James Welsh

Bret Kugelmass
We are here today with Dr. James Welsh, and we're going to continue our special COVID miniseries. James Welsh is the Chief at the Hines VA Hospital when it comes to radiation work, and also a radiation oncologist at Loyola University Medical Center. James, thank you so much for coming on the show.

James Welsh
Thank you, Bret. A pleasure to be here.

Bret Kugelmass
So maybe you can introduce yourself a little bit and just kind of tell us about your background, some of the projects you've been on, just so we can kind of build your story before we get to some of the more recent COVID work.

James Welsh
Sure. As you mentioned, I'm the Chief of Radiation Oncology at the Edward Hines VA Hospital and I'm enjoying my stint with the VA far more than I ever thought that I would. Had I known about the VA 20 years ago, I might have made a career out of it right from the start. But prior to getting here, I did my residency training at Johns Hopkins, stayed on staff there as an assistant professor, and then took a wonderful opportunity to work with developers of helical tomotherapy at the University of Wisconsin where I had the great honor and pleasure of being the first physician in the world to use this new image-guided intensity-modulated form of radiation therapy.

Bret Kugelmass
And what is it? Can you break us down a little bit more? What is this helical guided?

James Welsh
Sure, well, IG-IMRT or image-guided intensity-modulated radiation therapy has now become the standard treatment for patients who need radiation therapy in the United States now, and the technique is quite sophisticated, but fairly available and routine today. That wasn't the case 20-25 years ago when we developed the helical tomotherapy approach.

Bret Kugelmass
And what is it used for? Is it used to fight cancer? What is radiation therapy used for?

James Welsh
Yes, radiation therapy is primarily used for cancer, high doses directed at the malignant tissues, tumors, and low dose or no dose to the uninvolved tissue is the goal. For the last century or so, people have been striving to achieve that goal with ever-increasingly improved technologies. Today, helical tomotherapy, and other techniques of image-guided intensity modulation with photons is is the latest and greatest. I also get to work with proton beams once a week at the Chicago Northwestern Proton Center and that's another exotic and effective way of hitting the tumor targets full force but minimizing dose to the normal tissues and sparing them.

Bret Kugelmass
And so just tell me at a very high level, why use radiation at all, why not just cut the cancer out with a knife or something?

James Welsh
Well, if you could cut all the cancer out with a knife, that would be the ultimate solution. But there is often a limitation to surgical oncology. Malignant tumors tend to wrap around normal structures, blood vessels, nerves, with tentacles and they invade. And so even if you were to remove all the visible or gross tumors, chances are you're going to leave something behind if it is adherent to normal structures. And you can't take certain normal structures out like critical arterial blood vessels and nerves, etc. With radiation, it's possible to sterilize these malignant cells, maybe after surgery has been done to remove most of it or in some cases as definitive therapy to eradicate all the cancer right from the get-go and chemotherapy still has a role in the world of cancer treatment.

Bret Kugelmass
And just since you brought it up, what is chemotherapy? What's the role that chemotherapy plays?

James Welsh
So chemotherapy is an example of what we call a systemic therapy, meaning that it works from head to toe. So if we have breast cancer, for example, we could use surgery and we can use radiation, but often we will add chemotherapy to either help the radiation be more effective than it would be alone, or to address any microscopic disease set cancer cells that might have tried to sneak out to places where breast cancer likes to go. Chemotherapy as a systemic therapy, working from head to toe, can address that microscopic disease. In a similar vein, for both breast cancer and prostate cancer, we also use hormonal therapies, which are systemic therapies that work from head to toe because both prostate cancer and breast cancer are sensitive to hormonal manipulation.

Bret Kugelmass
I see. So when you say systemic, you mean like we're adding a chemical to someone's entire system, and it negatively impacts their entire system. And that's one of the problems with it.

James Welsh
Yes, you nailed it. While it has the advantage of working from head to toe, it has the disadvantage of working from head to toe.

Bret Kugelmass
And the radiation is like spatial, geometric, you point it and you direct it and you try to hit something specific. Is that right?

James Welsh
Absolutely correct. Yes. So surgery and radiation are called regional therapies or local therapies, as opposed to hormonal therapy, immunotherapy, and chemotherapy, which are systemic therapies that work with the entire body.

Bret Kugelmass
And then how do we know where to point the radiation? Is it like, you have to take an image first, and it's kind of like, you know, put a tape measure to the body or something? Or is there a way to do it in real-time where you're like seeing where you're shooting and adjusting the beam and shooting more?

James Welsh
Sounds like you should become a radiation oncologist, you have all the right ideas and the instincts, and you're absolutely right on all counts there. Because yes, before we start the course of treatment, we take various images. The images might be in the form of a CAT scan, or an MRI study, or more and more recently, more and more frequently PET scans and PET scans are Positron Emission Tomography scans. The positron-emitting radioisotope is attached to a glucose molecule, that glucose molecule is preferentially taken up by malignant cells because cancer cells are very avid for glucose. And these cancer cells track the radioactive form of this glucose, f18, fluorine 18, labeled glucose or FDG. This is one of the key ways that we can identify where the cancer is in a patient's body. If it's all localized in one place, for example, in the prostate, we would go ahead and aim the radiation at the prostate. But before each treatment, we might obtain an image to make sure that the exquisite dose distributions that we're talking about with intensity modulation or with proton beams are not just going to be precise, but are going to be accurate. To ensure that accuracy, we take an image right before each treatment, maybe a mini CAT scan, or just x rays or whatever we might have even MRI before treatment.

