Alok Khorana of the Cleveland Clinic and David Kross of Brigham and Women’s Hospital discuss management of depression, anxiety and distress in patients with cancer and the risk of thrombosis among cancer patients and how to avoid it.
That's my distinguished pleasure to introduce Doctor David Kroll. Uh, Doctor Kroll is the medical director for behavioral health, um, and, uh, assistant professor of psychiatry at, at the Harvard Medical School. Um, he's a fantastic friend and colleague of ours, and he's been doing this for several years. Uh, Doctor Kroll, we do see you on the screen and we see your slides, my friend. How are you? I'm good, thank you. How are you? Doing well, thanks. So without further ado, I'm gonna, uh, Doctor Kroll, take it away, my friend. OK, sounds good. Thank you very much for the introduction, um. I should note actually, I can't see you, um, and I might not necessarily get messages to pop up, so if you have questions or wanna interrupt me at any time, just, just speak up and that's OK. I don't mind being interrupted. Um. I'm really sorry not to be there with you and, and really grateful to the conference organizers for making it work for me and Jeremy to do this remotely. Um, for what it's worth, I think it's actually warmer in Buffalo than it is in the Boston area right now. Um, but at any rate, really glad to be able to be here. I'm gonna be talking about, um, The, uh, this other side of the coin, anxiety, depression, and existential distress. Um, my, just my disclosure, so I, I work for a telehealth company. Um, I'm not gonna be talking about any telehealth today. Um, so there's a lot to cover here, you know, I, last time I did this, uh, I had a similar topic, and I spent most of the time talking about, um, the new research into psychedelic treatments. Uh, some of you were probably there for that, um. What I'm gonna do today is mostly just kind of like a bigger update. So really putting that into the context of like, just what do you do in general? Like how do you come up with a treatment plan? Let's look at the updates on all of this stuff. Um, but think about how it all fits together because not everybody's necessarily gonna go straight to psychedelic treatments, even though I think a lot of people probably want to. Um, so we're gonna start with first-line treatments, you know, how do you make sure that you identify first things first and, and, uh, you know, not bypass that part. Um, we're gonna talk about the overlapping between, uh, what actually makes a, like a psychiatric diagnosis, what we call a DSM diagnosis that needs a specific kind of treatment, um, and the other kinds of psychological distress that tend to happen and crop up in the setting of cancer. Um, again, those are not the same thing, but they may overlap. And then we'll kind of go into a little bit of an update about um the psychedelic treatments, um, and just thinking about like advanced treatments in general. Um, there's not a ton of like research updates that I have to share about that in the last year, but, but just kind of updates in terms of practically speaking, how to access that, um, should your patients want to go through that, um, and then anything kind of a little bit more about what to expect on the horizon. So this is a little bit more, uh, just as a, just to set the tone, um, preaching to the choir here. I think I'm not gonna tell you anything you, you don't know here, uh, but mental health is a really important part of cancer care, right? When we try, when we take care of patients with cancer, uh, we take care of the whole person and the mental health is a big part of that. It's really stressful. People can experience, um, all sorts of crises, uh, in the setting of going through cancer treatment regardless of what the, the diagnosis is. Um, so here are just the statistics, um, you know, with active disease, we know that both anxiety and depression are really, really common, uh, when anxiety and depression are, are present, that can be associated with worse outcomes. Including mortality, uh, the same is true of survivors. Um, in survivors there are still really high rates of anxiety and depression, uh, even with successful treatment, um, higher than, uh, yeah, higher, uh, than in the general population, it's still associated with higher risks of mortality that includes, uh, lower survival rates in general, but also of course suicide risk. Um, probably not surprising there are racial disparities in terms of access to treatment. Uh, so it's really just important to think about the whole spectrum of disease and survivorship, you know, this is a group, I, you know, the, the, it's, it's the task of everyone, including the oncology team, to be thinking for and planning for what other patients' needs going to be beyond just the direct cancer care and, and, you know, mental health is a big part of that. So, uh, again, I don't think I'm telling you here anything that you don't already know, um. But, uh, just really important to keep in mind as we go forward. So Psychological distress can take many forms, um, you know, what, what do you do? And I actually often will, um, you know, give cases in primary care talks, for example, about, you know, so and so was recently diagnosed with cancer, they're having a lot of depression and anxiety, uh, what do you make of this, right? And the answer is it's not necessarily that easy to tell. Um, but I want to kind of start to go ahead and make the distinction between like what is an actual, um, DSM psychiatric disorder that would mandate a specific kind of treatment, uh, as opposed to what are the other kinds of psychological distress that commonly occur in cancer. Um, the good news is that the types of psychological distress that deviate from a regular, uh, from a, from a more typical psychiatric disorder, um, have actually been described as, as distinct items that are likely to, uh, occur, um. You know, one of the things though, that the DSM does not help us with very much. And this is a well recognized pitfall of psychiatric diagnosis and the kind of the manual that we use to do this is that the DSM tends to assume that symptom clusters appear at a specific moment in time, right? They have this list, you know, we think about like major depressive disorder, we're diagnosing ciggy caps, OK, if they have during this 2 week or 2 month snapshot, um. You have the following symptoms, you know, depressed mood, anhedonia, sleep problems, appetite problems, uh, psychomotor retardation. Uh, and by the way, um, It doesn't matter if you're sleeping too much or sleeping too little. It doesn't matter if you're too hungry, you're not eating at all. You have psychomotor retardation, uh, psychomotor agitation, meaning you're sped up or slowed down. Your sleep might be disrupted in the setting of like you're waking up early in the morning, or maybe you're having trouble falling asleep at night. Um, interestingly enough, there's a group of researchers that did a study, a research study, um, looking at all the different permutations of major depressive disorder based on the DSM criteria. By permutations, I mean if those of you who may remember, um, advanced high school math, if any of you did, I think pre-calculus and calculus, um, this idea of like calculating the permutations. And they found out that there are over 16,000 different permutations that would meet criteria for that one disorder, some of which involving symptoms that are very contradictory to each other. So this is already a really heterogeneous condition. Um, but what the DSM tends to do is talk about these conditions as if it's like just a snapshot in time. OK, if you have all of these symptoms, you have major disorder. If you have all of these symptoms, you have generalized anxiety disorder, um. But what it misses is that these disorders, these diagnoses actually tend to have longitudinal arcs. You know, it tries to get at that, the, the, the manual tries to get at this by saying it has to be present for a certain period of time, um, but the reality is they actually follow these fairly longitudinal arcs. So, generalized anxiety disorder is a chronic lifelong condition. So individuals who have GAD generally are anxious kids, and they identify, you know, you'll talk to them. Oh, I've always been a worrier. I've always been more anxious. I tend to