Podcasts about cfdna

Dr. Deb Muth 00:02What if I told you that before a single drop of chemotherapy goes into a cancer patient’s body, we can take a blood sample, grow their actual living cancer cells in a lab, and test 70 different drugs against those cells, all outside the patient’s body, to find out which ones actually work. And what if I told you that the conventional oncology doesn’t routinely use this test? Well, today we’re going to talk about why that matters and we’re going to go through and I’m going to share a story that is very personal to me. It’s about a 38 year old man with a rare complex cancer diagnosis and the precision testing that is helping to keep that cancer from progressing. Stay with me. This is one that is going to change how you think about cancer treatment. Dr. Deb Muth 01:05You guys can put a little ad right in here before we start the next segment here. Hey everybody, welcome back to Let’s Talk Wellness Now. I’m Dr. Deb and today we’re going deep. I mean really deep. It’s some of the most cutting edge cancer testing I have ever seen in clinical practice. Now, normally I don’t talk about cancer. And I would not be sharing this story if it was anyone other than my own family. I do have permission to share and talk about this publicly. So I want to do this. I want to make sure that I share this message. And he is giving his blessing to share this story because we both believe that it can save lives. So his name is Cameron. He’s 38 years old. And he is my son-in-law. And two years ago, he came to me with a small lymph node underneath his arm and a bullseye rash. So of course, being the lime literate person that I am, my first inclination was to say, yeah, this makes sense. You have an enlarged lymph node because you have this bullseye rash. You got bit by the tick. Let’s keep an eye on it. If it doesn’t go away, let me know. So Fast forward a year and a half later, he comes to me and says, mom, what do you think about this? This thing is getting a little bit larger. And I said, yeah, it’s a little larger. Not sure. Let’s keep an eye on it. He wasn’t feeling anything. All his labs looked okay. And then one day he was out chopping wood and he started getting numbness in that arm and he felt it again. And it had exploded in size. And so after some evaluation with my daughter and him, we decided to do a ultrasound. And we thought what was going to come back was a fatty tumor. It felt like one looks like one responded to one. He’s 38 years old. He’s healthy. There’s nothing in our mind that’s ever thinking the result that we’re going to get back. Dr. Deb Muth 03:28Is a possible lymphoma. Needless to say, we were shocked by that ultrasound result. And we go fast forward, we have the biopsy. I requested a total excisional biopsy. I was told by the oncologist that that was old school. They don’t do that that way anymore. And I need to stay out of this. I need to let the experts take care of this because that’s what they do best. And this came from a breast surgeon here in Wisconsin. And so I stepped back for a moment. I let him do his biopsy and what came back was adenocarcinoma of an unknown origin. Had we excised the entire lymph node, we would have had more tissue to work with. I think we could have gotten a better diagnosis. So over the course of the next two and a half, three months, we have some more imaging done. We have some more testing done. They send a pathology out to Mayo Clinic. And what continues to come back is this incongruent test results. If anybody’s ever had this, it’s extremely frustrating. One test shows lymphoma. Now it shows breast cancer. Then the next week it shows estrogen receptor HER2 positive breast cancer. Two weeks later, another test comes back and it says, no, it’s not HER2, it’s triple negative breast cancer. And now it looks like it’s out of the lymph nodes. Now it looks like it’s in the lymph nodes. And we do a PET scan and they can’t find cancer anywhere except in this axilla area. But now we find a lymph node on the right side. So it must have spread.Let’s go ahead and do a biopsy on that. And so they biopsy the right side and the right side comes back with nothing other than tattoo ink. Now, all of this is kind of crazy. I am not a cancer specialist. I want to start by saying that I am not a cancer specialist. What I am sharing today is from a mother-in-law’s perspective, from a medical detective’s perspective, I do know how to do research. I do know how to find answers. And so what I’m going to share with you Dr. Deb Muth 05:54Is totally my opinion and totally my experience. And I’m not telling anybody to do anything different than what their doctors are telling them to do. But I am telling you to ask questions. So I go deep down the rabbit hole and find out that Tattoo Ink can appear like metastatic cancer on a PET scan. And we all know everybody gets tattoos today. They’re all over everyone. And yet we’re not thinking about how this tattoo ink can cause problems for us down the road, not to mention that there are heavy metals in them and it’s a toxin and it’s creating an inflammatory process in your body that your body’s constantly trying to get rid of. So the surgeon says to us, well, yes, that’s normal that that lymph nodes inflamed. It’s normal that there’s tattoo ink in it. The body’s doing what it’s supposed to do. It’s trying to get rid of a toxin. Okay. I will agree with that, but My son-in-law is covered with tattoos everywhere. And why didn’t we mention the tattoo ink that was found in the left axilla? We are only mentioning it in the right axilla. So there’s a lot of controversy, a lot of confusion. Many of you would never know any of this because A, you either don’t look at your lab results. And if you do, you don’t understand what you’re looking at. And that creates a problem for us, right? You don’t know what questions to ask. So we go into the doctor and the doctor tells us you have cancer and we’re going to swoop you in. And in the next two weeks, you’re going to be doing chemotherapy and radiation. And six months from now, we’re going to be doing surgery and there’s no time for questions and you’re scared shitless and you’re just doing what you can to survive. And I get that. And I totally understand that. And I appreciate that. But I’m telling you that If that is your choice, that is your choice. But as you’re doing that, take the time to ask the right questions. When this happened to us, there was a lot of challenging things with the oncology team. Nobody bothered to allow them to be a partner in their care. They dictated their care, but didn’t allow them to be a partner. So, Dr. Deb Muth 08:17Here’s what most oncologists do when patients get a cancer diagnosis. They look at the tumor type, they look at the stage, they look up the NCC guidelines, the National Comprehensive Cancer Network, and they follow the algorithm. Now, I have an enormous respect for conventional oncology. I really do. Working with cancer is probably one of the hardest things in medicine that anyone can do. The advances in this field over the last 10 years have been remarkable. But here’s my issue. Standard treatment assumes your cancer is the same as the cancer in the clinical trial that created the guidelines. It’s assuming that you and your cancer are the exact same as everyone else. You are the unique fingerprint, not the cancer. And this is the problem because your cancer is unique, just as unique as if you had your fingerprint taken, the mutations driving your tumor, the drugs your cancer cells are sensitive to, the metabolic vulnerabilities of your cancer. These are all different from the person sitting next to you in the chemo suite that has the same triple negative breast cancer or HER2 positive breast cancer or prostate cancer or colon cancer that you have. So what do do about that? Well, in my world, in the integrative medicine world, we test precisely, intelligently with the tools that most oncologists have never heard of. Or if they have, they haven’t incorporated it into their treatment modality for a variety of reasons. Either it’s not acceptable by the organization that they work for, they don’t understand it, They’re not going to be able to change their protocol anyway because they have to follow the NCCN protocol. So they don’t do it or they use a portion of it and they don’t do anything outside the protocol. So today I want to cover three things with you, three tools that we used that I think every cancer patient should be asking for when they start treatment or wherever you are in treatment at this point. Dr. Deb Muth 10:44you need to have these tests done. I don’t have any affiliation with any of these companies. I don’t get paid to tell you any of this. So let me just start by saying that I understand the chemistry behind these and how important it is to give you precision cancer treatment. And that’s why I’m talking about them today. The first one we’re going to talk about is the North Star response. This is your cancer surveillance score in the blood. How much cancer is circulating in the blood. The North Star Select, your cancer’s genomic blueprint from a blood draw. And the Datar Cancer Genetic Chemoscale, the live cell drug sensitivity test that tells us which drugs actually kill your cancer. So let’s go. Let’s dive into this. Let me just take a drink here. I’m going to cough a little bit. I apologize. I have this horrible tickle. It just never seems to go away, but that is not for today to discuss. So what is all of this? OK, the North Star response is a test that was developed by a company called Billion to One. And yes, that name is intentional because of the precision involved. It’s a next generation sequencing test, meaning it reads DNA at an incredibly detailed level. And it looks at something called methylated circulating tumor DNA or methylated CT DNA. Now let me break this down in plain English for you, because this can get a little overwhelming. When the cancer cells die or shed, they release tiny fragments of DNA into your bloodstream. We call this cell-free DNA or CFDNA, and it’s hidden within that cell-free DNA. And there are fragments that come from tumor cells. We call those CT DNA or circulating tumor DNA. Here’s what makes North Star’s response different. Rather than just looking for mutations in that tumor DNA, which is what most liquid biopsies do, and a liquid biopsy is just a blood test, Dr. Deb Muth 13:03This test looks at something called methylation patterns. Think of methylation like a dimmer switch on a gene. In healthy cells, certain genes are switched on and off in a very predictable way. In cancer cells, those dimmer switches go haywire. And cancer DNA has a characteristic hypermethylation, meaning switches are turning on and should be off or off and they should be on. And these patterns are essentially a cancer fingerprint in the blood. Now the North Star response scans more than 2000 locations in the genome for these cancer specific methylation patterns. And then it adds them all up into a single number called the tumor methylation score or TMS. So for Cameron, Cameron’s blood which was drawn on April 20th, 2026, his baseline tumor methylation score came back at 13. Now here’s the critical thing, to understand this was his baseline test, his starting point. And the real power of this test is in serial monitoring, meaning we run it again and again and again over time. And if that number goes up, the cancer activity is likely increasing. If it goes down, we’re likely suppressing the tumor activity. And if it stays flat or falls, that’s telling us that the disease is responding. So this is now in the blood. We have an actual fingerprint and every test from here forward will be compared to this number. Now let’s talk a little bit about this because I was not familiar with this test at all. I wasn’t sure what to expect. I wasn’t sure what to do with it. I did not order this test. He’s working with Inveda Medical and they are fabulous over there. I will tell you that from the beginning. This is coming from a practitioner and from a mother-in-law. They were absolutely wonderful to us. So when I saw this North Star, I didn’t know, should it be zero? Should it be a hundred? And when I talked to the doctor, he said, Dr. Deb Muth 15:29This number is actually really good. An average person walking around who’s never been diagnosed with cancer, who doesn’t have cancer, their number will be between 75 and 100. Cameron’s was 13. I think that’s fantastic. But what was the first question that went through my head? It’s probably the same question that you guys are doing. How can he have cancer with a number of 13 when it’s less than the normal average? And if we’re supposed to use this to track what’s happening with his cancer, how are we going to do that once we remove the cancer? Is this number going to go to zero? And it could possibly do that. And we may not be able to use this to track whether or not the disease is actually gone. But what we can do is use this to track over the course of his lifetime to see if the cancer cells are coming back long before we detect them on imaging. And that’s the huge part of this.So this is not a test that just anybody should go out and get because you’re worried about cancer. It is a test that should be done in somebody that is already diagnosed with cancer. So let’s start by making sure we explain that, okay? So imagine if every time your cancer cells are active and they’re shedding and they’re multiplying and they’re fighting back, they’re leaving a signature in your blood not just any signature, but a specific chemical tag that says, cancer’s here. That’s what the North Star Response Test reads. Those tags across thousands of locations and gives us a single score. So we track that score over time like a thermometer for your tumor. If it goes up, we get concerned. If it stays stable or goes down, we celebrate. And we can catch a change in the blood often months before it will show up on a scan. Pretty important when we’re talking