Bret Kugelmass
And so there are almost like two types of radiation that are happening. We started off by talking about the radiation that's used to attack cancer. But there's the radiation that's used beforehand to image it right. So it can maybe just talk a little bit more about what that type of radiation is. You said something with glucose, and it gets purposely taken up, like what is it that is attached to that glucose? And how do you see that with the imager?

James Welsh
Great question and one of my favorite topics. So glucose is preferentially taken up by cancer cells because cancer cells have aberrant metabolism. They're not like normal cells. And incidentally, that's why they're sensitive to radiation. They focus too much on reproduction and less on repairing the damage from radiation. So that makes them more sensitive to radiation therapy. But because cancer cells take up glucose so avidly, we could label that glucose with the radioisotope. The isotope we tag on to the glucose molecule is fluorine 18, which is a positron emitter. The fluorine 18 is carried into the cancer cells by this modified glucose molecule, it's called FDG fluorodeoxyglucose and then the deoxy means that it's missing one of the oxygen molecules, and that's the key to getting it into the cancer cell but it can't get out because it no longer has the flux pump. It's trapped inside that cell that it accumulates in. Anyway, once it's inside a cancer cell, the f18 being a positron emitter, emits a positron, which is antimatter, it's the antimatter counterpart of an electron. It travels a very short distance and encounters its matter counterpart, the electron. Upon the two of them getting together well, we know what happens with matter and antimatter getting together, E equals MC squared leads to the production of energy, the energy is in the form of two gamma rays that go diametrically apart 180 degrees in the opposite directions. And we have sophisticated imaging cameras that are computerized that can tell us where the gamma rays came from, which tells us where the positron and electron interacted, which in turn tells us where the cancer was.

Bret Kugelmass
So you've essentially taken on a radioactive solution material, adhered it to glucose, gotten to the point where it's going to tell you where the cancer is, and then it almost shines a flashlight out so that our imagers can pick it up and hone in on exactly where it is. And then I guess you just see something like a lit-up image or something?

James Welsh
Exactly right I wish I could show you a picture, but you couldn't have described it any better. It is a bright spot on a scan, and you don't even have to be a radiologist or nuclear medicine specialist to see some of these abnormal bright spots on these PET scans.

Bret Kugelmass
Okay. And it sounds like we use radiation in medicine a lot already. Because like I've heard of PET scan, you know, I've heard of all the gamma this and CAT scan, like I've heard about this type of stuff just as you know a layperson. So that means radiation in medicine is fairly common.

James Welsh
I would say absolutely, yes. There's a whole field of nuclear medicine. There's a whole branch of diagnostic radiology, which for the most part still uses ionizing radiation in the form of X rays, then, of course, there's radiation therapy. So, medicine is deeply embedded with radiation and radiation applications.

Bret Kugelmass
And then you mentioned proton therapy at one point, can you explain the difference between using a proton style radiation to attack something from the outside in how that differs from using an X-ray? From the outside in?

James Welsh
Sure, well, X-rays are one form of radiation, electromagnetic radiation, but then there's a whole other branch of radiation. We call that particulate radiation. Protons are nothing more than strict hydrogen nuclei. So a hydrogen atom is a proton with an electron orbiting it. If you take off the orbiting electron, now you're left with the bare hydrogen nucleus, which is a proton. Those protons can be accelerated in fancy machines. The one we have is a cyclotron. Other facilities use synchrotrons or synchro cyclotrons, etc. But the point is that you can get them going up to enormous velocities, fifty percent, two thirds the speed of light, and aim them at tumors. And being a form of ionizing radiation, they have similar effects as x rays, but they also have advantages. Protons, unlike x rays, which go through a patient's body and produce an image if you want to. Protons stop, protons will stop at the desired depth of where the tumor is located. And therefore, they will not produce any radiation beyond the tumor and they provide relatively little radiation before the tumor. So it's kind of a magic bullet in the sense that through this, the so-called Bragg peak, where the radiation comes in at a low level, hits a peak at the tumor, and then comes to a dead stop afterward. That's the key to proton beam radiation therapy. It's quite exquisite, and it seems to work beautifully.

Bret Kugelmass
And you say it's like a magic bullet because it's like a bullet that you'd shoot and you can tell it at what distance to stop and impact something. So it's almost invisible, up until that distance, and that means it's not damaging any of the tissue on the way in or the way out and only damages the tissue where the cancer is where you want to damage it.

James Welsh
In principle, yes, there is some entry dose to be accurate, but there's relatively little if any exit dose and the depth at which the proton will stop is a function of the energy. So I might use 200, MEP protons to strike a tumor that's several centimeters below the surface. Depending on whether there's fat bone or muscle in front of that tumor, I might have to use slightly different energies but the depth of penetration of a proton beam as a function of the energy of that proton.

Bret Kugelmass
And the disadvantage of the x-ray in comparison is that you're damaging the tissue in a straight line on the way to the tumor and then beyond the tumor as it comes out of the body. But, and correct me if I'm wrong, you were talking about how you need a cyclotron for the proton, which is a very complicated, expensive piece of machinery. Whereas x-ray machines are everywhere they're in every hospital, every dentist's office, it's very easy to handle and procure. And, people are trained and know how to work with x-rays very easily. Is that right?

