Phillip Koo: Hello, my name is Phillip Koo. I'm the Chief of Radiology at the Banner MD Anderson Cancer Center. Brings me great joy to welcome you back to another series on our forum on precision medicine titled "PSMA Targeted Therapies in Progressive Metastatic Prostate Cancer". For today's session, we're going to be talking about radiation safety with targeted radionuclide therapies, which is a topic that often creates fear in the community, I think in large part because there's a lot of misinformation. And here to dispel a lot of those myths and sort of tell us the truth regarding radiation safety, we're very honored to have with us, Dr. Thomas Hope, who's Associate Professor at UCSF and also the Director of Molecular Therapy at UCSF as well. So welcome, Dr. Hope.

Thomas Hope: Great. Thank you very much. So I'm going to talk about radiation safety with targeted radionuclide therapy. And I'm going to start off by comparing external beam radiation therapy and targeted radionuclide therapy. And I think this is a really important distinction for everyone to be aware of.

So in external beam radiation, you're actually aiming a ray of photons at a patient and those photons traverse through the patient. And you obviously use different beams to focus on a specific area to get the dose in the tissue that you want. The toxicity with external beam radiation therapy is caused during the treatment itself. So it's where the radiation is aimed. After the patient leaves the facility, there's no more radiation entering or exiting the patient. The patient is no longer radioactive and there's no radiation being transmitted through the patient. And so the radiation given off from the patient's actually zero, the patient never actually emits radiation themselves. It's only being transmitted through the patient. And so there's also no toxicity beyond the region where the radiation is aimed.

With targeted radionuclide therapy, it's a very different approach, right? So here you're taking these small molecules, and in the case of this series, targeted to PSMA in prostate cancer, you inject that into the patient's blood. And then the PSMA labeled with lutetium will circulate throughout the body. And toxicity is actually caused by the biodistribution of the agent, where that PSMA is going, before it gets to the tumor. And then the lutetium will go inside the tumor and stay there for many weeks. It actually has a half-life of seven days, so it takes seven, eight, nine weeks for that radiation to fully decay. And so the radiation actually is emitted locally in the tumor and the patient will also emit radiation for a long period of time, for weeks in essence.

And so there's a huge difference in terms of traditional external beam radiation therapy and targeted radionuclide therapy. And I think this is where some of the concern comes from because with external beam radiation therapy, the patients are fully safe to everyone around them because they're not, quote, radioactive. But with targeted radionuclide therapy, the patients were actually emitting radiation therapy over time.

So just to re-highlight, so after treatment, patients with external beam emit no radiation and so there's no risk of exposure to others. But with target radionuclide therapy, the patients are emitting radiation continuously and so depending on the radionuclide, this can affect people surrounding them. And so that's what we're going to talk about today, is this potential toxicity from radiation that's emitted from patients.

So to understand this, and I think it's really important to understand units, and it can be very confusing even for people in the field, what these units mean. So I want to go through and define some units because once you have a handle of these units, it'll help you feel more comfortable with the terminology and therefore understanding the risk of the radiation.

So the first unit that one needs to understand is a millicurie or a megabecquerel. And these refer to, in essence, decays per second. So if you think about a radionuclide and you have a thousand radionuclides in a vile, and each radionuclide will decay at a specific rate, there's a half-life, right? So they will keep the decaying and every second, so many of those atoms will decay and give off a photon or an electron or some type of radioactivity. So millicurie is, in essence, a measurement of that decay at a specific point in time, how many events there are per second.

So a megabecquerel is, in essence ... Well, a Becquerel is a single decay per second and then obviously a mega and gigabecquerels because we're giving more than one atom decaying per second. And that activity will decay over time, right? So with the half-life, as the activity decays, the amount of millicuries will decrease over time. So millicurie, megabecquerel are similar units describing the amount of activity at a point in time.

Now that radioactivity, that decay, will emit photons and electrons and alpha particles, and that radiation will interact with tissue. It will hit tissue. And that will deposit energy in the tissue it interacts with. And we measure that in a different unit called gray or rads. So if you have a source that's emitting radiation and you put a piece of paper or a detector over here, you can measure the irradiation that's being emitted and interacting with the tissue, and that will give you gray or rads. So it's, in essence, a measure of energy in joules, in essence, of what's being deposited in a tissue.