about surveilling somebody for cancer returning, when we’re worried about it, and everybody knows the cancer patient is always worried after they get that clean bill health that something’s gonna come back, and most of the time they’re told that there is no way for them to determine that or know that from a blood test. And here is the blood test that can tell us, yes, it can. Dr. Deb Muth 17:51So I would really encourage you guys to talk to your oncologist about this. If you can’t find an oncologist that will do this, talk to an integrative cancer doctor. They will most likely be familiar with it. If not, ask them to find it for you and order it for you. So next, let’s talk about that genetic blueprint because North Star Select is a different test also by billion to one run on the same blood draw, but this one is doing something completely different. This is a comprehensive genomic liquid biopsy. Liquid biopsy just means blood tusks, meaning it’s looking for specific mutations in 84 cancer related genes, all from a blood sample, no biopsy needle, no surgery, just a blood draw. It looks for CNVS, single nucleotide variants, tiny one-letter typos in the DNA code. It looks for indels, small insertions or deletions in the DNA. It looks for copy number changes, the sections of the genomes that are duplicated or deleted. It looks at fusions. So when two genes incorrectly link together to create a dangerous hybrid, MSI status, micro satellite instability, which tells us whether immunotherapy is likely to work. And it has extraordinary sensitivity. It can detect a mutation that represents as little as 0.15 % of cell free DNA in the bloodstream. That is an almost impossibly small signal in the ocean of genetic noise. So what did this show for Cameron? This is where Cameron’s case gets clinically fascinating and where it tells the story of how his cancer is being held in check. Two major mutations were identified as actionable. One was called CRAS G12C. Dr. Deb Muth 20:11And it’s a variant-ELI fraction at 0.1%. Now, CRAS, if you’ve spent any time in integrative oncology, you’ve heard this name. CRAS is one of the most well-known oncogenes in cancer biology. Think of it like an accelerator pedal in the car. In a healthy cell, CRAS pushes the cell to grow when it receives the signal to do so. And then it stops. In cancer, crass gets stuck in the go position, like on the accelerator, foot on the accelerator, to the floor, going as fast as you can around that track, right? But it’s stuck there permanently. It doesn’t turn off and it’s supposed to be turning off. The G12C variant specifically is a mutation at a very precise location. Position 12 of the CRAS protein, where a glycine is replaced by cysteine. And this matters because CRAS G12C is now a drugable target. There are FDA approved drugs specifically designed to lock this mutation into its inactive state, essentially putting a foot on the brake. Now those are drugs like, and I’m gonna slaughter these names, Sordisib, a brand name is Lumacras, and Atacras, the brand name is Crastol. Neither is yet FDA approved for breast cancer, but they are approved for lung and colorectal cancer with CrasG2C. And Cameron’s tests identified 10 active clinical trials within a region that he could potentially qualify for with this mutation. The fact that his CRAS G12C is circulating at only 0.1%. That is a very low fraction. We call that a VAF, V-A-F, very low fraction. And it tells us something important. It means that this mutation is present in a small subclone of the tumor. It’s not the overall tumor burden. So either way, when we identify, we know it’s there. Dr. Deb Muth 22:37We can catch it and we can watch it. Now, here’s another interesting thing that we saw. His TP53 was at 0.23%. This is a tumor suppressor gene, the guardian of genome. And this gene is responsible for telling damaged cells to either repair themselves or self-destruct. And when it mutates as it is here in the position R196Q, that guardian goes off duty. The cell no longer has a reliable mechanism to prevent uncontrolled growth. So TP53 mutations are present in roughly 50 % of all human cancers. And there’s currently no FDA approved drug directly targeting the TP53 but there are clinical implications. TP53 mutant tumors may respond differently to chemotherapy and several investigational approaches, including TP53 vaccines and aurora kinase inhibitors are under active investigation. So we are seeing things happen in this part of cancer right now. Now there’s something called the VUS list and we are watching This is what we’re watching. beyond those two actionable mutations, NORSTAR Select identified what we call variants of an unknown significance, VUS, adenocarcinoma of an unknown significance, ACUP. These are mutations where we don’t yet have enough clinical evidence to determine whether they’re driving cancer or not, but we watch them. So on our mutation list was CDH1, a gene linked to hereditary gastric and lobular breast cancer, CDKN2A, a tumor suppressor cell cycle regulator, CDK12, involved in DNA repair, EGFR, ERBB, this is HER2 receptor, tyrosine kinases. Dr. Deb Muth 24:55I thought this one was pretty interesting since he had an IHC that showed a three plus HER2, but then when we confirmed it with FISH, FISH showed that was negative, but now we’re actually seeing genes expressing this HER2. So is there a HER2? Is there not a HER2? This is really important because if we don’t get these diagnoses right in cancer the first time, people will spend months and years treating the wrong type of cancer with the wrong type of medication. And this may be in part why some people do better than others. If we get it right out of the gate, they do good. If we don’t get it right out of the gate, they don’t do so good. Very important to have the actual genetic makeup of the tumor that’s growing in somebody. Now last, we have something called Notch C1, NRAS and RAF1. These are key pathway components. Now all of these were at very low baffs under 0.5%. These are just whispers, not shouts, but whispers that this cancer is excreting, but your body is listening. We have to be listening. We have to be able to watch these things and monitor these. Now here’s another note of clinical interest. It was an androgen receptor positive cancer. So also detected as a VUS.We know from tissue pathology that Cameron’s tumor was androgen receptor positive. So seeing this in circulation confirms that this AR expression of the cells are present in the bloodstream and that an anti-androgen approach remains worth considering. What that means is suppressing the testosterone. What all of you know I’m about ready to say is that I hate ever suppressing hormones, especially in a 38 year old male. That is not necessarily a good thing. So before we go suppressing hormones willy-nilly, we have to know that it’s the right thing to do. And we have to be able to combat all of the complications that are going to result of that. A 38-year-old male with no testosterone could lead to heart disease down the road, could lead to bone loss, could lead to dementia, Alzheimer’s. Not to mention the sexual side effects that are going to be present. And in a man that is very, very Dr. Deb Muth 27:20Difficult for someone to manage. So you have to be very specific and you want to be very, very diligent about what you’re doing in these cases like this. Now the MSI status was not detected. This tells us that cancer is not a microsatellite instability high, meaning that standard monotherapy may have a lower baseline response of probability and the strategic integration that we’re working with with in Vita could create an immunogenesis genicity becomes even more critical. So immunotherapy is going to be very critical in a cancer case like this and working with somebody that understands that and can carefully navigate that, especially if you have an autoimmune disease like Hashimoto’s or lupus, this is all very, very pristine and has to be looked at very carefully and done very diligently in order for somebody to do this without overstimulating that immune system and causing more problems. So when we looked at the blood and found this DNA fingerprint of the cancer cells circulating in the body, from that, what we see exactly is the genetic switches that are stuck on. They’re stuck on in the wrong position. This tells us which drugs were designed to fix exactly that problem. And it opens the door to clinical trials built for these specific mutations. It also gives us a list of things to watch for over time. And if one of those tiny little signals starts to grow, we know that cancer is gaining a ground in that area. And if it shrinks or disappears, we know we’re winning. This is like, I cannot tell you how exciting this is in the cancer world and the medical world because this is really pristine cancer therapy that we’re dealing with here. And to be able to have this is just so important to life saving events in treating cancer. So. Dr. Deb Muth 29:41Let’s talk about something called the Dittar Chemoscale. This is the battle before the battle. Okay, so I’ve saved the most remarkable test for last, and this is one from a company called Dittar Cancer Genetics. They’re based out of the UK. They are CAP and CLIA certified, which means it meets the rigorous standards required for clinical laboratory testing in the US. And this test is called the ChemoScale. And it is a live cell chemosensitivity assay. So let me explain exactly what that means because it sounds complex, but the concept is actually quite elegant. When we drew the blood from Cameron, the Dittar’s laboratory isolated what are called circulating tumor associated cells or CTACs. And these are actually living cancer cells and they’re associated cells that are traveling through his bloodstream. Excuse me. So let’s think about that for a moment. Real live cancer cells isolated from a blood draw. Those living cancer cells were placed into a lab environment and exposed to over 70 different drugs, both conventional chemotherapy agents and what we call repurposed drugs. I’ll talk more about those in a minute. The lab then measured how many of those cancer cells were killed by each drug expressed as a percentage of cell death. So the scale runs from zero to a hundred and below 25%, that drug doesn’t work well against any type of cancer in that person. Might work great in somebody else, but in that particular person’s cancer that they have, it’s not gonna work so great. Anything that’s 25 to 50 % is intermediate and above 50 % is a high response. And that’s really where Dr. Deb Muth 31:43we want to be. We want to see anything higher than 50 % because that’s a great medication that can be used to kill the cancer. This is not a theoretical test. This is not based on tumor’s genetic sequence and the computer algorithm that predicts the drug response. This is a HIS actual tumor cell being killed or not being killed in real time. That is the difference. So in traditional chemotherapy, we have our protocols. If you have triple negative breast cancer, if you have HER2 positive breast cancer, if you have prostate cancer, if you have colon cancer, here’s the protocol that you’re going to use because that’s the type of cancer you have. That’s what’s been studied. Now, the problem is most of these cancers have mutated over time, especially depending on how long they’ve been in your body, because that’s what they do to try to survive. They have to change so they can survive because your immune system’s constantly trying to kill them. And so this is a really important thing. And if we don’t take an individual into response or into our thought process when we’re creating these protocols, we may give a drug that doesn’t work at all towards that cancer and you just wasted seven cycles of chemotherapy with a drug that never would have worked in the first place or had such low resistance to it that it’s now just created side effects for you but did nothing to the cancer. And then we pull out another drug and we try that. And then we pull out another drug and we try that. Instead of us knowing precisely what we can use and what we can do. And this goes for both the conventional world and the alternative world. In the alternative world of cancer, we use things like IV vitamin C and tumeric and lately ivermectin and fenbendazole and mendendazole and all kinds of other things. And if we are not truly aware that this is going to do anything, we could be wasting somebody’s time and money. So I love that this test is available. I want to walk you through a little bit about what Dr. Deb Muth 34:01we are what we saw in our case, because I think this can make a big impact on people to ask the right questions. So this particular blood test looked at several different drugs. Cameron had sensitivity from 44 % up to 61 % on different medications. Now he was really lucky. The three main drugs that they would use to treat his cancer he had greater than a 50 % response to. So that was great. However, the drugs that were recommended for him to use out of the gate had less than 50 % activity. So he would have had one drug that was really good, one drug that was not so good. And we don’t know what the outcome would have been, right? So I think this is such an incredible, incredible test to have done. This is critical friends. I’m telling you if his oncologist had chosen the two drugs based on the general guidelines for his tumor, his cells would have largely not survived. But because we ran this test, we know. So we know to avoid the drugs that won’t work and we focus on the firepower where it really counts. So I want to also talk about this repurposed drug result because this is where it gets integrated for us. Now, this section is what I want everyone in our community, our Let’s Talk Wellness community, our members to understand. This is where conventional medicine and integrative medicine intersect in a peer-reviewed clinical validated way. So the Dittar test looks at live cancer cells against what they call