James Welsh
Yes, and no. x-ray machines are definitely ubiquitous. They're all over the place for diagnostic imaging purposes. But for radiation therapy purposes, the machinery is far more complicated. Maybe it's not as sophisticated and expensive as a cyclotron or a synchrotron. But these linear accelerators are not in every hospital. So they can cost a few million dollars. And because of the sophisticated image guidance, capabilities, and intensity modulation capabilities, they are expensive and delicate machines. But to answer your question about how we would get around the limitation of the photon beam because these x-ray photons do go through the patient. And they provide those before the tumor and after multiple intersecting beams can provide low doses to the normal tissues on the way in and out if they come from various angles, but where they intersect on the tumor, that tumor could be toast.

Bret Kugelmass
I see. So it's like imagine if I were, you know, I had like a few different laser pointers, you know, and each one isn't that bright, but I shine them all at the same spot. And that spot is essentially the summation of their energy. And that way you can create this three-dimensional targeting by using multiple lines of attack. Is that right?

James Welsh
Absolutely right.

Bret Kugelmass
Okay. And how common are those machines? Or even just an x-ray for therapeutic purposes in general? Does every hospital in the US have at least one?

James Welsh
No. So probably, one out of every 10 hospitals will have one.

Bret Kugelmass
And how many hospitals are in the US then like I'm trying to understand like how far away is any given person from one of these machines?

James Welsh
Well, in any major city, you'll find probably several, several of them, maybe a dozen of them here in the Chicago area, and across the nation. To put things in perspective, out of the hundreds of VA hospitals and 1000s of VA clinics, only 41 sites have radiation therapy capabilities on the premises. So it's not something that every hospital will have. And it requires quite an investment financially, and in terms of the physics and engineering, background and infrastructure, as well as the positions.

Bret Kugelmass
And one of the reasons I was asking about this is because I want to lead in a little bit now to the COVID work that you've been doing. Because you know from our previous conversation with Jim Conca, it seems to me that there's some real promise in treating COVID with these machines, which while they might not be available in every hospital, it seems they are available across the country if we needed to ramp up use. Can you just talk to me, maybe start with the history of how you even got involved in this particular line of study and what we know.

James Welsh
Well, as we said at the beginning, cancer therapy includes radiation therapy. So surgery, chemotherapy, immunotherapy now, and radiation therapy are the pillars of cancer treatment, but unknown to many individuals is the fact that radiation therapy has applications beyond cancer. For example, many patients with a hip replacement will have a single dose of radiation therapy to avoid the formation of bone spurs, heterotopic ossification after. If you're having hip surgery to reduce the pain and immobility associated with severe arthritis, the last thing in the world you need is bone spurs that cause pain and limited mobility after major surgery. So sometimes depending on the context, we will apply a single dose of radiation to that area. And it reduces the odds of getting these bone spurs or heterotopic ossification. Similarly, patients can have exuberant scars, they're called keloids. And one way of addressing keloids is to apply a dose of radiation after removing the keloid. Because if you just surgically remove a keloid, it often comes back with even more scar tissue and an over-exuberant growth than it did before. So surgery doesn't work on keloids. But surgery plus radiation does. And so these are two examples of how radiation therapy can be used for benign diseases. Those of us who do a lot of treatments of benign diseases might remember that many many years ago, I'm talking about a century ago, radiation therapy was used prior to antibiotics for addressing severe inflammation and pneumonia. And several of those papers from going back in the 1920s, 30s, and 40s document that low doses of radiation might be able to quell the over-exuberant immunological response to an infection. And in COVID-19, we see that some patients have over-exuberant immunological reactions to this virus.

Bret Kugelmass
So I'm going to try to take a step back and maybe dumb down the language a little bit. In all three of those cases, the bone spurs, the scarring, and the inflammation are all three of these essential, our body like overreacting in its attempt to heal itself and that's what the radiation is essentially being like, hold on. Cool. It slowed down a little bit. We know that you're excited to repair yourself. But we want to do this slow and steady.

James Welsh
I would say yes. You probably said it better than I said it.

Bret Kugelmass
You were much more precise. I just, you know, tried to break it down a little bit.

James Welsh
Right on the money. The body in its effort to heal itself sometimes overdoes it and radiation can restore balance, make sure that the healing response or immune reaction is not excessive and damaging.

Bret Kugelmass
Okay, so now let's come back to pneumonia because so they started using it for treatment. Pneumonia sounds very similar to a lot of what I've heard about with the body's overreaction or not an overreaction, but the consequences of getting COVID as well sometimes pneumonia are certain things to do with the lungs. So what was the result of the early work, you know, a century ago or 80 years ago, in terms of actually applying this type of therapy, like as a regular practice, to combat pneumonia?

James Welsh
So this is where there is a lot of controversy and disagreement, because the way I interpret a lot of this early literature is favorably, and I have to take the researchers at their word, and their word was that in many of these scenarios, the radiation was able to quell the inflammation and effectively treat this patient's pneumonia. Now, modern medical scientists would quibble that these were not prospective randomized, placebo-controlled clinical trials, and therefore they don't accept them. But not everything is amenable to prospective randomized clinical trials. And just because the study wasn't designed that way, doesn't mean we should disbelieve it.

Bret Kugelmass
And don't we have epidemiologists who study datasets that maybe aren't the perfectly controlled trials but are able to still, like, make conclusions from them and tell us? Yeah, we're not sure but like, the evidence, looking at it this way, and this way, in this way, all says yes, this is gonna work.

