I would like to thank Dr. Sporn and the organizing committee once again for the opportunity to be here and to participate in this very exciting meeting. I cannot claim to know Spanish or Portuguese or any of the other languages here, but I could walk through the poster area and see the quality of work done and the interest that all the investigators had in doing this work. This work is very important because it means that Nuclear Medicine in Latin America is very vital and will prosper in the coming years.

Dr. Sporn gave me the title of "Balance" for this lecture. I think as we look at life in general, that what he was referring to is that we have the component of life where we work, we have the component of life where we play, and we have the component of life where we are enriched by the thoughts of others and their creativity.

In terms of work, just in this meeting alone, there is at least a hundred hours of research work involved on the part of the investigator and their colleagues to gather the data, do the experiments, bring the work together and be able to write this up in a way that expresses the effort. At this ALASBIMM, there were 303 abstracts presented. If one says that each one requires 100 hours of work, this is 30,000 hours of work on the part of the people who sat in these halls and presented their work. The meeting planning represented an effort of 2 years by the organizers who met to put together the program that we have all experienced.

At these sessions we discussed most of the things that we can do in the current state of Nuclear Medicine, but life goes on and we have to look at what we will be doing tomorrow.

One definition of insanity is to keep doing the same thing and expect a different outcome. I do not believe that we are insane, I do believe that we must grow. To grow we cannot do the same thing; we have to look at what we will be doing that is somewhat different. There are some facts involved in this. One is that nuclear medicine procedures have been growing at about 5% per year. This is a much smaller fraction than all of the other imaging procedures. A goal that we should have is to increase the nuclear medicine procedures we are doing by more than 10% per year by the year 2005. In contemplating what to do to bring about that rate of growth, I came across this quote by George Bernard Shaw where he said "to be in hell is to drift, to be in heaven is to steer". (Fig 1)

I view this as indicating that we should take command of our future: we must decide where we are going and what we will be doing.

If one looks at clinical imaging today it is very likely that with the explosion in molecular biology that disease categories are going to be expanded. There will be evaluations of patients based on the expression of specific receptors. For example today we use estrogen receptors in breast cancer and now we are just beginning to use the expression of P53 in colon cancer. Soon we may be able to evaluate receptors that might be useful to identify the probability of re-stenosis. Therapy is going to be specifically tailored, for example, to reduce the cost of cancer diagnosis and treatment. Currently, this is an area where billions of dollars are being spent each year to evaluate patients and to treat them. Some of these treatments are unfortunately very ineffective. It is important to determine whether tumor therapy has been successful after a single dose rather than wait for a full course of treatment. After a single dose, we could then change things if this treatment is not working. Similarly, in coronary disease we have to look at the ability to distinguish between stable lesions and unstable lesions and to only treat the unstable lesions. There will be a number of imaging studies, high-profiled imaging studies, and research studies. Dr. Henry Wagner covered some of these research studies in his lecture, but these will not necessarily be used clinically. Clinical imaging is going to be focused on decision-making: we are going to look at key cell processes such as the upregulation of glycolysis in tumor cells where the FDG signal increases by up to 40 times in the tumor, compared to normal. Here are just 3 different images of the same area of the same patient imaged on a coincidence imaging system: a PET system, without attenuation correction and a PET system with attenuation correction. I think you can see the differences in the ability to distinguish this particular tumor. Resolution is really going to be necessary. I personally believe that coincidence systems will eventually evolve to this level of resolution. This kind of information is going to be critical to plan the therapy and determine the effectiveness of therapy again with the concept of defining the efficacy of therapy after a single treatment. In that fashion, if treatment is ineffective, it will be known early, and an alternative can be identified.

Currently, all the knowledge that we need to accomplish this is not available. We have to keep our eyes and our minds open to new things. One example is the burgeoning literature about the vascular endothelium and the potential role of anti-angiogenesis factors as tumor therapy. Unfortunately, tumors don´t always read the textbooks. This is a slide taken from an article that appeared in the Journal Science just a few weeks ago and in the article the authors showed this photomicrograph. This is a blood vessel.

Figure 2 Hendrix et al Am J Path observed vessels in tumors without endothelium. This example is from a melanoma.
News report in Science 1999; 285:1475

This is a red cell and there is no endothelium on this blood vessel. This is a vessel without endothelium where the nutritive material actually diffuses directly into the tumor to nourish it. If one had the drug that was designed to treat or stop the proliferation of endothelium within tumor vessels, it is not going to cure this tumor. In light of this finding, neither imaging or therapeutic targeting of tumor vascular endothelium is likely to be worthwhile.