repurposed drugs, meaning pharmaceuticals and natural compounds that were developed for the purposes, for other purposes, like it could be an antibiotic, it could be an herbal medicine, it could be all kinds of things, vitamins, whatever. But they have demonstrated anti-cancer activity in research. And when we’re talking about integrative medicine, this is a lot of where we get Dr. Deb Muth 36:26The integrative protocols from because these particular drug compounds are known for having anti-cancer benefits. And so that’s how integrative protocols get developed. But again, it could be just like medication, like cancer drugs. If your body doesn’t have a susceptibility to it, then you’re using a product that’s not necessarily going to work. And we all know we cannot take everything that somebody recommends just simply because it has an anti-benefit to whatever it is we’re treating. There’s only so many supplements you can take. There’s only so many things you can do before you get burnt out on taking it. We call it supplement fatigue. And so we want to be very precise with what we’re doing and target this very specific area. So one of the things that showed up really, really well for our case was artemisium, sweet wormwood. It’s an anti-malarial drug that has very potent anti-cancer effects. Now I found this extremely interesting in Cameron’s case because he does have a positive tick-borne illness called Babesia. And this is one of the things that we use to treat Babesia. The other thing I think is very interesting in this case is we are studying how parasites affect cancer these days. And that’s how Ivermectin, Fenbendazole, and Menbendazole have all gotten thrown into the treatment of cancer. And so for this drug or this herb to be sensitive to this type of cancer is really intriguing to me in the world of parasites and how parasites are truly decreasing the body’s immune system and causing cancer to grow. Another thing that worked, showed up really well for him was Valprolac acid. It’s an anti-seizure drug with HDAC inhibitor properties, and this disrupts cancer cell gene expression. There was a soy formula that showed up really well. Naltrexone, you guys have heard me talk about low dose naltrexone, LDN. This actually stimulates an endogenous opioid immune response feeling, and this drug actually showed up really well. Dr. Deb Muth 38:49Something as simple as quercetin. It’s an anti-inflammatory. This is a crass inhibitor in some studies. So this is really important. I’m sure most of you have heard about the benefits of green tea and green tea also actually has anti-angiogenic or anti-cancer benefits to it. Hydroxychloroquine, very popular drug. It’s another anti-malarial drug. So again, now we have two anti-malarial drugs that are susceptible to this type of cancer. And on top of it, he has a positive babesia test. So just saying, you got to connect the dots sometimes. You got to think outside the box sometimes. Metformin is very well known as a anti-proliferative in cancer. We use it to suppress the sugar because sugar feeds cancer. Nobody should be eating sugar if they have cancer. So this one showed up as well. And then CBD, we all know of the benefits of THC, the Rick Simpson oil, and CBD can be tested to see if that is beneficial to a particular cancer cell. This is different than THC. THC works very differently in cancer. CBD is your healthy component of it. It’s the part of the marijuana plant that does not make you high. So very important here. So now let me be very clear, because I always try to be very clear. This is not FDA approved. I’m going to repeat that. This is not FDA approved. This test is a laboratory developed test, not FDA cleared. These results represent in vitro testing, meaning in a lab, not inside the human body. And the results can differ in what we call in vivo, inside the body. And this is why I always say work with a qualified clinician who can interpret these results in full clinical context. But here’s why this matters. We now have evidence, live evidence of a cancer cell that shows sensitivities to compounds that are accessible, relatively safe, and some of which he may already be using, which some of them we were. Dr. Deb Muth 41:13We were already using some of them, which made us sit back and say, this cancer has been in there for two years. If it’s a triple negative breast cancer, it’s supposed to be an aggressive breast cancer that should have spread to a different organ already after two years. It is not, it has stayed in one spot. Also interesting in this case is that there is no breast tumor that they could find anywhere. This was all confined to the axilla into the lymph node. So to have this growing for this period of time with such a small tumor marker number, that 13 that we talked about in the North Star test originally, and to see some mutations, there’s a lot of questions to this particular case. And there are lots of questions to everybody’s cancer case. They are not all straightforward cancer cases. So this is what’s important to understand this fingerprint of these cancer cells so that you can identify exactly, exactly what’s going on and treat it exactly the correct way. Super important. So this kind of information gives us the direction in an integrative protocol. It’s not guessing. This is not eat more tumor, I can hope for the best. This is personalized tumor specific precision guided integrative oncology. It is very precise. There are several countries, several clinics like this around the country that offer this type of therapy. If it’s something that you’re interested in doing, I would encourage you to look at in Vita Medical. Hope for Cancer is another great facility. There are several great facilities around the country. Like I said, that could put together an integrative approach for you if this is something that you are thinking about doing. If you’re looking for answers, if you’re in stage four or stage three and you are not getting the results that you want to get, you want to look at a different approach. You want to do a combo approach of integrative medicine and traditional medicine and alternative medicine. Dr. Deb Muth 43:37I think this is so important to look at and have experts on your team. You know, in our case, Cameron’s cancer is very complex. It’s genomically aggressive in its presentation, yet it’s not progressing to distant areas, which is so wonderful. And I want to be careful here. I can’t tell you with certainty that this is any one thing. Biology is complex. Cancer is adaptive. It’s trying to survive. That’s what it is supposed to do. It is changing its shape. It’s changing its genetic structure. It’s changing everything to try to survive and try to hide against your immune system. Now we are not even close to the finish line in our journey, but what I can tell you is that what the integrative precision approach has done that standard care alone might not do. I can tell you that today and I will share our journey along the way for any of you that are going through this that want to look at a different approach as well because I think it’s important to have this information. So first of all, we know the tumor’s fingerprint. North Star response gives us that TMS score. so we can track it over time. And if the cancer tries to gain ground, we’ll see it in the blood before a scan, we’ll show it. We know the cancer’s genetic vulnerability. We know how to handle the DNA now. We know the watch list of things to look for. And when those signals start to grow, we have a roadmap of how to address it next, how to change it. We know which drugs will automatically work against the tumor cells. We’re not guessing based on a tumor type. We tested the cells. We know how many drugs in the commercial world and in the repurposed world will and will not work. And this is going to guide the treatment protocol that we walk forward with. So we’re not giving him drugs that won’t work or have a low response. Dr. Deb Muth 45:55We’re avoiding them completely and that matters because every ineffective drug is a dose of toxicity with no benefit. There is no lie to this. Chemotherapeutic drugs are toxic. That’s how they kill the cells, but they kill the good cells and the bad cells. And if we can avoid using a drug that’s not going to work, that is so important. And then we’re layering in those repurposed and natural compounds with proven activity against specific cells. This is not complementary fluff. This is biologically active tumor tested precision medicine. Very, very important. So here is what I need you all to know and what I want you to walk away with today. If you or someone you love is facing a cancer diagnosis before treatment starts, before the first infusion goes in, I want you to ask these questions so quick. Go grab something to write with. Pause this if you need to, because this is really, really important for you to do that. And we’re going to take a break for just a second while you guys go and do that. We’re going to give you a word from our sponsor, and then we’re going to come back. And I’m going to give you the four questions that I want you to ask specifically of your medical team so that you have the answers and the ammunition that you need to work with. So we’ll be right back. Dr. Deb Muth 47:29All right, everybody, welcome back. I hope you got your pencil, your paper, your pen, your phone, whatever you’re going to take notes with because this is important. So I’m to give you four questions that I want you to ask your medical team before you get started. Question one, can we do a chemo sensitivity test before we choose a chemotherapy regime? Ask specifically about DATAR, D-A-T-A-R. cancer genetics, Oncostat Plus, or a similar functional chemosensitivity platform. Very, very important to ask those specific things. All right, question two. Can we do a comprehensive liquid biopsy to identify actionable mutations and monitor tumor burden? Ask about North Star Select, Billion to One, Guardian 360, or Foundation One Liquid CDX? I’m gonna say those for you one more time, because I said them kind of fast. North Star Select by Billion to One, Guardian 360 or Foundation One Liquid CDX? Okay, question three. Can we establish a baseline tumor methylation score, TMS, so we have a surveillance marker to track over time? and ask specifically about the North Star Response Test. All right, question four. Is there an integrative oncology center that can layer precision guided natural compounds alongside conventional treatment? Research institutes like Inveda Medical Center, CTA CA Integrative Medicine, or Hope for Cancer, these people are doing integrative medical miracles. Let me tell you, I have researched every one of them. I have spoken to each of them individually before we made our decision of who we were going to work with. They are all fantastic. You want to work with an integrative nurse practitioner who understands oncology. And if you’re working with an integrative practitioner, you want to ask them these same questions about this test so that you can get the best outcome. Dr. Deb Muth 49:56For what you’re dealing with. You are allowed to ask these questions. You are allowed to want more information from that protocol that was designed for the average patient. You’re not average and your cancer is not average either. And your care doesn’t have to be. You do not have to settle for the same thing that the person sitting next to you in the IV suite is dealing with when you both have different cancers excreting different genetic material. This is so incredibly important. want to make sure you understand precision medicine is what changes the lives for people every single day, every single day. So I started this episode by telling you about a 38 year old man with a cancer that baffled conventional medicine and integrative medicine, an occult primary that was not found complex genetic genomic profile, a presentation that in many hands might have resulted in a one size fits all treatment protocol and a prayer. And instead we ran the tests, we mapped the fingerprint, we watched the cells, we guided the protocol, and we are still fighting with precision, with data, with intelligence. This is what Let’s Talk Wellness is all about not giving up. This is what not accepting we don’t know as a final answer and demanding the level of scrutiny and personalization that every cancer patient deserves. So if this episode resonates with you, please share it because somewhere out there, there is a person who is about to get the wrong chemotherapy because no one ran the right test. And maybe, just maybe, that This episode will be the reason someone asks the right question at the right moment. If you’re going through something like this, you need a group, you need somebody to connect with, please join our free Facebook group called Seen At Last. It is where we support one another, we share this information, we share knowledge, and we help people for free support and ask the right questions. Dr. Deb Muth 52:23And if you’re inclined in your heart to pray, pray for Cameron, we could use every ounce of prayer. If you are in a position where you can help support this journey financially, we do have a fund going in free funder. I can post the link below. Every little bit helps. If you have $5, $500, it doesn’t matter. We’re raising money for this treatment. And along the way, I am documenting every step of what we’re going through so I can provide more episodes like this for you guys to share the outcome and share what our journey is like so that it can help the next person along. I really always believe that whatever happens to us happens to us because we’re meant to share it. That’s why I’ve shared my personal journey. I’m sharing his personal journey and we want to help other people. So until next time, I’m Dr. Deb. Keep asking questions, keep advocating, and never ever accept being unseen.The post Episode 274 – Stop Guessing on Chemotherapy: The Live Cell Test Most Doctors Miss first appeared on Let's Talk Wellness Now.