be, you know, more anxious than my peers, you know, and, and this is like a lifelong story, it's an inherent part of their personality. They might not necessarily have clinical significant clinically significant anxiety at every moment of their lives. But they tend to get more generally anxious in the setting of stress, more prone to catastrophizing, and they have that history, right? So, um, somebody who has like legitimate generalized anxiety disorder is going to be able to tell you fairly easily, like, yes, I'm an anxious person. I've always been somewhat of an anxious person, um. And you know, this is kind of how I cope with stress with MDD, um, major depressive disorder, generally speaking, there's this history of relapsing and remitting depression. So people who are prone to major depressive episodes tend to have this history of, you know, I had a postpartum depressive episode, I had an earlier episode in my twenties, and I've kind of been prone to kind of like waxing and waning. Um, this is such a heterogeneous, uh, diagnosis. There are subsets of people who will have their first depressive episode in the context of cancer, and it may be later in life. So the absence of a history of major depressive disorder. Does not exclude that someone might have MDD, um, but often there's a clue, and, and MDD is gonna be one of the situations where it's gonna be a little bit harder to distinguish, um, but in addition to these diagnoses, you know, what we come, the three that come up most commonly in cancer are demoralization. And I will admit that demoralization is something that's gonna be very hard to distinguish from a major depressive episode, but the idea of demoralization is like more of a psychological state of, I don't wanna do this anymore. This isn't working. I'm feeling really hopeless. I'm feeling really burned out, as opposed to major depressive disorder, which is both a psychological and a physiologic state where you're gonna be having a lot of those neuro vegetative symptoms. So, I commonly see demoralization mostly like an inpatient setting, so somebody who has more advanced disease or they've had a really prolonged, difficult time of it, um, and they just don't feel like going on, and they, you know, may or may not really have major depressive disorder, but they just feel really burned out about their care and about their treatment. Um, fear of progression is a very specific subset of anxiety. This is a type of anxiety where people are, um, again, really common in cancer, really excessively preoccupied with worry about specifically about their disease progressing and what the next steps might be, you know, whether or not that correlates with their actual prognosis. Um, this is important to recognize because A, it's really common, um, but B, it's also associated with a higher risk of depression. The difference between FOP and generalized anxiety disorder is that people who are anxious are going to be anxious in general, and they can have that longitudinal history of anxiety, whereas people with FOP are just, you know, they don't necessarily have any history of, uh, anxiety they can identify, but they're very fixated on this one thing. Uh, and then finally, death anxiety. This is something that is going to be more common in individuals who have, uh, a recognized poor prognosis, um, but, you know, most people who are diagnosed with cancer are going to experience some degree of worrying about dying. Um, this can be really have a really significant impact on the quality of life and can be very difficult to deal with. Um, so again, just really important to recognize, try to, try to address that, identify when you see this again, is there a history of a DSM diagnosis, um, and also recognize that when people have this anxiety, there is this human tendency to say I'd rather be sad, uh, than anxious. I can't deal with this uncertainty, right? And so they would, uh, they might start to express more feelings about wanting to be dead. Uh, in the sense of like, I'm afraid of being dead, but I'd rather just go through with it and get it over with rather than deal with this kind of uncertainty. So, again, when you see this, recognize these phenomena are likely to, are, are, are likely to crop up, uh, and then your task is try to, you know, again, hope, hopefully with help from other team members, figure out what about this is just a very specific psychological state, uh, and how much of that overlaps with a, with a DSM diagnosis. Ultimately, you know, the reason that this is important. is because practically speaking, um, DSM diagnoses typically mandate specific kinds of treatments. And so, most types of depression and anxiety that are like, again, fall under this aegis of a, um, psychiatric psychiatric disorder might respond to psychotherapy, they might respond to antidepressant medication. Um, you know, we often say for most types of depression and anxiety, uh, antidepressant medication and psychotherapy are equally effective. The combination is more effective. That is an oversimplification, uh, because that sort of looks at the data in aggregate. The reality is for some individual patients, antidepressant medicine will be more effective. For some individual patients, anxiety psychotherapy is going to be more effective. Uh, you can't necessarily always predict that, but recognize that when you're treating a psychiatric disorder, you have these tool sets available to you that are going to, um, You know, thinking about like what, how do I access treatment and any of these options might be the right choice, um, for other kinds of distress, uh, kind of going on this list of like this idea of the fear of progression, death, anxiety, uh, I actually think that those probably are best characterized as adjustment disorders, the different subsets of adjustment disorder, right, just experiencing really clinically significant psychological distress without necessarily having a clearly identifiable psychiatric disorder, um. For those adjustment disorder category of of experiences, antidepressant medicines less likely to be effective. There are some people with adjustment disorder who feel better when they take an antidepressant medicine because it can just calm down the stress response and calm down anxiety. But for the most part, that's a group where you want to think about other kinds of supportive measures and psychotherapy if you can access it, um, and mobilizing the support system rather than thinking about rushing them into treatment per se. Recognizing that there may be, you know, medical options to treat with other aspects of this, so, um, you know, individuals who have poor sleep, for example, uh, often benefit from a medicine for sleep. Um, the secret weapon that I often reach for, particularly in cancer care, is mirtazapine. So mirtazapine is a first line antidepressant medicine that has two main side effects. It makes you sleepy and it makes you hungry. Um, and I remember when I was learning about mirtazapine as a medical student. Um, my initial thought was, well, who wants to take a medicine that's going to make you gain weight and feel really sleepy? And the answer is people who are feeling physically sick and not sleeping. And mirtazapine actually does have some anti-nausea benefits, um, and so, so for an individual who is dealing with cancer treatment, not feeling really wound up, not sleeping well, maybe not eating well, maybe loss of appetite, maybe having nausea, either as a part of their treatment or part of their disease, um, mirtazapine can often be the secret weapon. Uh, because even if it's, even, even if it's not clear that there's a clinical diagnosis of, uh, an anxiety disorder or depressive disorder, uh, it can split the difference because you can use it in low doses and it might have a benefit for anxiety and depression directly, but it should, uh, at least help with appetite and sleep for many patients. Um I'm actually gonna go to this in a little bit more detail in a moment, um, but, uh, if you do choose or your patient's really interested in psychedelic treatment, so again, I meant, I talked last year, I talked in a lot more detail about the research, uh, and the pitfalls about this. Um, still, we are in the setting process of like seeing phase 3 trial results come to fruition. Um, the data of psychedelics assisted