Now what about heart disease? This is a condition that will occur in 1 out of 3 people that will cause death in about 5 million people worldwide this year. There is a famous Catalan proverb which is probably relevant to coronary artery disease – and that is "the table kills more people than war does". I think we need to watch what we eat. Detection of coronary disease today is still by symptoms and it is confirmed by EKG stress tests, non-invasive imaging and coronary angiography. But what is going to happen in the next few years? It is very likely that a blood test is going to be developed very similar to the prostate specific antigen assay (PSA) that will say that this patient has coronary disease. When that occurs we will no longer use the EKG or stress echocardiography or radionuclide perfusion imaging for diagnosis. Instead these tests will be used for evaluating the severity of the process. In addition, we currently need to have a way of characterizing the lesion. Not all coronary lesions are the same.

It is important to recognize that the concept of non-invasive testing, while relevant 20 years ago, is no longer important. If one looks at the guidelines for coronary angiography, published on the American Heart Association Website, they are very similar to the indications for performing myocardial perfusion imaging. In my opinion, we currently see more and more patients going directly to catheterization, establishing the fact that they have coronary disease. After the diagnosis is made they are referred for a perfusion scan to determine whether a specific lesion is the cause of the patients´ symptoms.

Now let’s take the circumstance of angioplasty. This is another area where we have more to learn. Restenosis occurs in about 30% of the patients who are treated in balloon angioplasty. Stenting probably reduces the incidence of re-stenosis from 10 to 15%. Fig. 3.

Figure 3

An acute thrombosis following one of these procedures has gotten to be exceedingly rare due to the use of aspirin or ticlopidine and IIb/IIIa inhibitors. Now, people have advocated the use of brachytherapy to reduce re-stenosis. There was an initial report that described the use of brachytherapy in 1997 by Combatto and his colleagues, but even in that report, 2 of the 21 patients developed total occlusion of the vessels within 2 months of their treatment. This problem was the subject of an editorial that appeared in Circulation quite recently and it´s called Late Thrombosis after Radiation: Sitting on a Time Bomb and it viewed the potential causes of late thrombosis. There were delayed re-endotheliumization, fibrin deposition and platelet recruitment, impaired vasoreactivity or spasm, tissue erosion or unhealed dissection. I tend to think that most of these are not correct. The real answer is these irradiated vessels do not have a normal endothelium. We are forming a very unusual conduit for the blood to pass through it and it does not have the usual thrombolytic properties; and therefore, this vessel is much more prone to thrombosis. There was a study recently published in Circulation by Sukihara that sheds some light on this. These were arteries that were harvested from patients undergoing radiation therapy in the head and neck. Fig 4.

Figure 4

These were patients with head and neck tumors, which were treated with radiation and then they went to surgery. At the time of surgery, their blood vessels were harvested and they were tested for their response to endothelial factors that should cause vasodilation. The vessels from radiated patients who came to surgery were compared with those of patients with very similar tumors who did not have radiation. I would like to call your attention to what happened in the presence of acetylcholine, which is a very potent vasodilator. The radiated vessels had very little response. They did not dilate and the non-dilated vessels dilated normally. Again, we have a lot more to learn, but I think that there are things that we already know which can be very helpful in carrying nuclear medicine forward so that we can do more procedures by 2005.

A very important aspect of nuclear medicine today is the determination of myocardial viability. This is a test where nuclear medicine is the best there is, we are the gold standard. This is taken from a study again published in Circulation quite recently by Nagua and his colleagues. These investigators obtained biopsies from 16 akinetic or hypokinetic myocardial segments in patients who were undergoing coronary bypass grafting. At 2 to 3 months, 16 of the segments improved and the segments which did not recover had more than 17% fibrosis. It is interesting to look at this with reference to thallium uptake, less than 60% of peak and no response on Dobatamine Echo. I would like to call your attention then to the degree of fibrosis and the determination of viability when fibrosis is very prevalent. There was no response to low-dose Dubatamide Echo, whereas tissue that was viable on Dobatamine Echo had very high thallium uptake greater than the 60% peak thallium uptake threshold. Also if one looks at fixed thallium, partially redistributed thallium and reversible thallium abnormalities, these investigators found that when there was a fixed thallium abnormality, more than 50% of their biopsy specimens consisted of fibrous tissues. When there was partial redistribution or total reversibility of the thallium scan, only a very small fraction of that tissue was fibrous tissue.