Program notes:0:35 Cell-free DNA screening for cancer and diagnosis delays1:35 Populations-based screening2:35 24 different companies offer liquid biopsy3:01 Can we prevent chronic back pain after acute back pain?4:01 Impact score on chronic back pain5:01 Real-world setting lacks impact6:01 Primary care role7:01 Individual should assess their own back pain7:25 Resistance training and mortality8:25 Most benefit with aerobic and resistance training9:20 GLP1 and knee arthroplasty10:20 Using a GLP1 reduced risk of knee arthroplasty11:23 Can't imagine using them solely for this purpose12:25 End

Genome-wide noninvasive prenatal testing (GW-NIPT) was introduced in 2015 and became widely available in 2019. Nonetheless, we are still learning more about this important prenatal screening test. In January 2026, the ACOG released a new PA on this, which we will also review in this episode. Our main publication ti review, however, will be the AJOG May 2026's systematic review and meta-analysis on the finding of “genome-wide” cfDNA discordant results and what this may mean for the pregnancy. Although rare, this may lead (over a third of cases) to some adverse perinatal issues. Listen in for details. 1. ACOG PA Jan 2026: Screening for Fetal Chromosomal Abnormalities2. AJOG May 2026: https://click.notification.elsevier.com/CL0/https:%2F%2Fwww.ajog.org%2Farticle%2FS0002-9378(25)00865-8%2Ffulltext%3Fdgcid=raven_jbs_etoc_email/1/0100019d9ec37d7b-c586438d-021a-4097-8db3-c158e6f97c9b-000000/Vq6ksekOuvTxcv8OEZZ2uBesCg_hG6qlhqU_BlCnAK4=452