Now that then gets further converted to a rem or a millisievert. And what these units are, are the effect on the tissue. So if you think about different types of tissues, each type of tissue has a different sensitivity to radiation, et cetera. So if you think about the kidneys versus the bone marrow, that effectiveness of the radiation on those different tissues varies by the tissue type. And so the effective dose, measured in rem or millisievert, varies. So in essence, you take the radioactivity and it has an activity in millicuries. It deposits a dose in the tissue, which is measured in gray or rads, and that dose affects an effective dose in the tissue or a causal effect where it's causing DNA damage and injury to the tissue, which is measured in millisievert or rem, okay? So hopefully we can keep that track and we'll come back to this in a little bit to try to understand the type of doses we're talking about with patients who are emitting this radiation.

So let's talk for a second about lutetium-177, which is the radionuclide that's attached to PSMA-617. Lutetium has a half-life of just under seven days. So that means if you have something like 10 millicuries to begin with, a week later you're going to have a little less than five millicuries remaining. Now lutetium decays by giving off two types of energy. The first type is an electron. This is called beta decay. Ninety percent of the decay from lutetium will be in the form of an electron. This electron travels roughly about one, maybe two, millimeters in soft tissue. So it doesn't travel very far, but this electron is what causes tumor kill and also toxicity. So it's what causes bone marrow toxicity and salivary gland injury.

But lutetium also gives off a different type of radiation, this is called gamma decay. These are photons that are emitted from the lutetium-177. These photons travel much further and will go beyond the patient and expose people surrounding them. About 17% of the decay from lutetium is in the form of gamma decay. And these photons can both be imaged and measured, and this is what's going to cause potential injury to patients surrounding them. So this is what we're worried about in terms of radiation safety, it's this gamma decay.

Now let's just talk for a second about PSMA-targeted risks. So here is an example of a patient who underwent a PSMA PET who subsequently underwent PSMA radioligand therapy. And you can see there's numerable PSMA-avid osseous metastatic disease and soft tissue disease.

Now let's talk about effects on the patient. So remember how we said the electron that's being emitted from lutetium can injure the salivary glands and the bone marrow. And I think this really nicely highlights how different tissues have different sensitivities to radiation. So for example, you see how the salivary glands are very dark, right? It takes up a lot of radioactivity. And so, although the salivary glands are resistant to radiation, they're not very easily damaged by radiation, the high uptake results in dry mouth in many patients. The bone marrow on the other hand, has very low uptake. You actually don't see the bones in patients on the PSMA PET, but bone marrow, on the other hand, is a quickly dividing cell and because of that, it's much more sensitive to radiation. And so the irradiation from the blood pool activity, that transient blood pool activity, before the ligand comes out in the urine, will injure the bone marrow.

Now for patients and family members, there are actually two types of risks. So first is the emitted dose. The dose from that gamma radiation that's emitted outside of the patient that we talked about. But the other source of concern is urine. And we haven't talked about this yet, but if you think about it, nearly half of the radioactivity in a patient being treated with PSMA radioligand therapy will actually be excreted in a patient's urine. And the radioactivity in the urine is much higher than what a family member would be exposed to from what was being emitted from the body. And so it's really important in terms of radiation safety to pay attention to urine. So we obviously always recommend patients to sit down when urinating, wash their hands, double flush, wipe any urine that might've come outside of the toilet, et cetera, because that urine contains quite a lot of radioactivity and the urine is emitting those electrons.

Now the electrons generally aren't at risk to us because it's being emitted from within the patient who's being treated and is absorbed in the tissue of the patient, but in the urine, those electrons, if you were to touch the urine, would be interacting with your skin and potentially depositing a lot of dose on your skin. So the urine is something you want to be very careful about. And in patients with prostate cancer, this can actually become an issue because there are many patients who have urinary incontinence or are using Foley catheters. And these types of discussions should be had with the local radiation safety officers, about how to appropriately care for catheter bags, et cetera, and dispose of urine in a safe manner. In general, in the United States, radioactivity from a patient can be put into a toilet and flushed down a toilet safely, and it will decay through the timeline it will go through the sewage system in your city.