psychotherapy, uh, are promising so far. There is, it is on track for review, um, by the FDA, uh, probably in 202017, 2027. Um, it's not clear what the FDA will do. The FDA has been, um, somewhat conservative around these treatments, and it rejected a treatment last year for a similar psychedelic associate assisted psychotherapy for PTSD using MDMA. So we don't really know, uh, but these treatments are being studied and the research is, uh, very interesting. Um, just as a reminder, like what psychedelics assisted psychotherapy is, it is not a prescription for mushrooms to use in your basement. It is primarily a psychotherapy treatment. So, most protocols employ something around like 6 psychotherapy sessions with the idea of really having the therapist understand what your needs, who you are, what you're looking to experience. Um, then usually 1, maybe 2 sessions that are facilitated by, uh, psilocybin or another agent. Um, and that's guided by the therapist. Again, the idea being that if you were to take mushrooms on your own, you could have a really unpredictable experience, and it might not be good. Um, but having the psychotherapy prepare you for the process and having the guide to work through it, uh, can help, uh, make that experience more predictable and more targeted to what you're looking for. Uh, what people who have gone through this treatment will say is, um, A, uh, there are some direct serotonin, serotonergic effects of psilocybin, which may explain part of the anti-antidepressant effects, but also the psychological experience of this disruption of what's called the default mode network in the brain. The default mode network is a, Is a baseline activity in the brain where one of the core functions is, um, making a distinction that I am distinct from this computer or this coffee cup. Uh, I am an individual person and what people experience when this default mode network is disrupted by the agent. Is they experience, I'm a part of this world. I'm a part of something much bigger, a part of this planet. Um, and so the idea of this like, um, uh, intense sort of like. The idea that I am an individual who's going to die, uh, gets replaced with I'm a part of this planet and, and I'm going back into this, this, um. You know, part of what I already am. Uh, again, I'm not necessarily endorsing that, that, that, uh, I have not personally experienced it, uh, myself, but that's the kind of experience that people are talking. So, uh, basically, like, in order to get this treatment, you have to be, it's commercially available specifically in Oregon, um, and you can be part of it as a clinical trial, but otherwise it's not FDA approved, it's not, um, uh, it's not available for, you know, commercial use outside of Oregon. Uh, and the targets are going to be either existential distress in the setting of expected death, uh, or poor prognosis. Um, many of the research subjects have been, uh, studied in cancer, um, also being used in treatment resistant major depressive disorder. So I have a case study. Um, this will be brief. Uh, one of the things, and, and, and I welcome feedback on this. So since I work for a tech company, I have much more ready access to AI to help me do things like generate pictures of, uh, a patient that I made up. And so this is an AI generated patient. We're gonna follow him through this course, um. And I realized actually I'm giving you this case. I, I had intended to run this case by Jeremy to ensure accuracy, so bear with me if this is not a great treatment plan for uh lymphoma, but, but, um. We're calling this TM. He's a 52-year-old man with stage 4 mantle cell lymphoma undergoing RCHO, and he's at Roswell Park. Um, he has a lifelong history of mild to moderate anxiety, but this was not previously associated with any dysfunction, and he has never received treatment for it. Um, now he says that he is almost always preoccupied with anxiety about his cancer and his quality of life has deteriorated. He is not sleeping well, and he is not eating as much because of frequent nausea. He's beginning to feel depressed. Um, so you can probably guess what I'm setting you up for here. This is a case where like, Uh, you know, he, he doesn't clearly have a like glaring diagnosis of GAD, but his history suggests that he probably does have some mild GAD that's just never really impacted his functioning, uh, and that's just really now amplified in the setting of this like super stress bomb. Um, oh look, he's not sleeping and eating very well. Uh, what am I gonna do here? Um. So, you know, this is something that, again, thinking about this first line treatments, uh, this is not someone you necessarily need to rush to psilocybin treatment. Um, this is someone where medicine and or psychotherapy might be appropriate. Again, mirtazapines might be a nice choice for him given his sleeping and eating issue. Um, if you happen to have access to a social worker or a therapist. Or a social worker who is a therapist, uh, you know, they can often help kind of thinking about like the psychosocial support, mobilize the support system, help provide a little bit more direct support, uh, and consult with psychiatry, right? So this is nothing new, earth shattering. This is fairly common stuff, you know, lead with common, common treatments. However, you know, if you, if this case doesn't go well, right, this is a case that might lead to more of an advanced treatment. Um, he has now failed 4 cycles of chemotherapy, and he's planning to proceed to CAR T. He's really miserable. Uh, mirtazapine was modestly helpful for sleep, but not anything else, so it didn't work that well. It's not a slam dunk for everybody. Uh, and he has since been taking sertraline for anxiety and depression. And maybe this helps a little bit to take the edge off, uh, although his prognosis for remission on CART is still fair, fair. Again, I realize I, I, I really should have run this case by Jeremy, so apologize if I'm, this is a cringy treatment plan. Um, he has dealt with other health problems over the past year and remains extremely anxious about both dying and what his quality of life might be in survivorship. So this is starting to become a little bit more serious, right? This is, you know, he's tried a few first line treatment. First line treatment has not been effective. It doesn't mean future first line treatments won't be effective either, um, but this is something that's sort of progressing towards more of like something that looks like they might need advanced care. So, um. This slide is a little bit more complicated and so I'm gonna toggle back and forth between the different kinds of treatment categories, um. But in these advanced cases, again, I want to kind of like continue to try to make a distinction between what what would be appropriate for an advanced. Depression case, uh, that is resistant to treatment versus what would be more appropriate for, uh, just existential distress that's likely to arise potentially at the same time and may or may not overlap. Um, so when you have treatment resistant major depression, there are many options for that. You know, generally what that means is we go with first line treatments, but once you identify treatment as treatment resistant, which is actually technically speaking, um, failure of two therapeutic trials, some, um, insurance companies will require 4 before they'll authorize this. But generally speaking, that's when you want to be quicker to get psychiatry involved if you have access to that, um, and then thinking about like what are the advanced treatment options that includes advanced medications, uh, you know, adding an antipsychotic medicine. Uh, moving to ECT or transcranial magnetic stimulation, going with a ketamine or ketamine treatment, um, advancing the psychotherapy, or thinking about psilocybin-assisted psychotherapy. And again, I'm putting these asterisks. This is not an FDA approved treatment, but this is something that in particular in cancer, a lot of patients are gonna be asking about. And so in the context, what I'm gonna say about the psilocybin treatments is that's one of many options. Uh, and the idea is you want to, ideally, again with the help of a psychiatrist, if you have one consulting with you. Um, thinking about like, this is a chance to advance the treatment. This is a chance to