James Welsh
Absolutely. So Edward Calabrese from the University of Massachusetts, Amherst has been one of the big proponents of this because he and his colleagues have reviewed the literature, drawn some conclusions, and encouraged us to proceed with this in the clinical setting. Several others have interpreted the old literature as favorable, favorable enough to proceed with modern clinical trials. I think Dr. Khan and his colleagues at Emory were among the very first in the United States to apply it. One of my colleagues, Dr. Matthew Katz, in Massachusetts, is also participating in a clinical trial. I was hoping to be among the leaders of a large clinical trial through the Department of Veterans Affairs, but it might not come to fruition. But my colleagues, Dr. David Schwartz, and Michael Hagen put together an excellent protocol, which I think would have provided the definitive answer to this question. And I'm still keeping my fingers crossed that somebody, if not the VA, somebody will take the lead and proceed with this.

Bret Kugelmass
Well, let's take a step back first, what happened back in the day when they were using x-rays to treat pneumonia? What was the how many people are we talking like, you know, like 20 people or like 20,000, people had this

James Welsh
Somewhere in between, it's hard to tell, because just because somebody writes up their individual series of patients doesn't mean that the equally talented physician down the street who chose not to write the cases up that didn't do something similar. So it's impossible to tell just how many but we're not talking about single digits or a couple of dozen, we're talking about hundreds or thousands of patients.

Bret Kugelmass
And what is the mechanism? And now I want you to get granular and specific what is the mechanism by which radiation actually reduces inflammation, what is actually happening to the biology of a person that reduces the inflammation.

James Welsh
Okay, well, it's very complicated. The cytokine release syndrome or cytokine storm is the enemy of the patient who has an infectious disease. Now cytokine storm is just what we talked about before, an over-exuberant reaction of the immune system to something. Back when this term was first coined the cytokine storm was in reference to certain things like CAR-T cell therapy, Comerica Antigen T Cell Therapy, which is a very innovative approach to cancer immunotherapy. But when you're tinkering with the immune system, you can incite an overreaction of the immune system. And that was one of the examples wherein the cytokine storm or cytokine release syndrome was first noticed, because, yes, maybe there's an immune reaction against the cancer, but the immune system may be hyperactive and take no prisoners killing the cancer but damaging the patient along the way. Cytokine storm has been associated with infectious diseases, the Black Death, Yersinia Pestis causes plague, and some cases of plague are accompanied by a severe overreaction of the immune system, the so-called cytokine storm.

Bret Kugelmass
Where are these cytokines are they just in the lungs or can be anywhere in the body?

James Welsh
It can be anywhere in the body. So it depends on the individual disease entity or the inciting immunological stimulant. And in the case of the plague, or the H1N1 Spanish Flu from 1918, the horrible pandemic from a century ago, the death was often caused by cytokines that caused problems in the lung. And when you think about it, of course, if you're going to cause problems in the lung and you can't get the oxygen because there's too much fluid edema in the lung, they call it pulmonary edema and inability to get the oxygen from the air into the bloodstream. That's very, very bad news clinically, and that is one of the manifestations of pulmonary manifestations of the cytokine storm. And the cytokines can cause damage from head to toe. But in certain areas such as in the lung, it becomes potentially fatal.

Bret Kugelmass
Okay, so two more questions on these cytokines, at least. What literally is a cytokine? Is it a cell? Is it a part of a cell? Is it a protein that is a cellular weapon? What is a cytokine?

James Welsh
Well, maybe all of the above, in the sense that it is a cellular weapon. It is a chemical that is produced by cells, cells of the immune system. And that's what cyto means. Cyto refers to the cell. But cytokines are released from immune cells. And they can either directly attack pathogenic invaders, bacteria, viruses, are cells that are infected with viruses, fungi, parasites, or they can stimulate other immune cells to recognize and kill the invaders.

Bret Kugelmass
What's an immune cell? Is this in my blood? Is it in my, in every part, every organ in my body, what's an immune cell?

James Welsh
White blood cells for the most part. So white blood cells come in a variety of different forms, neutrophils and lymphocytes are a couple of the ones that are commonly known. These immune cells, these white blood cells will be attracted to a site of infection. They're attracted by cytokines that are being released by local cells. Let's say you have an infection in your finger, the cells in your finger will be releasing certain chemicals, cytokines, chemoattractants, that attract these white blood cells to the site of infection. And those white blood cells then can take action against the enemy.

Bret Kugelmass
And so the cytokine is almost a bit like a, like a scout or a messenger, it gets shot out from one white blood cell that detects something bad. It alerts all the other white blood cells, and they're like a mob that then comes rushing to attack and we all know what happens with mobs, sometimes mobs get too out of control.

James Welsh
Yes, they do. Now the science behind this is fairly complicated. It's fairly, it's quite complicated. There, there are over a dozen, maybe a couple dozen cytokines involved in a cytokine storm. And while some of them are there to overcome the infection, you kill the virus, virally infected cells or kill the bacteria, kill the pathogenic fungus or parasites whatever. Others are there to maintain the peace and establish a balance so that the killers don't go crazy and start killing beyond the enemies. So as an example, interleukin six is one of the cytokines, and that increases the concentration of another marker called C reactive protein, C reactive protein, in turn, increases the concentration of interleukin eight. Interleukin eight brings neutrophils to the scene. Neutrophils can be a powerful ally in our fight against infection. But in the case of gout, the pain in the joint is because of neutrophils going into the big toe, for example, and causing inflammation and pain when they really don't belong there. So you have to be able to short circuit the system and prevent this over-exuberant immunological reaction by neutrophils or other immune cells.