CardioNerds (Dr. Shazli Khan, Dr. Jenna Skowronski, and Dr. Shiva Patlolla) discuss the management of patients post‑heart transplantation with Dr. Shelley Hall from Baylor University Medical Center and Dr. MaryJane Farr from UTSW. In this comprehensive review, we cover the physiology of the transplanted heart, immunosuppression strategies, rejection surveillance, and long-term complications including cardiac allograft vasculopathy (CAV) and malignancy. Audio editing for this episode was performed by CardioNerds intern Dr. Bhavya Shah. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. CardioNerds Heart Success Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls The Denervated Heart: The donor heart is surgically severed from the autonomic nervous system, leading to a higher resting heart rate (90-110 bpm) due to loss of vagal tone. Because the heart relies on circulating catecholamines rather than neural input to increase heart rate, patients experience a delayed chronotropic response to exercise and stress. Importantly, because afferent pain fibers are severed, ischemia is often painless. Rejection Surveillance: Rejection is classified into Acute Cellular Rejection (ACR), which is T-cell mediated, and Antibody-Mediated Rejection (AMR), which is B-cell mediated. While endomyocardial biopsy remains the gold standard for diagnosis, non-invasive surveillance using gene-expression profiling (e.g., AlloMap) and donor-derived cell-free DNA (dd-cfDNA) is increasingly utilized to reduce the burden of invasive procedures. The Infection Timeline: The risk of infection follows a predictable timeline based on the intensity of immunosuppression. The first month is dominated by nosocomial infections. Months one through six are the peak for opportunistic infections (Cytomegalovirus, Pneumocystis, Toxoplasmosis) requiring prophylaxis. After six months, patients are primarily at risk for community-acquired pathogens, though late viral reactivation can occur. Cardiac Allograft Vasculopathy (CAV): Unlike native coronary artery disease, CAV presents as diffuse, concentric intimal thickening that affects the entire length of the vessel, including the microvasculature. Due to denervation, patients rarely present with angina; instead, CAV manifests as unexplained heart failure, fatigue, or sudden cardiac death. Malignancy Risk: Long-term immunosuppression significantly increases the risk of malignancy. Skin cancers (squamous and basal cell) are the most common, followed by Post-Transplant Lymphoproliferative Disorder (PTLD), which is often driven by Epstein-Barr Virus (EBV) reactivation. Notes Notes: Notes drafted by Dr. Patlolla 1. What are the unique physiological features of the transplanted heart? The hallmark of the transplanted heart is denervation. Because the autonomic nerve fibers are severed during harvest, the heart loses parasympathetic or vagal tone, resulting in a resting tachycardia (typically 90-110 bpm). The heart also loses the ability to mount a reflex tachycardia; thus, the heart rate response to exercise or hypovolemia relies on circulating catecholamines, which results in a slower “warm-up” and “cool-down” period during exertion. 2. What are the pillars of maintenance immunosuppression regimen? The triple drug maintenance regimen typically consists of: Calcineurin Inhibitor (CNI): Tacrolimus is preferred over cyclosporine. Key side effects include nephrotoxicity, hypertension, tremor, hyperkalemia, and hypomagnesemia. Antimetabolite: Mycophenolate mofetil (MMF) inhibits lymphocyte proliferation. Key side effects include leukopenia and GI distress. Corticosteroids: Prednisone is used for maintenance but is often weaned to low doses or discontinued after the first year to mitigate metabolic side effects (diabetes, osteoporosis, weight gain). 3. How is rejection classified and diagnosed? Rejection is the immune system’s response to the foreign graft and is categorized by the arm of the immune system involved: Acute Cellular Rejection (ACR): Mediated by T-lymphocytes infiltrating the myocardium. It is graded from 1R (mild) to 3R (severe) based on the extent of infiltration and myocyte damage. Antibody-Mediated Rejection (AMR): Mediated by B-cells producing donor-specific antibodies (DSAs) that attack the graft endothelium. It is diagnosed via histology (capillary swelling) and immunofluorescence (C4d staining). Diagnosis has historically relied on endomyocardial biopsy. However, non-invasive tools are gaining traction. Gene Expression Profiling (GEP) assesses the expression of genes associated with immune activation to rule out rejection in low-risk patients. Donor-Derived Cell-Free DNA (dd-cfDNA) measures the fraction of donor DNA in the recipient’s blood. Elevated levels suggest graft injury which can occur in both ACR and AMR. 4. What is the timeline of infectious risk and how does it guide prophylaxis? Infectious risk correlates with the net state of immunosuppression. < 1 Month (Nosocomial): Risks include surgical site infections, catheter-associated infections, and aspiration pneumonia. 1 – 6 Months (Opportunistic): This is the period of peak immunosuppression. Patients are at risk for PJP, CMV, Toxoplasma, and fungal infections. Prophylaxis typically includes Trimethoprim-Sulfamethoxazole (for PJP/Toxo) and Valganciclovir (for CMV, dependent on donor/recipient serostatus). > 6 Months (Community-Acquired): As immunosuppression is weaned, the risk profile shifts toward community-acquired respiratory viruses (Influenza, RSV) and pneumonias. However, patients with recurrent rejection requiring boosted immunosuppression remain at risk for opportunistic pathogens. 5. How does Cardiac Allograft Vasculopathy (CAV) differ from native CAD? CAV is the leading cause of late graft failure. Unlike the focal, eccentric plaques seen in native atherosclerosis, CAV is an immunologically driven process causing diffuse, concentric intimal hyperplasia. It affects both epicardial vessels and the microvasculature. Because of this diffuse nature, percutaneous coronary intervention (PCI) is often technically difficult and provides only temporary palliation. The only definitive treatment for severe CAV is re-transplantation. Surveillance is critical and is typically performed via annual coronary angiography, often using intravascular ultrasound (IVUS) to detect early intimal thickening before it is visible on the angiogram. References Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. doi:10.1016/j.healun.2010.05.034. https://www.jhltonline.org/article/S1053-2498(10)00358-X/fulltext Kittleson MM, Kobashigawa JA. Cardiac Allograft Vasculopathy: Current Understanding and Treatment. JACC Heart Fail. 2017;5(12):857-868. doi:10.1016/j.jchf.2017.07.003. https://www.jacc.org/doi/10.1016/j.jchf.2017.07.003 Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015. https://www.jhltonline.org/article/S1053-2498(22)02187-5/fulltext

In January 2026, the ACOG released its Practice Advisory on Screening for fetal Chromosomal Abnormalities. This comes after its Nov 2025 endorsement of the SMFM's Consult Series #74, “Cell-free DNA screening for aneuploidies: Updated guidance”. In this episode we will review the key parts of this PA. Is screening for microdeletions recommended? PLUS, we will focus on cfDNA for sex chromosomal abnormalities. Should screening for sex chromosomal abnormalities (SCAs) be an “opt in” or “opt out” process for patients? What are nest steps after an abnormal SCA screening result? Are commercial tests available for fetal gender recommended? Listen in for details. 1. ACOG PA Jan 2026: https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2026/01/screening-for-fetal-chromosomal-abnormalities?utm_source=higher-logic&utm_medium=email&utm_content=Jan-07&utm_campaign=acog2026-digest2. Society for Maternal-Fetal Medicine Consult Series #74: Cell-free DNA screening for aneuploidies: Updated guidance1 in November 2025.