think about like, what are the options here. Again, there are many different options. One of them is the psilocybin treatment. Um, but in existential distress and cancer, um, if, if in the absence of what's kind of a clear MDD diagnosis, uh, in particular, um, I'm really talking more about depression now at this point, um, you wouldn't want to be thinking about advanced treatments for depression so much, right? So this is really more of like demoralization, fear of dying, existential distress that's not clearly tied to like, What looks like major depressive disorder. This is one where you want to think about more, less about like what are all, what's what's the menu of options for treatment of MDD versus let's think about like existential cancer distress specifically. And this is one again where you might be able to get really good psychotherapy options. Sometimes group psychotherapy can be really helpful, but this is one where you might be thinking a little bit more, hey, this person is a good candidate for thinking about psilocybin-assisted therapy. Would they be able to access it? So, right now, the two ways to access it are, um, going to clinicaltrials.gov, um, and, uh, type in cancer and psilocybin. Actually, when I did this for the, uh, just to get a screenshot, ironically, the first one that came up was in Buffalo. Um, this is one that is specifically, uh, with chronic pain on opioids, so I don't know how many of your patients would be eligible for this, uh, but that is one option. But literally, you go into clinicaltrials.gov, you type in cancer and psilocybin, um, and then see if there's anything enrolling that your patient might be a candidate for, and then they can, they can look into that and, uh, again, you can diff different formulations, psychedelic as well. Um, and see what, what comes up. Um, if you're inclined to go the Oregon route, again, your patient will need to pay out of pocket for this. Um, these services, uh, again, can be the wild west cause it's not really an, an approved medical treatment yet. Uh, but the Oregon Health Authority actually has, uh, guidance for people looking to do this, um, and can find, identify more reputable places to do it. Um, so I shared a link earlier on a slide. Um, it's pretty easy to Google, uh, but if you have access to my slides, you can click it, um. Just go to the website, get a little bit more detail, and, and the patients can actually find the treatment there if they're inclined to do that. Uh, but again, they'd have to travel to Oregon and pay out of pocket. So, Um, just kind of summing up where we are, I think I'm right at time. Um, first line treatment is still first line treatment, so please continue to think about first line treatments for most of your patients, particularly at the outset. Um, remember that medicines will help in some cases, but, uh, for patients with more of adjustment disorder type issues, you want to be thinking more about psychotherapy and other methods of like mobilizing psychological support. Um, and the psilocybin treatments are really exciting. Um, they may change the game if they do get FDA approved, but they are not yet FDA approved. They're not widely available, uh, so accessing them just requires a little bit of, of finesse, um, but they are, you know, pretty promising, so I think that, uh, I'm at time. Thank you so much, Doctor Cole. I'm gonna ask you to, um, stay on standby if you don't mind. Uh, I'm gonna choose our next speaker and then we're gonna invite you back for a little Q&A unless there are any burning questions for the moment. But, uh, thank you doc. That was fantastic. We really appreciate you. Um, I'd like to introduce our next speaker, uh, Doctor Olo Corona from the, uh, Cleveland Clinic. Um, Doctor Corona was, um, a ruthless, um. Professor, um, at me as a, as a fellow when I was there just kidding, he's he's, um, a great friend and colleague, huge Buffalo fan, by the way, um, Doctor Corona is gonna talk about, um, the Corona score what uh his eponymous, uh, score among other improvements that he's working on Corona. Thank you. It's great to be back in Buffalo. I trained here. Um, it's great to see old friends. Thank you to Matt and Francisco for the invitation to discuss. Um, I am going to talk about cancer associated thrombosis, which includes primarily venous events, so deep venous thrombosis, pulmonary embolism, but also arterial events, stroke, MI, peripheral arterial embolism, and together these events have risen over time. Uh, the figure on the left shows the rates of VTE for people without cancer and then rates of ETE for people with cancer. And as you can see for people without cancer, the rates have stayed pretty steady over a 20 year period, whereas for people with cancer, they've given, uh, risen quite significantly. Same thing on the right, uh, the left is a Danish registry, the right is a US registry, but the same thing you see across different types of cancers and you see across different time periods and then every time in every cancer, the more recent time period has the highest rates of, uh, venous thromboembolism events. We don't quite understand why this is happening. Uh, it's partly almost certainly related to increased, uh, exposure time, and by that I mean that cancer patients are living longer and are being exposed to cancer drugs for a longer period of time, and many different cancer drugs, including immune checkpoint inhibitors, including, uh, bi-specific antibodies, uh, CART, um, and certainly chemotherapy are associated with high rates of, uh, continue to be associated with high rates of DVT and, and PE. Uh, I don't need to tell this audience that thromboembolism is very consequential for people with cancer. Um, the diagnosis of a VTE leads to a need for prolonged therapeutic anticoagulation, which paradoxically also carries an increased risk of bleeding. Uh, once you get one blood clot, you're at a risk for a second blood clot, so there's a high risk of recurrent VTE. Um, both, um, the diagnosis of ETE, the anticoagulant medications, uh, the need for emergency room visits, hospitalization, all of that adds to cost burdens to the patient and cost burdens to the system, and delay or interrupt anti-cancer therapy, uh, and possibly most strikingly, there's a strong association of ETE with a worsened overall survival as well as increased short-term mortality. And those two are a little bit different. I wanna talk about them because it's relevant to one of the papers I'm gonna discuss today. Uh, worst in overall survival is if you take a bunch of people with cancer in the same state, same treatment, and some of them get a clot and some of them don't, the ones who get a clot have over 6 months or a year or 2 years will have increased, will have, will have worsened survival for reasons we don't fully understand but are possibly related to. Uh, either being a surrogate for a more aggressive malignancy or some type of interaction between the coagulation cascade and the way cancer progresses, and that science really still needs to be sorted out. Short term mortality is when the blood clot itself is lethal, and, uh, together venous and arterial events account for about 1 out of 10 deaths in cancer patients, and they're tied for the 2nd leading cause, cancer being obviously the number 1 leading cause of death in people with cancer. It's very consequential for cancer patients. Today I'm gonna talk about just 4 things, OK, so bear with me. I know it's Sunday morning. I know there's a hockey game later on today, so we'll, we'll, we'll, we'll get through this. The 1st 2, there's not a lot to talk about, so it's kind of gonna build up to the, the second half here, uh, very quickly on risk assessment, um, for. Uh, many years, one of the ways to assess risk is by type of cancer, and in this paper that was published, uh, uh, presented at AS, they sort of continue to show the same thing. It's the same cancers you've always known to be associated with, uh, DVT or PE, pancreatic cancer, primary brain tumor, but also a lot of hematologic malignancies, ALL, AML, uh, myeloma, um, and so no surprise there. But risk of ET is not just driven by cancer but by other factors as well. Um, as, as Matt mentioned, there's a score that my colleagues and I developed, uh, almost 20 years ago. Um, and since then there's been different