Bret Kugelmass
Okay, so now my second question. What is the mechanism by which radiation communicates with the cytokines to quote-unquote short circuits and make sure they don't get out of control?

James Welsh
So this is where it gets very interesting and very complicated. I mentioned interleukin six, which is one of the proinflammatory interleukins or cytokines that help destroy the enemy. But in the overabundance, six interleukins six can provoke problems and be more harmful than good. So there's a drug that has been designed to inhibit that, tocilizumab. A lot of us thought that this was going to be the secret, secret weapon to fighting COVID. But as I said, there's more to it than just interleukin six, there's a couple of dozen cytokines involved in a cytokine storm. And maybe if you just knock out one of them like interleukin six, it's not the full answer. And while tocilizumab is controversial, and some studies have shown that it does not decrease death and intubation rates in moderately ill patients, others are saying that for those who are at death's doorstep, and are severely critically ill, tocilizumab may in fact have some benefit. But the point I'm trying to make is that a drug that attacks only one out of the two dozen interleukins that are involved in cytokine storm is certainly not addressing the big picture or the whole story. Radiation seems to have a dampening effect on a variety of different proinflammatory cytokines, and a stimulatory effect on those that are anti-inflammatory. And as an example, interleukin 10, in contrast to interleukin six, which is pro-inflammatory, and interleukin 10, is anti-inflammatory. It reduces so-called TH-1 responses and inhibits the release of cytokines thereby quelling or controlling or preventing cytokine, storm radiation seems to stimulate the IL-10 and dampen the IL-6.

Bret Kugelmass
And how can that be possible? How can radiation which as I understand it is just like a wave of energy? What is it doing to one molecule that might stimulate it and another that might dampen it? Is it just destroying some more selectively that is a little bit weaker? And then that sends a signal? Is it giving more energy to an electron as it's sending a communication signal across a certain pathway? What is it literally doing to those cells to stimulate and dampen?

James Welsh
Well, to paraphrase Paracelsus, the dose maketh the poison, but the dose maketh the cure as well. And depending on the context, you might need a high dose, for example, to kill cancer, or you might use a very low dose to address the immune system in this fashion that we're talking about. And radiation works by damaging the DNA of cancer cells. But it does different things in the immune system. And at very low doses rather than killing cells, it can activate certain cells or amp in certain cells in this immunological reaction, for example. And while nobody knows exactly how all this works, my lab and team are exploring something called microRNA response. MicroRNAs are our ribonucleic acid molecules, RNA molecules that seem to control gene expression through a very novel mechanism that I won't go into much detail about here today. But it looks like low dose radiation causes a signature of micro RNA responses that in turn dictate this immunological reaction that we're talking about from a big picture. So at the very microscopic level, it might be microRNAs, but in the big picture level of the patient, it seems to be the calling of the cytokine storm.

Bret Kugelmass
Okay, so now in the modern suite, we have some historic literature on how this has worked to dampen inflammatory reactions in the body. Now, what about in the modern context? Since COVID started? Do we have data coming back yet from you know, people? And I mean, not just like, official clinical trials, but like anyone who has tried this? Do we have a set of data that we can look at and say, yes we shot them with low dose radiation and it dampens this, or this guy got shot at this level? You didn't dampen that? How many pieces of data are we pulling in right now?

James Welsh
Data is coming in, but it's not as plentiful as I would have hoped it would have been had some of these clinical trials, such as the one I was proposing come to fruition. Nevertheless, there's a big trial in the United States called PreVent, which was, of course, as the name sounds like, designed to prevent patients from going on the ventilator. And that is the context where I think radiation is going to be most effective. Somebody who is sick enough to warrant hospital admission, possibly wind up in the ICU, but not yet sick enough to go on to the ventilator. That's the context where this low dose radiation could be a benefit. If you wait too long, it might be too late to do much benefit based on some data coming in from Mexico and elsewhere.

Bret Kugelmass
But yes, okay. Yeah. So great. So Mexico where else and how many like, and once again, I don't really care if it's an official study, but how many doctors have tried this on patients? Are we talking once again, 10, 100,000, whether it's part of a trial or not, you know.

James Welsh
In this context, in this era, it's probably not hundreds and thousands, like it was a century ago because there are more restrictions on the use of machinery such as linear accelerators for COVID pneumonia. There might be hospital restrictions on doing something that is not FDA approved off a protocol. So they might have to get IRB, Internal Review Board, approval before administering to these patients, and it's not happening as often.

Bret Kugelmass
And do you need linear accelerators? And do you need the special angle x rays that we're talking about? Or can you just use it? Since the lungs are, you know, like a big cross-section of your chest? Can't you just use a more simplified single X-ray, therapeutic machine and just blast it?

James Welsh
You might very well be able to do that.

Bret Kugelmass
Or since it's a low dose could you possibly use an imaging one just for a longer period of time or at a higher setting?

James Welsh
Quite possibly, yes. So, some of my engineering and physics colleagues are trying to figure out whether or not conventional x-ray, diagnostic x-ray machines could be adapted to provide sufficient dose to the lungs that would quell the cytokine storm of COVID-19. And while it's a tiny dose for a linear accelerator, it's a big dose for an x-ray machine. So it's somewhere in between, in that gray zone where the radiation oncologists who treat cancer are unfamiliar with these doses. But the diagnostic radiologists who don't treat patients, but use x rays for imaging are unfamiliar with these doses that are much higher than what they're used to.