The device is an electrode on the end of a catheter and a tiny magnet right next to the electrode. The device measures the electrical activity in the endocardium and the motion in that area magnet creates a signal which is sensed by a plate behind the patient. A graph is made of the motion of the magnet something like a global positioning system finding out where the magnet is in space. This technique provides 2 pieces of data: one is motion and one is the presence of electrical activity. This device puts out a color graphic showing motion and showing QRS complex. This is what was found not on the patient I just showed you, but on the representative sample where they have compared this Noga study to SPECT imaging and to PET imaging of myocardial perfusion. We are not alone in our abilities to make advances and I think we must be very careful and we must move as quickly as possible to develop new techniques.

Similarly, as we look to evaluate new techniques we have to be cautious about what we are actually measuring. Perfusion imaging can be used to evaluate novel revascularization. Some patients have percutaneous myocardial revascularization or transmyocardial revascularization. These are techniques which are useful in patients who do not have good targets for the surgeons to create a bypass graft or where the vessels are so diseased that PTCA cannot be done. TMR is where the surgeon opens the chest and shoots the laser beam from the outside in. PMR is where the cardiologist places the catheter in the heart and shoots the laser beam from the inside out, so with percutaneous or transmyocardial laser revascularization. Both of these techniques are known to relieve angina well and suggest that the patient should have improved perfusion. There have been at least 5 studies published using myocardial perfusion imaging on these patients; none of which have showed improved perfusion. There is only one case report showing improved perfusion with a PMR technique. Investigators began asking, "why should the pain go away?" The answer is that pain is conducted by sympathetic fibers, and if sympathetic innervation were decreased in these patients, then one might have relief of pain even if one does not have improved perfusion. So in a very clever study these investigators performed C11 ephedrine scans before and 66 days after the TMR procedure, and what they found and what is graphed here is the percent of myocardium that is abnormal. The lesions got worse suggesting that the enhancing of the patient´s life in terms of relief of pain was not due to enhancement of perfusion, but was related instead to killing the nerve fibers conducting the impulse to the brain. We clearly need to go beyond perfusion imaging if one looks at what typically happens with lesions over time to cause myocardial infarction.

It is well established that most lesions are relatively mild and suddenly progressed. There was a study published by Yokoya and his colleagues again in Circulation of what these investigators did. They performed 4 angiograms and they followed 36 patients who had PTCA over a period of a year. Fig.7

Figure 7

What they did was they looked at the vessels that did not have the angioplasty. They looked at the coronary disease progression in the vessels that were considered not clinically involved, so here is the result on the first angiogram looking at concentric and eccentric lesions. These lesions had 40% less stenosis by the time the fourth angiogram was done. Look at the progression: the patients went from this point on the third angiogram to this point on the fourth angiogram. They had progression both on eccentric lesions and concentric lesions, a remarkable sudden progression of lesions, and up to this time we have no good way of identifying which of these lesions will progress. This leads to the question of the unstable plaque. The Wall

Figure 8 (click=zoom)

If the artery has a stable plaque the lesion is composed of fibrous tissue and calcium. The lesion has low metabolic activity. This plaque is unlikely to rupture. The unstable plaque is filled with lipid and macrophages and has very high metabolic activity and is associated with inflammation. C-Reactive Protein (CRP), an acute phase reaction substance that is an indicator of inflammation, is increased by a factor of 3 in patients with active inflammation and these patients who are much more prone to acute infarction. This plaque is very likely to rupture. Now we are not talking about a tight stenosis, but rather a lesion that may occur in a relatively normal appearing vessel on the angiogram. There are many potential targets that we can use to identify the unstable plaque. One of them is a monocyte chemo-attractant peptide which can infiltrate or identify those macrophages which have already infiltrated the atheromatous plaques. One can see in one of the immune stain specimens right here and on the autoradiograph following administration of radiolabelled MCP1. There are many other potential substances that could be useful and all of these can be labeled with single-photon tracers. We could look at up-regulation of a variety of factors including the lipid in the lesion and the metabolism of the plaque if we want to look at the plaque metabolism that could potentially be done with FTG. Well, if we could see these things why haven´t we seen these things up to now? I think the reason is that the lesions are exceedingly small and because the lesions are small it becomes very difficult for us to resolve the lesions with our existing techniques.