variations of that initial risk score that have been presented. This was evaluated in a recent Ash abstract and now it's a full paper. For, so for nearly two decades of clinical risk assessment, 28 studies, 12 versions of the different versions of the risk score, and bottom line is that these, all these modifications showed limited discriminative ability and not superior to the original score, which is great for sort of my personal brand, but not so great for the field. So hopefully we'll have, um, something better coming along. What could something better be? This is a paper from Ang Lee's group presented at Baylor, presented at Ash also. Looking at plasma proteomics, so they took people with cancer with a clot, and people with cancer without a clot, and then sort of did proteomics-based assays and then a time dependent sort of curve to see which way they ended up. They found people who are at high risk for clots, people who are at low risk for clots, and then they analyzed which proteins are up regulated and which proteins are down regulated, and some of the proteins you'd expect, especially related to platelet aggregation and signaling, were up regulated. Uh, inflammatory pathways are regulated, so both insights into pathophysiology and potential biomarkers, but unfortunately nothing yet from prime for ready for clinical use at this present time. So not a lot of progress on risk assessment. Um, primary prevention, no new studies because the studies have been sort of pretty clear over the last decade or so showing that if you have people with ACE score of 2 or higher and you give them a prophylactic agent. With either a director of anticoagulant or a low molecular heparin, you will benefit them. You will benefit them by reducing the risk of DVT or PE and potentially you'll benefit them by at least reducing the risk of mortality. Um, and so that data's been out there. There's been 6 randomized trials of different sort of versions of this. They all show the same thing. This is a meta-analysis that captures all of those clinical trials, and it's been in the guidelines since 2019. So ASCO, ASH, NCCN ISTH, um. Eye tech, all of them say the same thing. If you're a patient with a score of 2 or higher, uh, they're not at risk of bleeding, consider, uh, putting them on a prophylactic agent. I'm not going to ask you to do a show of hands because I already know the answer, but most of you are not doing risk assessment and most institutions are not doing thromboprophylaxis. We know that because we've done survey data and that sort of confirms it. Uh, and part of the reason for not doing it is that we are great at doing clinical trials, but we are not great at implementation science. And so we wanna think about not just doing trials, but once you get those trial results and once they get into the guidelines, how do you make sure that those results translate to real benefit for people with cancer? And that's a separate art and science in itself, and we wanna think about it that way and not just say, oh well, the trial's done, so of course everybody should be on. You know, X, Y, and Z, it's easier when it's a new cancer drug because it's such a sort of a, you know, uh, prioritization of that. But for supportive care drugs, um, for screening, you know, colonoscopy, for instance, colonoscopy has been around what, 30, 40 years at this point, and only 60% of people get screening colonoscopies. And so implementation science is a science that's grown up around implementing the results of clinical trials and for that there's new data that was just published in uh JCOP just like two weeks ago, um. Uh, and this is out of Vermont and University of Vermont, and they've done a really a terrific job of creating a service specifically dedicated to thromboprophylaxis in people with cancer. So the way the service works is that there's an electronic assessment of risk, which is pretty easy because most of the components of the risk score are just the, the height, weight, white cell count, hemoglobin, platelet count, and the type of cancer. It's all easily captured by EMR and so they assess the risk. Identify the high risk patients and a signal goes out to a service that's composed of APPs and pharmacists and those people go and meet the patient while they're getting their systemic treatment in in the infusion center and say, hey, you've been identified as being at high risk. We want to offer you an option for thromboprophylaxis. What do you want to take it? Um, and so this takes away the burden of decision making from the oncologist because the oncology visit is obviously much more prioritized around, around the cancer treatment and sort of management of, of the cancer and, you know, sort of transitions that burden over to a different service. And when this happens, they published previously, 90% of patients say yes, they wanna go on prophylaxis, and over a two year period, they were able to show that 80 to 90% of patients continue to be referred to the service and continue to get prophylaxis. In this latest paper, they published the outcomes results. So previously they've done a process, you know, how many patients can we get to prophylaxis. Now they're telling us what happened once you got prophylaxis. And no surprise if you had thromboprophylaxis, there's a substantial reduction in the risk of ETE. So, and you can see that graph in the middle is PE, nearly cutting in half the rates of PE in this population, and no significant increase in bleeding because they're pretty good at selecting which patients should go, go on, um, anticoagulation. So proof of principle that it, you can make this happen, that patients will accept it, and that it will benefit patients and possibly even more surprisingly. They showed that if you went on prophylaxis you had reduced mortality. Um, it's actually kind of hard to explain these results because we haven't seen it in large randomized trials. Maybe they're sort of confounders that we haven't seen, uh, but they set it up exactly how I described it. A bunch of patients were identified as high risk, referred to the prophylaxis clinic. Most of them got prophylaxis, and if you got prophylaxis, your six month mortality, uh, was cut by almost half, more than half, uh, 0.46 adjusted odds ratio. Uh, so this paper, as I mentioned, just came out, you know, you can choose to believe or not believe the mortality results, but at least it's not the opposite. You're not worsening mortality. If anything, you're benefiting mortality. This is a supportive care drug that is potentially benefiting mortality, certainly benefiting a reduction in, uh, PE, DVT, hospitalization, and so on. So, again, I'm, you know, I, I would ask you to advocate within your health system to set up something like this. This is proof of implementation science. We've had the results of prophylaxis out now for 78 years, really needs to be in, in, um, implemented. OK. Risk assessment, primary prevention. Uh, now, next two things are treat both really related to around treatment. Um, one is, of course, how to pick the right anticoagulant anticoagulant for people with cancer. Range of randomized clinical trials. Several 1000 patients have essentially all shown the same thing, which is that if you randomize a cancer patient with a DVT or PE to either a low molecule heparin or a direct oral anticoagulant, typically they'll do better with a direct oral anticoagulant, and that's better for patients because there's no daily self-injection. In the US, co-pays for oral agents are typically less than for, for injections, uh, and they'll have slightly less recurrent VTE, um, and so for. For the most part, most cancer patients with an acute DVTRPE are being treated with direct oral anticoagulants. There are some concerns, which are concerns related to bleeding, uh, and these showed up in the initial trials. So Hawkoy was a trial with a drug called edoxaban, uh, which is not very widely used in the US, um, and that showed a very high rate of bleeding in the GI cancer population of people with a DVT or PE. So this is like a pancreatic or colorectal cancer patient, new DVT gets an anticoagulant and more likely to bleed because they have a GI primary GI cancer. Same thing in Select D, which used rivaroxaban, very high rates of bleeding in the esophageal and gastric cancer population. But