Bret Kugelmass
So give me an order of magnitude I don't need to or I would be curious, but the audience probably wouldn't make sense of what the units of measurement are. But with respect to a lung x-ray, that somebody might get an imaging lung x-ray, is it 100 times as much radiation, 10 times as much radiation, 1000 times as much radiation.

James Welsh
So just to put things in perspective quantitatively, the unit of radiation is called the gray. And one gray is one joule of energy in one kilogram of tissue. So we measure things in gray. When I'm treating cancer patients, I might aim to administer sixty gray, seventy gray, eighty gray to a tumor. In contrast, diagnostic imaging studies, for example, a CAT scan, are on the order of a 100th of a gray, a centigray, one centigray for a CAT scan. The dose that we're talking about for COVID-19 treatment is somewhere around 20 centigray, to 100-150 centigray. So a few dozen CAT scans, but not even one radiation therapy treatment for cancer somewhere in between that in the gray zone of grays.

Bret Kugelmass
And out of the let's say 100 or so, maybe sub 100 times this has been tried. What's the data coming in so far? Does that seem promising to you how many people have had relieved inflammatory response?

James Welsh
So I know that Dr. Mohammed Khan and his colleagues at Emory have presented some preliminary data. And they're constantly updating their experience, presented stuff at the Astro Meeting, American Society for Therapeutic Radiology Oncology. They've presented their work, they've written papers, and they have generally had positive experiences. In contrast, however, some of my colleagues in Mexico might have used this as a last resort after trying this drug and that drug and not getting success. Now a patient is intubated or about to be intubated and declining rapidly. And in that context, the radiation doesn't seem to be working quite as favorably, as if it's done earlier. So I look forward to seeing the systematic results presented in a scientific format. So we can all interpret this properly.

Bret Kugelmass
And so what's the sweet spot? Do you think based on what you've seen so far, is the sweet spot like right before they become intubated? Or is it like after they become intubated, but before like, people start getting really, really concerned? What's the sweet spot?

James Welsh
I think the sweet spot is before intubation, if the patient has had respiratory compromise to the point where they have to be put on the ventilator, radiation might not be capable of reversing that. So if we see a patient who is sick and declining, rather than allow them to decline day after day after day, and then wind up on the respirator within the next week or five days, if we see that pattern emerging, we intervene earlier. And the VA trial was designed to pick patients up at the emergency room. And if they were sick enough to be admitted to the ICU, but not so sick that they needed to be intubated right now. These are the patients that would stop off in the radiation therapy department, get their dose and then go to the ICU. That's the way I envisioned the treatment going. And I think that's the sweet spot, then there's a dose of metric sweet spot some people are using 150 centigray, some advocate 30 centigray. And like I said, the dose makes the poison, but the dose makes it pure, too. And I have my opinions on what the right doses are, but time will tell.

Bret Kugelmass
Okay, so first what is your opinion on what the right dose is? And then I have a follow-up question that does it matter if it's done the whole dose? Actually, first, let me ask a different question. A CAT scan, was it the CAT scan that can be modified? The diagnostic tool?

James Welsh
A CAT scan could be but also fluoroscopy x-ray machines, regular x-ray machines that provide images of the chest.

Bret Kugelmass
Which are everywhere, right that those are everywhere?

James Welsh
They are everywhere. But they would require some special some significant retweaking.

Bret Kugelmass
And how long is like the button pressed for to give you your normal fluoroscopy dose, your one centigray dose, how long is it blasting for?

James Welsh
The fluoroscopy machine? Yeah, it would have to be on for several minutes in order to give a dose like that with the conventional dose rates. So it would have to be adapted in order to do this in a more efficient fashion because right now, we're not talking about a full centigray with the x-ray, maybe with a CAT scan. But a CAT scan, after all, the patient is lying here in the X-ray tube is going around the patient taking x-rays from 360 degrees of angles. And that leads to the equivalent of hundreds of chest x rays. Still, that adds up to only about one centigray. So we're talking about orders of magnitude lower dose with conventional x-ray machines. So we'd have to engineer them quite extensively.

Bret Kugelmass
But do we think that that would still work? Let's say it was a conventional x-ray machine and we left it running for a few minutes. Is that the same in terms of the equivalent effect of having a more powerful dose for a shorter period of time?

James Welsh
Yeah, I think in this context, it probably would be the equivalent. Now we have to be mindful of the fact that diagnostic x rays are at a much different energy than therapeutic x rays for cancer. Diagnostic x-ray tubes provide energy in the kilo electron volt, range 1000s of electron volts, whereas the machines that I use are millions of electron volts, MEV. So that means that the skin dose is going to be different. And the skin dose would be higher for that radiology x-ray machine. And we'd have to be careful of not overdosing the skin, and we'd have to perhaps modify the treatment angles.

Bret Kugelmass
But for the lower dose ones, there isn't as much of a worry about what would happen to the skin. Right?

James Welsh
We don't want to overdose the skin unnecessarily. But in order to give, say, 30 centigray to the lungs with the diagnostic machine, we still might be on the order of a couple of 100 or a couple 100 centigrade to the skin, which is still one radiation therapy for cancer dose.