In this episode of The ICHE Podcast, we take a deep dive into the evolving role of plasma cell-free DNA (cfDNA) metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious diseases. Hosted by experts from UCLA Health, this discussion breaks down what cfDNA mNGS is, how it differs from more traditional pathogen detection tools like PCR, and where it fits in the diagnostic landscape. Dr. Ishminder Kaur, Dr. Daniel Uslan, and Dr. Shangxin Yang join the episode to explore the clinical utility, benefits, and pitfalls of this rapidly emerging diagnostic modality. The group reviews several individual studies, highlighting how they approached their research questions, key findings, and the implications for patient care and antimicrobial stewardship. The conversation also addresses challenges such as interpreting complex results, cost considerations, and potential overuse. Whether you're a clinician, laboratorian, or infection preventionist, this episode provides critical insights into when and how cfDNA mNGS may enhance your diagnostic toolkit—and when it might not. Each guest closes with a practical takeaway: concrete advice for healthcare professionals who are considering incorporating cfDNA testing into their own clinical or infection control practice.

Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785     Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Imagine if a single blood test could tell clinicians in real time how successful a cancer surgery has been. A recent study from the University of Brasília, published in Oncotarget, suggests that such an approach might soon be possible. By tracking changes in cell-free DNA (cfDNA) levels before, during, and after colorectal cancer (CRC) surgery, researchers have found a potential new way to monitor tumor removal and predict patient outcomes. Cell-Free DNA and Colorectal Cancer Surgery Cell-free DNA consists of tiny fragments of genetic material that are released into the bloodstream when cells break down. In healthy individuals, these fragments come from normal cell turnover, but in cancer patients, some of this DNA originates from tumor cells. cfDNA detection has been used to track cancer progression and treatment response in diseases like lung, breast, and CRC. What had not been investigated until now was how cfDNA levels fluctuate during cancer surgery itself. Since surgery is the primary treatment for CRC, understanding how cfDNA levels change during surgical intervention could provide valuable insights into whether the tumor has been fully removed and how the patient's body reacts to the procedure. The Study: Measuring Cell-Free DNA in Real-Time In the study, titled “Assessment of cfDNA release dynamics during colorectal cancer surgery,” led by first author Mailson Alves Lopes and corresponding author Fabio Pittella-Silva, scientists analyzed ​​blood plasma samples from 30 CRC patients at three critical time points—before, during, and after surgery. Using highly sensitive genetic tests, they measured changes in cfDNA concentration to determine whether surgery had a direct impact on its release. The goal was to check whether cfDNA could serve as a biomarker for evaluating surgical effectiveness and predicting the probability of cancer recurrence. Full blog - https://www.oncotarget.org/2025/02/26/how-a-simple-blood-test-could-predict-colorectal-cancer-surgery-success/ Paper DOI - https://doi.org/10.18632/oncotarget.28681 Correspondence to - Fabio Pittella-Silva - pittella@unb.br Video short - https://www.youtube.com/watch?v=jC5_xqIrbtA Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28681 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, colorectal cancer, cfDNA, surgery About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Join us as we review recent articles and news featured in The DIGEST issues #59-61, including cfDNA and incidental detection of cancer in pregnancy, vitamin K2 for nocturnal leg cramps, the danger of as-needed anti-hypertensive medications in the hospital, GLP-1 agonists for alcohol use disorder, short-course (7 vs 14 days) antibiotics for bacteremia, and patient-collected HPV testing for cervical cancer screening. Fill your brain hole with a fully digestible meal! Featuring Laura Glick MD, Nora Taranto (@norataranto), Paul Williams (@paulnwilliamz), and Matt Watto (@doctorwatto).  Claim CME for this episode at curbsiders.vcuhealth.org! Patreon | Episodes | Subscribe | Spotify | YouTube | Newsletter | Contact | Swag! | CME Show Segments 00:00 Introduction and Overview 02:57 The IDENTIFY study: Non-Invasive Prenatal Testing and Cancer Detection with cfDNA 05:54 Implications of Non-Reportable Results in Prenatal Testing 08:51 Vitamin K2: A New Approach to Managing Nocturnal Leg Cramps 12:07 Practicality and Future of Vitamin K2 in Clinical Practice 23:21 The Dangers of As-Needed Antihypertensives in the hospital 32:21 Exploring GLP-1 Agonists for Alcohol Use Disorder 40:24 Shorter Antibiotic Courses in Sepsis 46:09 Advancements in Patient-Collected HPV Screening for cervical cancer Credits Written and Produced by: Nora Taranto MD, Laura Glick MD, Matthew Watto MD, FACP; Paul Williams MD, FACP Show Notes: Nora Taranto MD Cover Art: Matthew Watto MD, FACP Hosts: Nora Taranto MD, Laura Glick MD, Matthew Watto MD, FACP; Paul Williams MD, FACP    Reviewer: Emi Okamoto MD Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP Technical Production: PodPaste Disclosures The Curbsiders report no relevant financial disclosures.  Sponsor: Bombas Head over to Bombas.com/curb and use code curb for 20% off your first purchase. Sponsor: Pretty Litter  Go to PrettyLitter.com/curb to save twenty percent on your FIRST order and get a free cat toy.  Sponsor: Rocket Money  Cancel your unwanted subscriptions and reach your financial goals faster with Rocket Money. Go to RocketMoney.com/CURB today.

Vidcast:  https://www.instagram.com/drhowardsmithreports/reel/DGV5FSROObD/This condition of late pregnancy, heralded by dangerously high blood pressures and organ failure, kills 70,000 women worldwide each year.  Seattle obstetricians and precision medicine researchers at the University of Washington now announce in the journal Nature a test that can predict this devastating complication with 80% accuracy months before its actual occurrence.Using a machine learning analysis of cell-free DNA from the placenta shed into 1,854 blood samples from pregnant women, the researchers pinpointed signs of early tissue dysfunction associated with preeclampsia.  With further test refinement and inclusion with standard pregnancy test batteries, this cell-free DNA assessment could save many lives.https://medicalxpress.com/news/2025-02-blood-cell-free-dna-placenta.htmlhttps://www.nature.com/articles/s41591-025-03509-w#preeclampsia #cfDNA #pregnancy #women

BUFFALO, NY - January 27, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 21, 2025, titled “Assessment of cfDNA release dynamics during colorectal cancer surgery." Researchers from the University of Brasília investigated how cell-free DNA (cfDNA) levels in the blood change before, during, and after colorectal cancer surgery. The study found that cfDNA levels increase significantly during and after surgery. The findings suggest that cfDNA could help clinicians evaluate surgery effectiveness and monitor patient outcomes. cfDNA consists of small DNA fragments released into the bloodstream when cells die and break apart. In healthy individuals, cfDNA usually comes from normal cell turnover, while in cancer patients, some of it originates from tumor cells. Measuring cfDNA levels offers valuable insights into a patient's condition and is already being used to track disease progression and treatment response in cancers such as lung, breast, and colorectal cancer. Colorectal cancer is one of the most common cancers worldwide, affecting millions of people each year. Surgery is often the primary treatment, but up to 50% of patients experience cancer recurrence afterward. In this study, the research team, led by first author Mailson Alves Lopes and corresponding author Fabio Pittella-Silva, analyzed blood samples from 30 patients at three key time points: before, during, and after surgery. It was found that cfDNA levels increased nearly threefold during surgery and doubled after surgery compared to pre-surgery levels. The increases were even higher in individuals over 60, those with preexisting conditions such as diabetes or heart disease, and patients with elevated levels of carcinoembryonic antigen (CEA), a common cancer marker. Patients with the highest cfDNA levels were those with larger or more aggressive tumors, likely due to greater tissue damage during surgery. Additionally, longer surgeries were linked to higher cfDNA levels. “[...]we observed that cfDNA concentration may rise in correlation with the duration of the surgery, highlighting its potential as a marker of surgical quality.” These findings suggest that cfDNA could be a valuable, non-invasive biomarker for clinicians to monitor colorectal cancer patients. Tracking cfDNA levels may help better evaluate surgical outcomes and determine whether patients require closer follow-up care. While these findings are promising, further research is needed to standardize cfDNA testing and validate its usefulness. Larger studies could help establish cfDNA testing as a reliable tool for cancer care and postoperative monitoring, with the potential to become a routine part of clinical practice in the future. DOI - https://doi.org/10.18632/oncotarget.28681 Correspondence to - Fabio Pittella-Silva - pittella@unb.br Video short - https://www.youtube.com/watch?v=jC5_xqIrbtA About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. Rajesh Rao speaks with Dr. Jasmine H. Francis on whether sequencing of plasma-derived ctDNA can noninvasively diagnose ocular-involving histiocytosis. From her Ophthalmology Science article, “Plasma-Derived Cell-Free DNA for the Diagnosis of Ocular-Involving Histiocytosis.” Plasma-Derived Cell-Free DNA for the Diagnosis of Ocular-Involving Histiocytosis. Francis, Jasmine H. et al. Ophthalmology Science, Volume 4, Issue 5.