Caravaggio, which used apixaband, did not have a higher rate of bleeding. Is that because Apixaband is a better drug, or is it because all the clinical trialists learned from these first two trials? Because these trials occurred in sort of chronological order. So were they just selecting outpatients that they thought were likely to bleed and so they didn't enter them into Caravaggio, or is it just that Eex's, uh, a better drug in terms of preventing bleeding? Don't really know because in the cancer population there has not been a head to head study, uh, but just keep in mind that there are bleeding concerns for Dox, particularly in patients with GI cancers, particularly with those with an intact primary in the GI tract, so an intact gastric mass, intact esophageal mass, those types of things. In general, people have kind of believed that apixaban's probably a better drug, and you can see in this ash abstract rates of anticoagulation prescriptions over the past few years and steep decline in warfarin and low molecule heparins, a rivaroxaban's kind of holding steady. Apixaban's kind of taken over the market, um. It is a twice a day drug, whereas rivaroxaban is a once a day drug, so there's adherence compliance issues might be slightly different, but those, those are the trends as kind of we see right now. Three New England papers I want you guys to know about. Uh, one is extended treatment. So all the trials I showed were about. Acute treatment of DVT or PE, which is pancreatic cancer, colorectal cancer, some cancer gets a DVT or PE, 6 months of anticoagulant therapy. What do we do at 6, after 6 months? Nobody really knew until this trial came along. Another huge trial, 1700 patients had already finished 6 months of anticoagulant therapy and were randomized to ask the question, do they need to stay on full dose anticoagulation or can we cut the drug in half? This was only apixaban, so either full dose apixaban or reduced dose apixaban. And bottom line is that reduced dose was just as good. Uh, recurrent VT occurred actually in fewer people in the reduced dose, so 2.1 versus 2.8%, and bleeding was 12% in reduced dose versus almost 16% in full dose. So reduced reducing the dose after six months is now basically the new standard of care for long-term treatment of DVTNP in patients with active cancer. Um, what are the predictors of bleeding? This was an update at Ash. It's what you would think. So GI primary, pulmonary embolism, uh, anemia, thrombocytopenia, sort of, you know, the expected sort of, uh, uh, uh, things. Two other New England papers just came out over the last couple of weeks that I want you to know about. They're actually not specific to cancer, but they have some relevance. One was the COBRA trial, which asked the question that I sort of. I asked you guys earlier, is Apixaban a better drug or is, uh, are, are, you know, they've never been tested head to head essentially and so this was an investigator run very large Canadian trial. Uh, Lana Castellucci was, uh, ran this trial out of a very large Canadian network, uh, randomizing, as you can see, thousands of patients to either Apixaban or rivaroxaban for the treatment of acute VTE. Um, this is not cancer patients, although I think there are a few cancer patients, but it's mostly non-cancer patients. And as you can see in the graph on the right, bleeding rates were better with Apixaban. Again, not directly relevant to cancer, but probably informs the cancer population. And so conclusions of this paper were that risk of clinically relevant bleeding significantly lower with Apixaban than with rivaroxaban. This is during a 3 month, uh, 3 month treatment period. Uh, so very interesting new data. Second is the CTRC trial. This is looking at stent placement for post thrombotic syndrome. This is also non-cancer, but may have some relevance in the cancer population. Uh, so these, these are people with a DVT or PE or DVT, excuse me, that had a post thrombotic syndrome, and that was treated by putting a stent in. So this is an interventional radiology run procedure and it's an interventional radiologist run clinical trial. So Suresh Vedantam is the first author of this paper, just came out like 5 days ago or something, um. And I don't wanna sort of go through all the different ways that they calculate post thrombotic syndrome, but just sort of take my word for it that if you put the stent in, patients did better, um, and so the editorial in the New England says that this is the strongest available evidence that endovascular therapy, by which they mean a stent, leads to reduction in severity of post thrombotic syndrome and improvement in quality of life. Um, this is for people with moderate or severe PTS, so not for everybody with PTS, but moderate or severe PTS. So new. Treatment on the horizon. My guess is IR people are gonna adapt, adopt this pretty quickly. It's rare to have randomized trials in, in the IR setting. So the fact that they had one, that they were able to successfully complete it, got into the New England, the, this is all sort of good for the field, I would say. OK. So that's what's new in risk assessment, prevention and treatment. And now very briefly, I wanna talk about factor 11 inhibitors because you're going to be hearing a lot about that over the next, next year. So, as I've sort of already discussed, there are many unmet needs in people in the prevention and treatment of cancer associated thrombosis. Uh, first of all, even though I talked a lot about primary prophylaxis, all of those trials were either investigator run or sort of, uh, post-marketing studies, and there's no primary prophylaxis agent that has regulatory approval for primary prevention of DVT or PV in the cancer population. The risk of bleeding we talked about, adherence and compliance can be an issue with both daily agents, and then some DAs, there are concerns for drug-drug interactions with different anti-neoplastic drugs. So there's a lot of unmet needs in this population. How can we address that? One is to try and repurpose older drugs, um, and there's some really interesting data from many different randomized trials that were looking at lipid lowering agents, specifically statins, and by the way, they found that, hey, if you're on a statin, yes, of course we can prevent coronary artery disease and all those sort of the good things that statin does, but also you can reduce VTE which is really not what statins are designed to do, um, but they are kind of magic pills, so. This is a large meta-analysis of different trials that all show the same thing, 30% reduction in the risk of ETE. Some studies have even higher specific statins have the highest, you know, there's some statins that have more risk reduction of ETE than, than others. Uh, so three of us, uh, proposed to the NIH to run a large randomized trial to prevent VTE. It's called the SATCAT trials. It's statin for the prevention of cancer associated thrombosis. Uh, we, it is risk adapted, so we're taking patients at risk of, uh, DVT or PE using a score of 2 or higher, and then randomized to rosuvastatin 20 mg once a day, which is kind of an intermediate dose of a statin. We don't wanna go too high because of concerns of LFT abnormalities and myalgias. We don't wanna go too low because we, we wanna get the effect of, of the statin, uh, versus placebo. This is for people for whom you would not be using a DA because you're concerned about, um, uh, bleeding risk. Uh, the study had a one year lead in phase to just sort of select the centers and get IRB approval and all of that, so that portion is done and hopefully we'll be randomizing people in the next month or so. Probably is going to run over a few years. OK, so that's one way to reduce bleeding, use a drug that's already out there, that has some efficacy and does that doesn't cause bleeding. That would be sort of the biggest advantage of a statin. Second, uh, approach would be to target factor 11, um. And this comes from sort of rethinking how coagulation happens and so I want to present this concept to you that hemostasis, which is sort of the prevention of bleeding and thrombosis, are two different aspects of the coagulation cascade. So hemostasis is needed when there's like a rupture in the vessel wall and the rupture needs to be plugged. And that's driven as shown by sort of the