Now let's go back to our units. So when we were talking about gamma photons being emitted from a patient, it will interact with family members and those around the patient. And if we were to measure the radioactivity emitted from a patient, it measures roughly 2 mrem/hr at 1 meter. So this is a standard thing, if you've gotten one of these therapies, you might notice a radiation safety officer standing next to you with a meter stick and a Geiger-Müller counter and measuring the radioactivity emitted from the patient. So it will measure about 2 mrem/hr at the time of dosing, and maybe it'll fall to 1 mrem/hr at the time of discharge. The reason it falls so quickly is because a lot of radioactivity will be excreted in the urine. Again, the urine is a major source of radioactive contamination, that's something you do need to be concerned about.

Now, what are we talking about 2 mrem/hr, 1 mrem/hr? What do these numbers mean? I think it's really important to put these units into a context because it's very hard to rationalize those numbers as a risk to a family member. So if we remember that 1 mrem is about equivalent to 1 mSv, so we can convert, remember, the dose or the energy that's deposited from the radiation to the effective dose in the tissue, by going from millirem to millisievert. And 100 mrem equals 1 mSv.

Now I put in this little red box some doses that we interact with in a daily life. So to sort of put into context. So for example, if you were to fly from San Francisco to New York City, the extra dose you receive by being higher up in the atmosphere, so you get more cosmic radiation, is about equivalent to 0.05 mSv. So 0.05 mSv. A chest x-ray is about 0.1 mSv. A CT of the head, you get up to 2 mSv. If you're talking about the average yearly dose in the United States, it's around 3 mSv, and then that goes up with more complex imaging studies. So for example, the highest dose would be an FDG PET/CT might have upwards of 20 to 25 mSv of dose. So that gives you an idea of different doses in millisieverts that we interact with on a daily basis.

Now think about this, if you stand one meter away from a patient who is treated with PSMA-targeted radiotherapy and you stand one meter away for 10 hours, that will expose a family member, that individual, to a dose equivalent to a chest x-ray. So 1 mrem/hr times 10 hours gives you 10 mrem, which is about equivalent to the dose a patient would receive from getting a chest x-ray. And most of us never think twice about receiving a chest x-ray and the radiation from that. Five hours next to a patient, one meter away, would be equivalent to a flight between San Francisco and New York City. So I just want to use these numbers to sort of put in minds of clinicians and patients how much dose is being emitted from patients and how much risk there is to the patient. And again, remember the majority of the risk is actually in the urine because if you were to ingest that urine or touch the urine, the dose is much, much higher because the dose from the electrons is much more effective at depositing energy than from photons or the gamma rays.

So another thing to keep in mind, I think this is also important, is age is important in terms of risk of cancer. Now, a couple of things here, if you look at this slide, we're talking about the risk of 1000 mSv. Remember we were saying that 10 hours being one meter away from a patient is equivalent to 0.1 mSv? So in order to get into the realm of doses that actually have effect, you have to get 10,000 fold higher than that. But if you do get a dose that's 10,000 fold higher, this is the lifetime increased risk of cancer per thousand millisieverts. So for example, if you're the age of 40, receiving 1000 mSv will result in about 5-6% increased risk of cancer. And this data all comes from Hiroshima survivor data, very high dose rates, very different from medical imaging, but it gives you an idea of the scale of dose and the impact on risk of cancer.

The point I want to make here is that the younger you are, the more effective that dose is at causing cancer later on in life. And so when I talk to patients, I oftentimes sort of say, "The dose to those around you is very low. If they are two meters away from you, the dose is very, very low, but I would recommend probably not being around young children." I'm always overly cautious with young children. This dose is still many, many fold lower than the 1000 mSv here, but I would always recommend minimizing exposure to young children. I always use the example of a young child sitting on your lap. You don't want someone who's young reading a book on your lap for a long period of time who's very close to you. So just to highlight that age is an important factor in terms of risk. Once you get to 40 and on, this risk falls, and obviously it drops off over the age of 60.

Now in medicine, we have this term called ALARA, which stands for "As Low As Reasonably Achievable". And in general, in medicine, we believe that having no exposure to radiation is better than having any exposure to radiation. So we always make recommendations to try to minimize radiation as much as potentially possible. And so that leads to a lot of these recommendations patients might be receiving during treatment to minimize the dose to those around them. But I think it's really important to keep in mind, particularly, if you're a patient with prostate cancer, you're most likely over the age of 50 or even 60, maybe even 70, and your partner's similar age to you, the risk of a secondary malignancy is incredibly low in your partner and is probably nearing zero and isn't measurable. So just keep that in mind, you do want to be safe and you do want to minimize exposure to those around you, but at the same time, hopefully with some of the numbers I've provided you, it can put into context, the risk to the patient.