I personally believe that Nuclear Medicine must carry on the next frontier just as Ultrasound has gone from putting the transducer on the chest and taking a picture to putting the transducer in the body and taking a picture transesophagially or intravascularly. Nuclear Medicine must say that we too can take pictures by putting our detectors inside the body. We have in the case of a vascular lesion, a small lesion, but we have the potential to use radiopharmaceuticals that can give a very high contrast. The concept is summarized in this cartoon that we would inject our radiopharmaceuticals and then in the catheterization procedure we would sample the various blood vessels. We would then create a graph and the graph would now be related to the patient´s arteriogram. We would know by the uptake of the radiopharmaceuticals whether or not there are specific receptors expressed at various sites of the vessels which are consistent with unstable plaque. These are the lesions that should be treated, and in the role of making nuclear medicine more directed toward therapeutic decision-making, this kind of information would be particularly useful.

One other area that is likely to be important for radionculide imaging is programmed cell death. Programmed cell death is very important and there is a tracer, a human protein, Annexin 5 which has very high affinity for phosphatidylserine which is exposed on the surface of apoptotic cells. Apoptotis is present in a many diseases: Excessive apoptosis in AIDS, Alzheimer´s disease, Ischemia reperfusion, progression of heart failure, chronic hepatitis whereas the decreased apoptosis is seen in cancer and autoinmune disease. The way the signal works is that in the normal cell phosphatidylserine is kept inside the cell by 2 pump mechanisms. When the cell undergoes apoptosis these 2 enzymes shut off and another enzyme scramblase is activated. At that moment, phosphatidylserine is suddenly expressed on the external surface of the cell membrane. It is either not there or it is there, and when it is there, Annexin will bind to PS which is expressed on the cell surface. PS is very widely distributed intracellularly and it is a normal physiologic protein.

A few experimental studies suggest that this material might actually be very useful in clinical practice. One of these is in transplant rejection where alloreactive T-cells of the host recognize foreign antigens and these T-cells ultimately release substances which enter the graft and cause the cell to initiate its own mechanism of suicide. These are heart transplants which are placed in the abdomens of rats and there is a native heart here and a transplanted heart right here in the pretreatment state. Fig. 9

Figure 9

One day after implantation of this heart transplant, there is no uptake seen. By the fourth day, this heart transplant has remarkable uptake of Annexin and this corresponds with significant apoptosis in the graft. The graft still works. It beats, and more importantly, what happens when you treat this animal if you give the animal cyclosporin does the signal go away? Well, as I´ve shown in these two panels the answer is yes so you can stop this progression of apoptosis. You can keep this graft alive and you can show that you have stopped the signal so you can see apoptosis when it´s present and you can see the lack of apoptosis when it´s absent. Similarly another problem in the transplant arena is transplant rejection. Well, it turns out that Annexin doesn´t work as well as we had hoped in this arena, but MCP1 does. MCP1 works because macrophages are present in large amounts and it does seem to work. The same model here is the heart transplant. This is an animal with chronic rejection showing some uptake of this tracer. Coming back to the tumor issue and the specificity needed to really treat patients, specifically again in a rat this time, but hopefully in a human within the next 2 years.

Here we have 2 animals which have implanted tumors. In these 2 animals, we can see that there is a remarkable difference in the degree of apoptosis even though the animals had the same tumor implanted. These animals were treated with doxorubicin and one can look at the remarkable change, pre-treatment in blue, post-treatment in red. One can see that there is a remarkable difference. One animal responded very well, such as this animal, and some animals responded very poorly, such as this animal. One would like to have different treatments in these two circumstances.

Well, I hope in these remarks that I’ve given you some thoughts that might expand your mind and your vision in terms of where nuclear medicine is going. There is a concept which is now gaining popularity called neurobics: it´s like aerobics which is the idea of exercising to the point where you can enhance the physiology of your heart. Neurobics is exercising your brain so you can learn more and do more and expand your horizon. I hope that in the time that you have spent at this meeting listening to wonderful science and meeting with wonderful friends, you too have had a neurobic experience and together we can identify the things we will be doing in 2005 to improve the things we are doing today. Thank you.