coagulation cascade on the left. Thrombosis is what we think of as pathological thrombosis, so you know, it's within the lumen of the vessel, uh, and they're both tissue factor driven. So you remember sort of from training that TF, you know, is the initiator of the coagulation cascade, and that's true for both hemostasis and thrombosis. TF drives the initiation of the coagulation cascade, but. Factor 11 amplifies, uh, to a great degree thrombosis on the right, uh, but not so much hemostasis. It only plays a minor role in hemostasis. So the concept is if you take out factor 11, you would not have as much of an issue with hemostasis on the left, um, but you would have an impact on thrombosis. So you could prevent clots, but you might not cause bleeding. And there's a lot of data from epidemiologic studies because there are people who are factor 11 deficient and they don't bleed as, you know, like a hemophiliac would for instance, um, and there's animal studies that just kind of show the same thing and so this has led to the development of a large number of molecules that are all targeting factor 11, um, but the difference between the prior generations of anticoagulants and factor 11 inhibitors is that. Low molecular heparins were all kind of the same class of drugs. You know, they're very similar. They work the same way. They're all subcutaneous. They're all, you know, once a day or twice a day. Duac are also very similar. Factor 11 inhibitors are all over the place. So, you have some anti aptamers, you have monoclonal antibodies, you have small molecules. The antibodies can be given once every 2 weeks or once every 4 weeks. The small molecules have to be given once a day. Some are twice a day, I think. And So they, the mechanism is different. Some of them work on 11 and 12, some work just on 11. So they don't behave as a class the same way as prior classes of anticoagulants would. And I'm saying all this because the data that's already come out is a little bit confusing. Um, I thought I had slides on asyexion, which is the one that's most likely to get approved, but I don't, so I'm just gonna tell it to you here. The so far the biggest positive trial for factor 11 inhibitor is with the small molecule asendexian, which is a bio compound, and that was tested in a very large randomized trial of stroke prevention. Um, and there's been nothing approved for stroke prevention in decades, and so this is for people who had a stroke, ischemic stroke, or a very severe TIA, and they're randomized to placebo or ascendexian, and ascendexian reduced the risk of recurrent stroke but did not increase the risk of bleeding. So really good evidence that you can reduce thrombosis but not cause bleeding, and that was compared to placebo. There was no increase in bleeding. Um, so that's a fast track to FD FDA. Most people expect it will be approved by the end of the year. On the other hand, The monoclonal antibodies have been a little bit of a mix, uh, so these are data over the next couple of slides from an antibody called ebelizumab which targets factor 11 as an antibody, um, really highly effective in reducing bleeding compared to rivaroxaban. So this is an atrial fibrillation given to prevent stroke. Um, you're giving the drug and you're looking to see if bleeding is as good or better than, uh than rivaroxaban, and it was actually much better. And so the people who made Abilisciab, which at the time was a small company called Anthos, and they were later bought out by Novartis, um, launched these two very large trials of treatment of ET in cancer, Astor and Magnolia. One was comparing with Apixaban, one was comparing with Delteparin. Um, there's no data on these two trials, but they had accrued for a couple of years and then suddenly trial enrollment was stopped last year. There's no publicly available data that tells us why, um, assuming it's a failure of the drug, but we don't really know, we'll probably know by Ash this year, so maybe I'll have an update for you. Uh, next year on this, um, so suspended to recruitment late 2025. On the other hand, there's a different antibody, SHR 2004, which is a Chinese molecular antibody tested in ovarian cancer post-op prophylaxis. Zero VT events compared to 4%, uh, with standard treatment which is oxaparin and river oxaban. So one apparent failure, one apparent success, don't have a full paper, don't have analysis on this, but it's only an abstract presentation. Uh, similarly, another antibody, uh, Regeneron had 22 different antibodies, both targeting sort of different aspects of factor 11. One's the catalytic domain, which is 7508 CA, uh, and that was actually superior to enoxaparin for VTE prevention. This is a Lancet paper. And so Regeneron's moving forward with their antibody um in a very large population of patients again targeting primary prevention and treatment for primary prevention they're using the same sort of risk code that I described earlier randomized to either the drug or placebo. Again, this is for patients for whom you would not use DA because you're concerned about the risk of bleeding. The study just launched, I think the first patient went on like last week or something. Uh, so hopefully, we'll have data on, on this trial in sometime in the next couple of years. Um, and they are also launching, I don't have a slide, but they're also launching a treatment study that should be starting later this year. That's Roxycat 2. So just on time, but, uh, to summarize, cancer associated thrombosis remains an important clinical problem. Lots high prevalence, high incidence, impact on survival with patients, very consequential for people with cancer. We're making a lot of risk progress in terms of risk assessment, thromboprophylaxis, growing therapeutic, uh, options. We now have data on extended, uh, duration dosing, but you. Still have a lot of knowledge gaps including sort of better assessing bleeding risk, implementation science, I think is a huge issue, and then figuring out where do factor 11 inhibitors fit in sort of this large uh uh landscape is, is going to be sort of the next big challenge. So I'll stop here. Thank you for your attention. I So, if you don't mind. Thank you so much, Doctor Carana. That was a fantastic talk, uh, aspirational, frankly. So, um, Doctor Cole yourself as well. I'm hoping to get him back on screen, uh, folks, if we can. If there are any questions I'm happy to field them. Yes, there. Yes, sir. Thanks morning, Corona for your excellent lecture. This is, this topic is the highest anxiety problem for hematologists, and I'm gonna ask you about uh your experience. The, I'm gonna ask you about certain practical questions about how you manage this kind of patients. Several questions, but it'll be short. One, patient with brain metastasis, uh, especially certain malignancies will tend to bleed in the brain, you know, like melanoma or RCCs, things like that, or have DVT. How do you manage your practice? Second, If you have DAC failure, if someone wasexiban and DAC failure, is it class failure or is it just you can change within the DOAs? Uh, Third one, how do you manage antiphospholipids with the, with the DVT with the cancer patients? And the last one is patients with the DVT. And PE for malignancy, are they indefinite anticoagulation as you show trial they have, but are you going to continue indefinite? Yeah, great. So this is like a memory test. Let me see. Um, I, I may have to limit it to one question per answer, but, uh, we'll do our best. Yeah, so in terms of failure of anticoagulation, yes, I treat it as a class failure. So if they're on a DA and they fail, I'll switch to low molequid heparin. Uh, if they fail on a low molecular heparin and a DA, I'll go up on the dose of the low molecule heparin. Uh, there's data from Canada, not a randomized trial, but sort of a large series of pushing the anti-10A level to sort of the high, a higher number. Um, or if you're on a once a day drug, you could go once a day low molecule heparin, you could go twice a day low molecular weight heparin. Um, so you kind of switch the class and if you already switched the class, then you play with the dose if it's a low molequide heparin for dox, there's no playing with the dose either you're, you know, unless you're on reduced dose. If you're on reduced dose, you go to full dose, but if you're