Now, that being said, when we think about ALARA in minimizing radiation exposure, we want to think about three things. So we're going to inject the radioactivity into a patient, that patient's going to emit these gamma photons, and those gamma photons are going to expose those around them. There are three things in general you can do to minimize dose. One is time. So radiation dose is directly a factor of time. So remember in the slide I showed a couple ago talking about 1 mrem/hr. You stand one meter away for 10 hours, you get 10 mrem. You're not going to stand one meter away for 10 hours, right? So you minimize the time around the radioactivity and that will minimize your dose.

So for example, I always give the example, if you have a partner who just was treated with radioligand therapy, you can give that person a hug very safely. You just don't want to hug them for 10 hours, right? So it's the time that's very important to minimizing dose and keep that to your advantage when you spend time around patients who have been treated.

Secondly, is distance. So dose decreases by the square of the distance. So if you double the distance you are from the patient, the dose will go down by a factor of four. And this is the easiest way to minimize a dose. Generally, I say that if you're more than two meters away from a patient, the dose is very near to zero and you're, in essence, getting no radiation from that patient. So the key here is if you're at a dining room table, maybe you sit at the other end for a couple of days to minimize dose, but you can safely be in the same room with patients who've been treated with PSMA radioligand therapy. And just maximizing the distance is an easy way to minimize the dose.

And then lastly, although it's not really relevant in this setting, is shielding. We typically talk about shielding, even though it says number two there, it should be number three. If a patient were to be behind a wall or something like that, you can obviously minimize dose even further. We use this a lot in the hospital setting because we're around radioactive patients much more frequently than the general population. And so we want to be extra careful about minimizing dose to ourselves as well.

So the take-home points, and hopefully I made these points throughout this talk, is first, radiation exposure from external beam radiation therapy and targeted radionuclide therapies are very different. External beam, only when the beam is on, patients aren't a risk to those around them afterward. Targeted radionuclide therapy, the patients are injected with radioactivity and will emit radiation for weeks after treatment that can potentially irradiate those around them. The dose to the patient which results in toxicity is from beta emission. But in general, beta particles don't leave the patient and they don't interact with family members except for urine and urine is the big contaminant that we want to pay attention to.

Gamma emission, this gamma-ray that will extend beyond the family can expose family members to dose, but the dose rate is very low. And remember the 10 mrem, if you're around a patient for 10 hours who's emitting 1 mrem/hr is about equivalent to a chest x-ray. So the dose rate's very low. And just keep that in mind, when you're trying to rationalize the risk from your loved ones who've been treated. And number four, there are definitely ways to minimize exposure and those would include time, distance, and shielding in order to minimize the dose to those who are around you. So thank you very much. And if you have any questions?

Phillip Koo: Great. Thank you very much, Tom, for that great presentation. It's wonderful how you were able to break down a very complex topic into easily digestible parts. Also interesting to learn how social distancing might've originated from radiation safety. So let's start off with some conversations with Alicia and Neal, both of you had enrolled patients into the VISION trial in the past. What are your thoughts on some of the radiation concerns that you faced from patients given your experience with the VISION trial?

Neal Shore: Well, I'll be happy to answer. Well, first, I agree that was a wonderful presentation. Tom, you did say one thing that I have to say really resonates with me as a urologist, you said, pay attention to urine. That's what we do as urologists, we're all about urine, but all kidding aside, that was the concern for me with a couple of my patients who had external catheters. One patient had an indwelling Foley catheter, one patient had a suprapubic tube catheter, and one patient had bilateral nephrostomy tubes. And so we did spend more time with those patients in terms of the issues that you brought up, in terms of just the traditional universal precautions about how to work with their catheter bag, drainage systems, and how to be cognizant of incontinence. So I really thank you for that. It wasn't a deal-breaker for getting the patients into the VISION trial.

I think the points that you make, Tom, are so good because so many of my urology colleagues and I think medical oncology colleagues are really ... We work a lot with radiation services, but indeed, targeted radionuclide therapy, this TRT acronym, I like it because it specifies the difference in the fields of radiation. So I guess one question I might have for you, Tom, is what are some of your suggestions for further enhancing this radiation safety education? You're spending your career doing it, but how do we get this knowledge, in addition to doing programs like this, for our referring colleagues, urologists, and med oncs, as part of the multidisciplinary team. Because TRT is here and it's going to get approved, hopefully, and it's going to really dramatically change how we treat many of our advanced cancer patients, particularly prostate.