Bret Kugelmass
So I guess my next set of questions is around why aren't more doctors doing this off label with diagnostic equipment for their patients that are bound to be intubated? And I guess the first part of that is if you're about to be intubated, and you've got COVID, what are the chances you're going to die? Is it pretty high? It's quite high, it's probably over 50%. Still, that if you're severely ill, and you wind up getting intubated. The odds of you leaving the hospital are not likely. So if I'm a doctor then and my patient is about to be intubated, I'm thinking there's going to be a 50% chance they're going to die. And I know that you know, these levels of radiation, you know, while might be higher than diagnostic purposes are not, you know, like you've been saying as high as treatment. Why wouldn't I, as a doctor, give them this option and say, hey, let's do this. We're not using the big fancy hospital equipment. So we don't need the board’s approval. I'm a doctor, I'm allowed to prescribe things off label, why wouldn't they just start trying this?

James Welsh
Well, I think you and I are the same kinds of doctors.

Bret Kugelmass
But you have a degree and I'm just, you know, talking. I'm an imaginary doctor.

James Welsh
I think the majority of physicians are reluctant to proceed down that road of the route of doing something off-label. And part of it might be because of the fears that have been instilled in us with our education about the linear no-threshold hypothesis, and there is no safe dose, and all doses of radiation could cause cancer, etc, etc. But in your hypothetical situation, somebody is so sick, that they're going to be intubated so soon and radiation has the potential to change that horse. I'm of the mindset that it is not unethical or unreasonable to give this a go. And I would not fear the consequences of cancer coming 10, 20,30 years later, which I think is extremely unlikely, and would not happen. But even if, if I did accept the LNT hypothesis, linear no-threshold hypothesis, I still would argue that the risk-benefit ratio might be worth it in this context. But you and I are in the minority when it comes to this stance.

Bret Kugelmass
And is there possibly a problem where there are a lot of doctors out there that would do this, but don't know that this is even a possibility? And I'm thinking even outside the context of like the American medical complex? Because like, let's say I'm looking around the world, and you know, okay, so let's say we've had 400,000 deaths here so far, and we've got the vaccine on the way and we're in a rich country we're the first ones. I'm thinking about all of these other countries that know that they are have like, at least a few 100,000, if not a million more deaths coming their way over the course of the next year. And they should be scrambling for options on how to treat them using available equipment. It seems like in other countries, it would be, it would be a no brainer for them to start, at least practicing with this. And it would be opt-in, obviously, the patient would say, like would say, Yes, I want to try this rather than have something shoved down my throat, and I might get to never breathe on my own again. And I might stop breathing period.

James Welsh
Yeah, I don't disagree with you at all. And that's why I with Dr. Katz, Matt Katz, that I mentioned earlier, as well as some of my colleagues from this group called SARI, Scientists for Accurate Radiation Information. And one of the guys in the group, Jerry Cuttler, is from Canada. And he has been a strong advocate for using this radiation therapy, both on protocol and off protocol. And I agree with you that if more hospitals would allow it if more ethics boards would allow it if more physicians were aware of this, and willing to try it, it might change the course of this pandemic.

Bret Kugelmass
Yeah. And I mean, listen, if there was a therapy available that was effective as we think this could be. And once again, we're not saying that this beats COVID. We're saying this beats the human's over-immune response to COVID that might kill you. Let me ask another question. What organization besides SARI, which, obviously, like, based on the name, I can already tell, and obviously I'm of this camp based on all the research I've done. It's a group of doctors that know that radiation has been mischaracterized. But are you part of any groups that aren't that but are just normal radiation therapists that you could call up like the head of like the president of the, you know, radiation doctors society, the normal one and say, listen, we look, we gotta get this information out, you've got a newsletter with 10,000 doctors on it? Like they need to at least know that this is a possibility to do this off label with available diagnostic equipment.

James Welsh
Yeah, I wish it were as simple as you're describing. I was the president of the American College of Radiation Oncologists just a couple of years ago, and I did call the current president and chairman of the board of ACRO, the American College of Radiation Oncology. And Eduardo Fernandez is the doctor who was quite receptive to it. And I think he informed several of his colleagues in Central America, South America, and throughout Latin America. And maybe they are doing this on protocol and off protocol. I think Eduardo has been in touch with colleagues in Europe as well. So I'm hoping that behind the scenes, unbeknownst to me, that people are doing exactly what you're describing and asking for, and maybe through individuals such as Dr. Fernandez, Dr. Katz, people like Jerry Cutler, who is a nuclear engineer in Canada, but very informed, educated, and persuasive. Maybe people are taking that advice, heeding that advice, and making things happen. But I wish it were happening at a more rapid rate.

Bret Kugelmass
In your best guess, and I know you're gonna be pulling teeth getting this out of you, but I'm going to ask it anyway. In your best guess what percentage of deaths could be avoided if this therapy was employed widely?

James Welsh
Well, you're right. It isn't going to be easy to get this out of me. Because I don't know. And as a scientist, I'm going to plead ignorance until the data is available in an unequivocal format, meaning that the results of prospective randomized clinical trials are unambiguous and I know the answer and now I can give you a specific number. Having said all of that, in my opinion, I think that I wouldn't be talking to you today and I wouldn't be designing clinical trials if I didn't think that there was something to this. And I do think there is something to this, I've read the old literature, and I've spoken to a lot of colleagues and scientists who are very in tune, with all of this subject matter. And I believe that it would be a positive trial, and might cut down by a substantial fraction.

Bret Kugelmass
Okay here's what I'm gonna do as a scientist, I'm going to let you have wide error bars. Okay. So I'm going to say, I'm asking you for plus-minus 30% here. What do you peg the number at for deaths that could be avoided? What percentage of deaths could be avoided, you have huge error bars, huge error bars, what's your best guess?