already on full dose, you don't push the dose beyond that, whereas in low molecule heparin you can push the dose beyond full, uh, beyond, uh, full dose to by either going to twice a day or, uh, pushing the anti-1NA level. Um, the, sorry, the first question was about, can you just go ahead, brain metastasis, yes, so. Great question about brain math. So the um. First is setting expectations. So everybody involved in the care of the patient and the patient should know that brain mets are at risk of bleeding no matter what you do. Even if you don't anticoagulate, there is going, there is the risk of intracranial bleeding. Um, but typically treated brain mets don't have a very high prevalence or incidence of bleeding, and so anticoagulation is not a contraindication. And if you needed to choose anticoagulation again, setting expectations, uh, of that there is a possible risk of bleeding, I typically tend to use Doax because Doa have been proven to have less risk of intracranial bleeding compared to either low molecule heparin and certainly compared to warfarin, so. And then antiphospholipid, you know, I, as you know, the DAC data is kind of controversial there. I, you know, I tend to use lamo heparin in that sense. Great questions. I'm. Alright, I've got a question, uh, for Doctor Kroll. Um, do you think there could be a cure, quote unquote for depression, any magic bullet, um, and any preventative strategies that you might envision for the future? Um That's, that's a tall order, um, because I mean, remember, like depression is really multi multi heterogeneous and heterogeneous and multifactorial, right? So like to really cure depression, you have to like get world peace, cure poverty, like all these things that are like really, really tall orders, um. I, I, I'm trying to think about this really more along the lines of like. You know, curing medical depression as opposed to curing sadness and despair. Um, and you're with. Curing depression, uh, like, and again, that kind of medical syndrome of depression, um, like any other disease state, like I don't think that there is, that we're likely to be able to cure it 100% of the time, you know, like, and, and even for cancers with really great prognoses, like there are some patients who don't do well and don't respond to treatment. But I think that with the systematic approach of kind of going, starting with first line, moving to more advanced, and then kind of identifying new, new ways of doing this, um. We're going to be able to get to a state where um. We can say depression, or at least the medical aspects of depression is a much better prognosis. Um, you know, right now, the prognosis is just all over the place because it's so heterogeneous, and some people do really, really well and some people don't. Um, and I think it's really more about just like moving the needle further and further like it is with, with cancer research. Thank you, doc. That was an unfair, unrealistic question. You nailed it. I had to challenge you a little bit. Yeah, it's OK to ask. Uh, Doctor Edmonds, Doctor Hona, I think you were here for my talk yesterday when I presented those two initial pieces of data, one in mice that showed that you could, uh, decrease the inflammatory environment of the mouse by, uh, eliminating the myeloid differentiated, uh, cells as opposed to the lymphoid. And then the second set of data that's more recently shown that thymic volume predicts for all-cause inflammatory markers going up over time if you have lesser thymic volume, I would challenge you to potentially look at something like thymic volume. As a surrogate marker for these inflammatory changes in adults and see if they correlate with thrombotic risk over time because it would be really nice to prove that there were real immunologic measurable things that you could use to predict who is at the higher risk. Yeah, that's a great point and a great suggestion, and I agree completely. I think we have switched conceptually to thinking of thrombosis as a thromboinflammatory phenomenon and not just like a pure thrombotic phenomenon. Um, and I didn't have this was an update, so I didn't this and this data from two years ago at AS that showed that for immune checkpoint inhibitors you could predict the risk of ETE by C-reactive protein dynamics, so it didn't matter what the what the CRP level was at starting immune checkpoint inhibitors. But if it went up during ICI therapy, that predicted thrombosis, but if it stayed stable and went down, then it did not. So I think that's sort of surrogate evidence also. But uh yeah, great suggestion. Thank you for pointing that out. And a quick follow up question on that. Are you measuring inflammatory indices on your statins, um, trial, preventative trial? We are collecting some surrogates for that, yes, yeah, I mean, that's kind of the hypothesis, honestly, for statins too is that, you know, they're anti-inflammatory drugs to some extent, you know, we don't really quite know exactly how they work in coronary artery disease, and that's one of the theories, um. Yeah, one of the quick thing is that the data that you showed just from last year with regard to decrease in all cause mortality from cancer patients who are on thromboprophylaxis recapitulates data that was presented even 20 years ago on the same phenomena that people have observed this over time and especially for metastatic disease in that older literature was very much decreased by this. Is there any better understanding of the metastatic cascade and thrombosis? Based on that older literature and current literature and all-cause mortality and the tie-in between the coagulation cascade. Yeah, great question. I, um, there are several papers looking at neutrophils, neutrophil extracellular traps, um. Uh, and sort of this creation of a metastatic niche that's, you know, the reason, so I'll give you an example of tissue, you know, we talked about tissue factor, for instance, um, and many even cancer biologists are unaware of this, but tissue factor is up regulated in every single malignancy, every single malignancy, uh, so if you take pancreas for, for example, normal, normal pancreas has no tissue factor at all. There's no reason to, right, because pancreas don't bleed. But as soon as you go from the transition of a panin, which is like a precursor to pancreatic cancer, and you go through like panin 1A 2B, 3, and eventually to pancreatic cancer, somewhere along that continuum, even before you, it becomes pancreatic cancer, you get tissue factor expression on pancreatic tumor cells, and that's recapitulated in ALL, it's recapitulated in lung cancer, even in cancers that don't thrombose like breast cancer, uh, you, you see TTF expression on the surface of breast tumor cells. And so there's this sort of real need for cancer cells to activate coagulation and probably it has something to do with protecting a metastatic niche or propagating uh cancer cells and you know there's a great paper in cell that was there last year I can send you a reference later on, um, so that is certainly an area of active investigation and we're probably further along than we are 20 years ago, but do we fully understand it? I don't think so. There's still a lot of work to be done, so. a quick, quick, but kind of random question like, so with the, with the advent of cell-free DNA and the detectable, you know, burden of disease in that regard, right, the, the soluble components, so if you will, uh, and there's a couple of papers I saw with little clumps of metastases, right, these little, they kind of go in little, uh, clumpy pockets right throughout the body. I'm just curious if there's any effort to look maybe at cell-free DNA, um. Concentrations and uh see if that may correlate. Yeah, great question. So we MSK has data from their MSK impact database that CTDNA kind of predicts for risk of ETE, uh, and we are currently doing a study at the Cleveland Clinic looking at CFDNA, CT DNA, and seeing prediction after resection of colorectal cancer metastasis. So fantastic. Is there any last questions? If not, I'm gonna let Doctor Krona off the hook, Doctor Kroll off the hook. Going once, going twice, and sold. So thank you so much for that wonderful session. Please give him a hearty round of applause. Thanks everyone. Mr.
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