In this inaugural episode of the Surgical Oncology Insight series of SurgOnc Today®, Dr. Shishir Maithel, Editor of Surgical Oncology Insight, SSO's open-access journal, discusses with Dr. Brett Ecker the results of a systematic review and meta-analysis characterizing the incidence of cfDNA-positivity after resection of colorectal cancer liver metastases  with quantification of its sensitivity and specificity for postoperative recurrence, as reported in his article, "The Prognostic Role of Post-operative cfDNA after Resection of Colorectal Liver Metastases: A Systematic Review and Meta-Analysis."

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.CVS is laying off 2,900 employees as part of a cost-cutting plan and potential business breakup. Humana's Medicare Advantage star ratings have dropped significantly, impacting profits. Healthcare workers face burnout, while the payer-provider relationship is evolving. Mission Hospital in North Carolina is struggling after Hurricane Helene, and Steward CEO Ralph de la Torre is being sued by senators. Healthcare companies are urged to prioritize patient-centric experiences. The text also highlights upcoming healthcare conferences, telehealth trends, and insights into the relationship between providers and payers.The FDA has officially declared the end of the shortage of Zepbound and Mounjaro, putting pressure on companies selling compounded alternatives. Biopharma conferences in 2025 are important for showcasing clinical trial results. The FDA is set to make several key decisions in the fourth quarter, including approving a rival to a popular Pfizer heart drug. Roche plans to address an $8 billion sales gap due to biosimilar competition. Lilly is investing $4.5 billion in a "foundry" for advanced drug manufacturing. Additionally, there are resources available on topics such as AI in clinical research, genetic screening, gene therapy, and biosimilars. Other industry news includes potential sales of pharma units by Chinese company Wuxi, and the US's commitment to African manufacturing in HIV programs.Sanofi has sold the global rights to a rare autoimmune drug for cold agglutinin disease to Recordati in a potential $1 billion deal. Recordati will make an upfront payment of $825 million to Sanofi, with milestone payments of up to $250 million. Meanwhile, Novo's lowest dose of Wegovy remains on the FDA's drug shortage list. AbbVie has trimmed its full-year earnings guidance due to R&D milestone costs, following the success of its Parkinson's disease candidate Tavapadon. Relay Therapeutics is laying off 10% of its workforce to streamline its research organization. The pharma industry is prioritizing scaling GLP-1 manufacturing capacity to meet the demand for weight loss drugs. Lilly has ended its obesity drug shortage, while Novo continues to face shortages. WBL's proprietary library prep for cfDNA whole genome sequencing aims to enhance specificity, sensitivity, and data quality at low concentrations. In other news, BMS has received FDA approval for an Opdivo regimen in NSCLC and Bavarian Nordic's MPox shot shows antibody responses wane after 6 to 12 months.Dr. Matthew Schrag, a vascular neurologist at Vanderbilt University, is not prescribing the new Alzheimer's disease treatments, Kisunla and Leqembi, due to concerns over risks and costs. Schrag has a history of challenging prevailing science in Alzheimer's and has exposed instances of potential misconduct by researchers. In 2021, he raised allegations of data manipulation against Cassava Sciences, leading to ongoing scrutiny and calls for their phase 3 trials to be stopped. Despite distancing himself from the controversy, Schrag's findings have had a significant impact on the company. The article also discusses Roivant's unique approach to drug development, the latest advances in oncology research, and the challenges in navigating the path from preclinical studies to regulatory approval for gene therapies. The text highlights the importance of efficient therapeutic development processes and increasing diversity in clinical trials. Additionally, it provides links to resources on selecting clinical trial sites, unlocking partnerships for small biotech firms, and optimizing AAV manufacturing processes. The newsletter also includes updates on Medicare drug price talks, a groundbreaking trial for lung cancer treatment, and a map of a fruit fly's brain that has impressed neuroscientists.

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world. Bayer has developed a successful audience targeting strategy that drives meaningful engagement, with Crossix audience segments optimizing campaigns and aligning messaging more closely with the patient journey. This precision targeting has proven effective in reaching the most qualified audience and increasing engagement.Philips issued a fix for ventilator problems linked to injuries and deaths, Siemens Healthineers received FDA approval for a 3D mammography system, and Synchron's brain-computer interface technology met safety goals. Additionally, the wearables market is expected to see growth, while the FDA missed a target date for releasing rules on pulse oximeters. Medtech Dive provides insights on medical technology trends and top conferences in 2025.A private equity firm, TPG, is set to acquire a majority stake in e-prescribing giant Surescripts. HCA's Mission Hospital in North Carolina faces challenges after Hurricane Helene, while UHS has been forced to pay significant damages related to child sexual abuse allegations. Efforts to combat burnout among healthcare workers are highlighted, along with sponsored content on safeguarding healthcare against cybercrime.Eli Lilly is investing $4.5 billion in a new manufacturing and research center in Indiana, while Amgen faces a class action lawsuit and Johnson & Johnson invests $2 billion in a North Carolina facility. Bayer, J&J, and Pfizer are collectively laying off nearly 500 employees, with new developments in cFDNA methylation assays and royalty financing for biopharma companies. ImmunityBio is also undergoing layoffs in California.Roche is facing an $8 billion sales gap due to biosimilar competition, prompting investments in new blockbuster drugs. Kailera Therapeutics has secured funding for obesity drugs, and the cell and gene therapy industry is experiencing rapid growth. Pharmavoice covers these topics and more in their daily newsletter.2seventy Bio is close to reaching cash flow breakeven, attributing their survival to transparency and a committed staff. Pfizer's withdrawal of sickle cell therapy Oxbryta has raised questions among investors. Royalty financing has become crucial for biopharma companies as traditional fundraising methods falter. Lilly's drug pricing practices are under scrutiny compared to Novo Nordisk. Various updates on investments, layoffs, and legal actions can be found on Biospace's website.

Our immediate past episode summarized a validation study of cell-free DNA (cfDNA) isolated from maternal plasma for fetal RBC genotyping in alloimmunized patients. And now, in this episode, we will highlight a BRAND NEW ACOG Clinical Practice Update on this very subject! YEP... we now have new ACOG guidance regarding using maternal derived cfDNA for fetal RBC antigen detection as an option for care in alloimmunized pregnancies. This is how "medicine moves fast"! Listen in for details.

In September 2022, a cell-free DNA assay using next-generation sequencing and quantitative counting tech for fetal antigen status determination became clinically available in the USA. This allowed maternal screening for fetal RBC genotypes for RH negative patients. This test was recognized by thre ACOG in March 2024 as one option to “triage” anti-D immunoglobulin in RH negative women. But can this technology be trusted in alloimmunized patients? In women with antibodies against foreign antibodies, this cell free DNA fetal screening option MUST get it right. We now have that data. In this episode, we will summarize remarkable results, published ahead of print on July 25, 2024 in the Green Journal. This study is a win for science and prenatal care. Listen in for details (BillontoOne, Inc is not a sponsor for this podcast).

Dr. Medhat Askar joins the podcast to discuss the utility and validation of donor-derived cell-free DNA (dd-cfDNA) testing for solid-organ recipients. Dr. Askar also discusses the regulatory status of dd-cfDNA in the United States.