James Welsh
If the clinical trial that I helped work on with doctors, Schwartz and Hagen at the VA, were implemented, I would have predicted that 30%-50% of the patients who were treated would have warded off a negative outcome.

Bret Kugelmass
Yep. To me, that is such a large number of lives that we can save. Looking forward, I mean, already, if let's say, you know, potentially could have saved, let's say, 100,000 or more lives in the US, across the world, we're gonna be looking at millions of lives lost, you might be talking about saving a million lives, if we can get this information out there at least. And you know what, and they'd know, pretty soon if this weren't just, you know, less than 100 people trying this, but we had hundreds of doctors trying this across hundreds of patients, we know in a few months if this was on the right track. And then we could really gather the support to do real trials. But I am still just so frustrated, knowing the potential of this, that doctors aren't just doing this off procedure off label, whatever you call it, with existing equipment that they've got access to when they're looking at people who are going to die in front of them.

James Welsh
I'm extremely frustrated about it myself. And one of the things that I and others might do is since the VA is not going to support this large clinical trial, maybe we just do this clinical trial at our own individual institutions. So I'm going to work with Dr. Schwartz to see if we can disseminate the protocol throughout the United States, maybe to individual VA hospitals, but also across the globe. See if anybody is willing to go ahead and do it at your own institution. Yeah, they would have the statistical power to say thanks to having hundreds and hundreds of patients on this arm, hundreds of patients on that arm, we know the answer with certainty. But if this hospital a does this, and hospital B does this as well, and hospital C does this. Maybe we could pool our data and still have some.

Bret Kugelmass
Yeah, that's, that's what I'm thinking. Pool some early data, forget the controlled trial. Let's just get some more data in. And I'm almost wondering, and I understand that hospitals, it might be hard logistically with the administrators and they might say, no you're gonna be fired if you do this. Are these machines available for like outpatient in any outpatient areas that a doctor with his own practice, who just rented medical office space, but still has one of these machines could do it for his patients?

James Welsh
Yes. But now we got to think about the scenario we're talking about somebody who is so sick, that they're calling the ambulance to go to the emergency room and get admitted to the hospital isn't going to stop off at the radiotherapy clinic down the street and get a dose before hopping back in the ambulance. So it's logistically challenging to get the hospital on board.

Bret Kugelmass
Yeah, yeah. But there might be some situations where a doctor works in a hospital and out of a hospital. It's his patients. Maybe as a family doctor, he's known them for a long time and can kind of explain the situation. He sees it getting worse. You know, he's on the phone with him every night. And you know, he says, okay, like it's getting worse. I know you're about to go to the hospital. I've got this other option before we shove a tube down your throat. Would you like to do it? Just knowing how many numbers are so big, we're not talking about like a few people. Like with the 10s of 1000s of doctors and hundreds of 1000s millions of patients. Imagine that we could collect, you know, 1000s of data points in the next couple of months. And, and then present that, to then the board's in the people who set up the trials and stuff.

James Welsh
I agree. And I think most radiation specialists would agree with you too, the fact is that we're a relatively tiny subspecialty in comparison to pulmonary medicine, general medicine, and the various other branches of medical professionals that work with COVID patients. And these individuals might not be aware of the topic that we're talking about here today. Or if they're aware of it, they might not be convinced, because there are perhaps more individuals who are naysayers than those who are on the plus side. So I appreciate getting the chance to get the message out. But hopefully, I'm not just preaching to the choir, because if I were talking to radiation oncologists and radiation biologists, I don't think that I would be convincing anybody because I think most people aren't convinced that clinical trials are worthwhile. But it's those outside of our medicine, of this radiation medicine specialty, who also need to be informed and make objective decisions based on information.

Bret Kugelmass
And one more question for you, and then I'll let you go. If we wanted to try to really communicate with a broad base of doctors, emergency room doctors, pulmonary specialists, and radiation all at once. Is there a go-to other than JAMA? Is there a go-to media channel that we can start blasting this information out to to get their attention and at least make them aware?

James Welsh
As I said, the American College of Radiation Oncology is one venue that you could have an inside track with, because of the leadership being already aware of this issue.

Bret Kugelmass
But, again, we possibly would be preaching to the choir. Yeah, I'm thinking more like, you know, I don't know if the Wall Street Journal has a medical section or something, something more like, you know, widespread and common than, like a specific medical society. It just seems like information flow is the hardest part here because it just seems like an ethical no-brainer that if someone's entering into the state that we should start trying this more.

James Welsh
Yeah. And just to be fair, I could be completely wrong. As you said, the error bars are huge. And maybe trials will prove that my hypothesis is inaccurate and that we would not be saving 1000s of lives, and perhaps we would be harming patients. I doubt it. But I don't know for a fact. Having said that, to answer your question, I think what Jim Conca has been doing has been very, very helpful. I know that he's written a couple of articles for Forbes that has been extremely popular one of them with well over 100,000 reads. So I encourage him and others like him, who have media outlets, to continue to spread the word.

Bret Kugelmass
Well, Dr. James Walsh, thank you so much for the time. I know I've run you through the gamut here, but I really appreciate it. I know our audience appreciates that. And I hope that I can talk to you about this more in the future as well.

James Welsh
I really appreciate the chance to speak with you today. I look forward to talking to you about this topic and many more nuclear-related topics in the future.