Thomas Hope: I think my ... How do you get information out there is doing things like this, as you just mentioned, but I think the other thing to keep in mind is that TRT is generally done with nuclear medicine and in our field, this is what we do, right? We've been dealing with radioactivity injected into patients who emit radiation for years. The main example of that, historically being radioactive iodine, you have the same issues with urine radiation, gamma exposure, everything's very similar and the doses are in the same range. And actually, the gamma percentage is higher with I-131, so there's more radiation safety issues with that.

And so there actually, you might not be aware of it because we don't do this in urology very often, but there's a fairly robust system put in place in most hospitals, and nearly every hospital offers I-131 treatment, so radiation safety officers are all present. So I think having nuclear medicine be part of the therapy team and helping educate the urologists, medical oncologists, about this, who might not be as familiar with these types of therapies, is key. But once you start doing this, I'm sure at your hospital, Dr. Shore, you found this out, when start asking around, you're like, "Oh, we do have people who have knowledge in this." And radiation safety officers, radiation safety committees, all of these things are actually regulated by the NRC and are required to be present in all hospitals. And so the experience is actually there, it's just sort of bringing them into the loop into a disease that they haven't historically been active in.

Alicia Morgans: So thank you. And thank you for such an excellent presentation. Just to respond to Phil's question, we actually had, I think, a pretty smooth time using lutetium in the VISION trial. We definitely had a patient who was incontinent, who we had to think about strategies of how to make sure that that was not an issue in terms of contaminating the room and contaminating things otherwise, and catheters ended up being part of the solution for that. But the other issue that our medical oncology patients end up facing, and many of the patients on VISION potentially could face or when they're treated as outpatients could face, is potentially being admitted to the hospital, going through the emergency department right after they've had their lutetium. And this happened to a couple of our patients. So if you had to give just a couple of quick pointers to patients or to physicians to communicate to their patients, what would they be for a patient who needs to now go to the emergency department and potentially be hospitalized and they need to communicate about this?

Thomas Hope: Yeah. So that's a really good question about when these patients come in and when they're radioactive and they're emitting radioactivity into the hospital. So the first point you want to get across to any patient who's been treated is never, ever prevent yourself from going to the hospital when you need to. The risks of radiation are irrelevant in the setting of acute care that's required for a patient. I think that's really important to get across to a patient. So then the question becomes, okay, you do go to the hospital, then what? And I think important thing is to tell the hospital, the ER, you always tell them what's going on with you, but to mention that you're radioactive. Remember, the dose rates I just described are very low, so you're not endangering the ER nursing staff in a significant way, but you want to let them know because, for example, one of the nursing staff might be pregnant. You might not know that. And you want them to be aware of it because you might be ... We obviously want to minimize exposure to certain populations where we're being overly cautious.

Then what will happen is the people who you've told will then communicate with the radiation safety officer, radiation safety committee, and depending on where they throw you, are you going to be admitted or discharged, et cetera, they might use different rooms to put you in, et cetera. And so every hospital typically has a system in place for the admission of these types of patients.

Now, that being said, I think one of the questions might come up is, do you want to be admitted at the hospital where you were treated? Because oftentimes it's easier that way, because the communication's quicker, the radiation safety officers are the same, and so it might be more simple. But a lot of these patients travel a great distance, so it might be a little bit more difficult in a more rural community center that doesn't have as much experience with this, but that's, I think, the only thing that one might consider, is maybe going into a hospital that's more familiar with these issues. But in general, I think the point I wanted to get across, these are relatively safe things, even if you do go to a hospital, but never, ever try to stay away from a hospital because you're fearful of putting other people at risk.

Phillip Koo: Great. Thanks, Tom. So there are some global variations in release criteria and the practices of radiation safety, in Europe versus Australia versus the U.S. And frankly, even in the U.S., there are variations by state or even by facility. Can you talk a little bit about that focusing on the PSMA therapy, particularly from the European and maybe Australian point of view?

