Computer Assisted Diagnosis

What else is happening? Well, we're getting a lot of information. We're getting contrast. We're getting graphy, we're getting 3D. And so there are a number of researchers working on computed assisted diagnosis. And it's sort of putting together not only ultrasound images together, but mammography, MRI, CT ultrasound, and then helping the clinician to improve their diagnosis so the person's reading it will be able to get additional information and be able to at least some of the early results improve their ability to make diagnoses.

Another area is automated ultrasound. And while people have looked at this over many decades, the equipment has improved. There's higher resolution, there's some more simplified ways of acquiring information. And one day we hope to have an automated machine, perhaps similar to ct. And mr.

Therapy

Ultrasound Guided Therapy

Well, we're looking at ultrasound guided therapy, and people are using radiofrequency ablation, cryotherapy chemo modernization, high intensity focused ultrasound, and even developing ultrasound contrast agents that can treat the tumors. And with ultrasound guided therapy, we can actually see the tumor. We can demonstrate the placement of the needle in the tumor, and then look at the effectiveness of treatment, both immediately, prior to localization and then after to see how effective it is.

So for instance, in this case here where liver metastasis was treated with chemo embolization, we actually see a pre contrast and post contrast, and we see this tumor. The central part is necrotic, although notice there is a peripheral rim of activity. And in this tumor, only small areas of infarction or the effects of the chemoembolization were identified.

And so as you look here on the real time, you'll be able to see the contrast entering in the arterial phase filling those areas that are still viable, and of course, lack of filling of contrast in those that have become necrotic.

Here's another example. Looking at the effectiveness in three dimensional ultrasound of the past. So of the carcinoma where we see the tumor here, and then where the tumor was, you'll see there's a hole there. So in this case, the treatment was very effective really destroying the tumor. And of course, we're getting no contrast in the area at real time guidance.

There's a lot of work going on and be able to guide the biopsy or treatment needle to the area of interest. And here we're doing it in three dimensional ultrasound, looking at the bright area, and we're able then to focus and make sure we're exactly in the area of interest.

We're also doing work as being done in many places around the world, looking at the effectiveness of angiogenesis, of course. And what we're talking about is how good are drugs and anti-angiogenesis tumors. Tumors will tend to generate more blood flow. And in this case here we're seeing a very superficial tumor here. Notice there has been some effective treatment with lack of flow, whereas in this area here, as we'll see, there in fact is still evidence of tumor vessels.

So again, we're at the beginning of using ultrasound to see the effectiveness of a variety of agents in treating tumors.

Therapeutic Contrast Agents

Now, this is an example of what's being developed for using contrast, enhanced detection of tumor and using microbubbles that have things placed on 'em. Ligands, toxic agents that can attach two vessels attached to tumors and be effective in treating non-invasively a variety of tumors in regions where there's angiogenesis going on, and we see the bubbles there within the vessel here.

And we can then turn the energy up and burst the bubbles and hopefully cause positive effects.

Here is an example of an agent, targeted agent, containing toxic agents. After intravenous injection, the target microbus are attaching to a tumor. We use sound energy, which you see is rupturing the bubbles and forcing the agent into the tumor in this case, resulting in the area of the necrosis.

So these are under development, and we'll be seeing more of this in the future.

Monitoring Treatment Effectiveness

So in the future? Well, we're going to definitely see advances in technology and that will expand both our clinical utilization in both diagnosis and therapy. And I think showed you some examples of advances in diagnosis. In contrast, agents in the elastography in computer assisted diagnosis and in therapeutic ultrasound, the beginnings of using contrast agents with a variety of therapies and using ultrasound to guide to into tumors for treatment and monitoring treatment effectiveness.

A Day in the Future with Ultrasound

Now, what will a day in the future look like? Let's take a look. You'll get up maybe a patient in our home at AM using a very small ultrasound machine built into their TV or computer. They taken a shower, they thought they felt a b breast mass. They use a small ultrasound to see that they'll call their physician. The physician over the line will look at the image and an appointment was made. It was suspicious for a mammogram at eight 30.

The patient is in the office of the mammographer, and the ultrasound demonstrates a mass, which is confirmed by a computer assisted diagnosis and elastography. And at AM as we see her here in the lower image, the tumor is seen to be very vascular. And if we can look at that again, let's go backwards. We'll be able to see is there's no contrast. When we inject it, it begins to fill. If this were a small cyst, which initially it looked like 'cause it had no internal echoes, but in fact this is very vascular tumor. So although it's small, less than a centimeter, we're able to make the diagnosis.

And then at AM we did an ultrasound guided biopsy and electronically looking at the cells. And then the specimen was removed. We used an ultrasound microscope, a very high frequency ultrasound to confirm it was malignant at 1230 the same day.

The tumor was staged by using lipo sonography to evaluate the tumor sentinel nodes. And I think here you can see the lymphatic channels. And in fact, this individual had more than one sentinel node. In this case, the nodes were normal, which means there was no significant tumor. And so we could do a limited amount of surgery.

So at one 30 a PET CT scan was done and showed no evidence of distant metastasis. Well by two 30, a video conference between the various physicians seen by the patient, the diagnostician therapist was conducted and it was decided to destroy the tumor using a non-invasive ultrasound. That's high intensity focused ultrasound, which was formed since there was no evidence of this metastasis, no evidence of metastasis to the nodes.

And so by three 30, using high intensity focus ultrasound to destroy the tumor under MRI guidance, the study was completed by four 30. Contrast enhanced ultrasound elastography was performed and demonstrated no evidence of residual with tumor. And by five 30, the patient was discharged with instructions from her physician that she can return to normal activities by the next morning. And she's scheduled to have a follow-up contrast enhanced ultrasound in six months.

Well, this can give you some idea where we could go in the future with these advances that are occurring.

Conclusion

So in conclusion, the future, there will be continued advances in technology, which in turn will expand the utilization of ultrasound. However, the most advanced medical technology is useless without knowledgeable physicians and other healthcare providers that know how to use it. The best healthcare providers cannot work to the fullest capacity without the appropriate medical technology. And finally, the combination of technology and knowledge is greater than the some or the parts.

So that's something I think we all realize, that when there are advances, there are two parts, the technology and the knowledge, and we as physicians must supply that knowledge. We have aids, we have computer assisted diagnosis, we have better equipment, but also we must know how to use that equipment and must know how to interpret.

Thank you.

Very good.