Thomas Hope: Yeah. So the different countries have different rules about when patients can be released into the general population. And that's usually based on things like that unit, the millirem per hour, how much radioactivity a patient's emitting before they're allowed to be discharged from the hospital. So generally in the United States, we like to see patients below 2 mrem/hr, without even providing them any guidance. So if you're emitting less than 2 mrem/hr in the United States, generally by NRC guidelines, you actually don't even need to provide the patient guidance about how to minimize dose to those around them. We're sort of lucky in the United States with the experience from lutetium DOTATATE because we now have many years of experience treating patients with lutetium-based target radionuclide therapies and so the radiation safety is obviously very similar. Both are excreted through the urine, both emit the same gamma photons, and the biodistribution is similar enough that the risk is very similar.

And so the thing I do find interesting that you pointed out is that the recommendations provided at different hospitals in the United States vary dramatically. So in essence, if you think about a spectrum in the U.S., one end of the spectrum is iodine guidelines. Remember how I said I-131 has a higher exposure rate? So they have all these rules about using your own utensils, because it comes out in your saliva, changing clothes because of contamination, and bagging your clothes for multiple weeks and washing them separately for iodine therapy. That would be one end of the spectrum. I think that's overkill. That's not what we do.

The other end of the spectrum is there are hospitals in the United States that don't provide any guidance. That say, "You're below the 2 mrem/hr cutoff from the NRC, we don't need to tell you anything. Maybe we'll deal with people who have urinary incontinence, but other than that, you're free to go into the general public." So that's one, the other end of the spectrum. There's no right and wrong here, it's sort of where you feel comfortable making recommendations, I'm somewhere in the middle on that spectrum.

In Europe, they just have a much more strict guideline in terms of the amount of radiation that you can emit in order to be released into the general population. And so even with thyroid ablation, they have to admit patients that we would never do in the United States. So these differences have existed for many, many years, simply because of differences in rules around release criteria.

Phillip Koo: Great. So we'll go on to the closing comments. We'll start with Alicia, then Neal, then Tom you'll have the last word.

Alicia Morgans: Well, I just really appreciate you going through these equivalents thinking about it's equivalent to an x-ray, or what do you do when you have incontinence or admitted to the hospital? I think these are really practical things that we can all hold on to to share with our patients. And that's going to be really helpful because there is a little bit of an unknown around radiation in this way. We've used external beam radiation for a long time. We've used radium, but that's an alpha particle. So now going to a new type of radiopharmaceutical and embracing it wholeheartedly, if it is approved, I think does require this little bit of extra knowledge that I appreciate you sharing. So thank you.

Neal Shore: Yeah, I would say the same. You gave a great primer on the definitions and the history. I love the history, both the Curies and Becquerel, they shared a Nobel Prize in physics for understanding radioactivity. And you did a wonderful job of, in a really concise way, of describing it. I'm going to watch your presentation a few more times. I love the acronym, ALARA, as reasonably acceptable, that's cool. That kind of gives sort of a correlate to first, do no harm for a lot of the things that we do.

Just to reemphasize everything that you said, Tom, we're into this new period where the multi-disciplinary care of patients is optimized in so many ways, breaking down barriers, and medical oncologists and urologists working together now with nuclear medicine, radiologists, radiation oncologists, primary care physicians, cardio-oncologists, neuro-oncologists. And this is really the ultimate way that we're going to enhance care. So I really thank you. And one of the barriers, I think, for a lot of us is not understanding adequately what's safe and what isn't and your presentation was ideal for that. So thank you.

Thomas Hope: Great. Well, I guess I get the final comment, but I think in general, you guys highlighted the main points. I think the main point for me would be that this isn't unknown. That you, at all of your hospitals, have colleagues who are experts in this, who know about this, and bring them in if there are any questions. There are resources available to help patients understand, help clinicians understand, and to make sure that these treatments are done in a safe manner, which they can easily be performed very safely. And there are decades, I mean, the first iodine therapy was done in the 1940s. The field of nuclear medicine has been involved in these treatments for decades, and it can be done very safely, and there's an incredible amount of knowledge about radiation risk that's available. So just be sure to work with the people in your local facilities to understand this and make sure that everyone's on the same page.

Phillip Koo: Wonderful. Thank you very much. Just another reminder that nuclear medicine is your friend, so we can all work together and achieve great things. So thank you all for your time and we look forward to hearing from you again in the future. Thanks.