Proving that our podcast tagline, “Medicine Moves Fast” is true… this episode highlights something that is, once again,

Organ transplantation is a modern marvel, with more than 157,000 solid organ, and more than 9,000 marrow and blood transplants occurring worldwide in 2022. Organ donor and recipient matching and compatibility screening has progressed significantly in recent decades as molecular methods have progressed rapidly to support this and other fields. Specifically, typing of human leukocyte antigens (HLAs) has expanded to consider ethnic population variation and cell free DNA (cfDNA) monitoring is now being used to monitor recipients for biomarkers that indicate organ rejection.  Our guest for this episode, Dr. Lee Ann Baxter-Lowe, Director of the HLA Laboratory at Children's Hospital Los Angeles has been working in the field of transplantation science for virtually her entire career. Join us for a great explanation of the science and a first-hand recounting of developing the assays, from decades ago, before thermal cyclers existed, to her cutting-edge work using digital PCR to progress the field even further. Lee Ann also shares very personal aspects of her career journey in her conversation with Cassie. This includes her describing the scientific “studies” of her and her cousin as children, her venturing into the world of HLA typing when it was emerging, and the role her family has played in her career, which gets personal quickly when she shares that her husband is currently dealing with a blood malignancy. Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Alex Aravanis is a leader in research and development of technologies and clinical tests utilizing the latest tools in DNA analysis and data science. In this episode, Alex delves into two interconnected topics: liquid biopsies and epigenetics. He begins by tracing the trajectory of genome sequencing and tumor sequencing, setting the stage for a detailed exploration of liquid biopsies as an early cancer detection method. The discussion encompasses key concepts such as cell-free DNA, DNA methylation, sensitivity, specificity, and the predictive values associated with liquid biopsies. Transitioning to epigenetics, Alex examines the intricate interplay of DNA methylation and aging biology and explores the possibility of using cellular reprogramming to reverse epigenetic changes that occur with aging. We discuss: Alex's background in applying engineering to problems in medicine [3:15]; A primer on human genetics, and the history and current landscape of DNA sequencing [11:00]; The advent and evolution of liquid biopsies for early detection of cancer [23:15]; The role of cell-free DNA in cancer detection: how incidental findings in non-invasive prenatal testing led to the development of liquid biopsies [40:15]; The development of a universal blood test for cancer detection and a discussion of specificity of tests [46:00]; Advancements in cell-free DNA analysis and development of a multi-cancer screening test at GRAIL [51:00]; DNA methylation explained [58:15]; Optimizing cancer detection with methylation analysis of cfDNA in small blood samples [1:02:45]; The importance of understanding sensitivity, specificity, positive predictive value, and negative predictive value in cancer screening [1:08:00]; The performance of the GRAIL Galleri test and its ability to detect various types and stages of cancer [1:21:00]; Do early cancer detection methods, like liquid biopsies, translate to improvement in overall survival? [1:27:45]; The role of epigenetics in aging [1:39:30]; How cell-free DNA methylation patterns can help identify a cancer's tissue of origin [1:45:30]; Cellular and epigenetic reprogramming and other exciting work in the field of aging [1:52:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

CME credits: 1.00 Valid until: 17-01-2025 Claim your CME credit at https://reachmd.com/programs/cme/testing-for-solid-tumors-tissue-and-liquid-biopsy-approaches-using-ngs-technologies-for-cfdna-and-ctdna-analysis/16555/ HER2-targeted treatments have been extensively researched and approved in breast, gastric, and non-small cell lung cancers. Are these same therapies effective at treating other HER2-positive tumors? Join our faculty as they examine the potential role for HER2-directed antibody-drug conjugates in treating advanced solid tumors and discuss the latest data around the efficacy and safety of these agents.

Vidcast:  https://www.instagram.com/p/C0pH9cArYEY/ Analysis of breast milk and detection of cell-free tumor DNA, cfDNA, the so-called liquid tumor biopsy for early detection of breast cancer, is nearly 11 times more effective than using blood..  Spanish researchers studied 19 women who developed breast cancer during or shortly after pregnancy and a control group of 12 healthy breast milk donors. The data showed that the concentration of cfDNA was 90-fold higher in breast milk compared with blood.  As a result, it is possible to detect the presence of breast cancer using breast milk in 87% of cases compared with only 8% of cases using blood.  This method's overall sensitivity is 71% and its specificity is 100%.  In two cases, breast milk liquid biopsy detected cancer 6 to 18 months earlier than standard diagnostic methods. Using $$ breast milk for an earlier diagnosis can be the driver for complete eradication of breast cancer with minimally invasive surgery, radiation, or chemotherapy.  The technique will also permit earlier discovery of cancer that has already spread improving chances for effective control. https://aacrjournals.org/cancerdiscovery/article/13/10/2180/729382/Early-Stage-Breast-Cancer-Detection-in-Breast #breastmilk #breastcancer #liquidbiopsy #earlydetection #cfDNA

Vidcast:  https://www.instagram.com/p/Cy_dyL1RlWX/ Ovarian cancer is the 3rd most common cancer in women's reproductive organs and it usually goes undetected until it becomes untreatable and deadly.  University of Southern California researchers have now developed a liquid biopsy called OvaPrint capable of pinpointing high-grade serous ovarian cancer with an overall accuracy of 91%, a positive predictive value of 95% and a negative predictive value of 88%.  The test differentiates circulating DNA from aggressive ovarian cancer from the DNA with benign origins.  The test isn't perfect, but it is an exciting first step toward developing reliable screening for one of the most dangerous cancers that befall women. https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-1197/729529/OvaPrintT-a-cell-free-DNA-methylation-liquid https://tinyurl.com/3yccp5bv #ovariancancer #liquidbiopsy #ovaprint #usc #cfDNA 

Dr. Rachna Shroff, chair-elect of the 2023 ASCO GI Cancers Symposium, and guest host Dr. Shaalan Beg discuss new research presented at GI23, including new data from SWOG 1815 in biliary tract cancers, advances in biomarker studies in mCRC such as the PARADIGM trial, and promising updates in ctDNA technology. She also highlights the exciting potential of AI in oncology. TRANSCRIPT Dr. Shaalan Beg:  Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of Oncology at Science 37. Today we'll be discussing key abstracts and other highlights from the 2023 ASCO Gastrointestinal Cancer Symposium, which celebrated 20 years of transformative care in GI cancers. I'm delighted to welcome Dr. Rachna Shroff, the chair-elect of this milestone meeting. Dr. Shroff is the interim division chief of Hematology Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for Clinical and Translational Research and is the chief of GI Medical Oncology. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Shroff, it's great to have you back on the ASCO Daily News podcast. Dr. Rachna Shroff: Thank you so much for having me. I'm so excited to be here. Dr. Shaalan Beg: The ASCO GI Cancers Symposium has been heralded as one of the biggest conferences in the GI cancer space and has occupied this space for the past two decades. Some would say that this year's conference was probably the best GI Cancers Symposium to date. Can you comment on the 20th anniversary milestone and the impact of the symposium on GI cancers? Dr. Rachna Shroff: Absolutely, and that's so great to hear that that's the feedback that you've heard. I have to say GI ASCO is absolutely my favorite meeting of the year, so that is my full disclosure. But I think that this was a tremendous meeting, and I think it was so beautiful that it was also coinciding with the 20th anniversary. It meant so much to us to have Dr. Margaret Tempero open the meeting because she really was the impetus for creating a GI cancer-focused meeting that really brought together multidisciplinary expertise. And so to us, that is what this 20th anniversary represented—20 years of multiple different specialties coming together to discuss how to improve cancer care for patients with gastrointestinal malignancies. And it has been a transformative meeting to see the impact of research presented at this meeting and how it has been implemented over the course of 20 years. And I completely agree that this year in and of itself had some incredible pivotal data that there is no doubt will be practice-changing, and that is absolutely the purpose. I also think that the beauty of this meeting is the networking opportunities for all of us to come out of our individual silos, come together, and discuss cross-cutting care across the spectrum of GI malignancies. And I think that this meeting really did that quite well. Dr. Shaalan Beg: There were many practice-changing studies that made headlines this year, and for me, one of the most anticipated studies was a trial that you led for cholangiocarcinoma and much-anticipated results. The study finished enrollment at a record pace. Can you share your key findings of cholangiocarcinoma? And I'd really like to hear your perspective on cholangiocarcinoma studies. Dr. Rachna Shroff: Yes, it was actually a really big year in the hepatobiliary space, and I was proud to present SWOG 1815, LBA 490, which was the pivotal randomized phase 3 trial looking at gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin. This was a study that was opened across the entire NCTN and based on a single-arm phase 2 trial that had shown some promising early efficacy of the triplet chemotherapy regimen. As you mentioned, this study accrued 441 patients in two years. And it's really a testament to the fact that the cooperative group mechanism can and should be asking important questions in large, randomized studies and that it is even possible to do in what are historically thought of as, quote-unquote, “rare tumors.” The study was a randomization of two to one to the triplet chemotherapy versus the standard of care for newly diagnosed biliary tract cancer patients. And the primary endpoint was median overall survival. And while the median OS of the triplet regimen was numerically improved at 14 months compared to 12.7 months, this did not meet statistical significance. Other efficacy endpoints, including median progression-free survival and overall response rate, were also numerically improved but not statistically significant, with an overall response rate of 31% with the triplet regimen versus 22%. There were some prespecified stratification factors, including disease site and disease stage, and there may be some interesting signals that bear out of that in terms of perhaps gallbladder cancer and locally advanced patients may be benefiting from the triplet regimen a little bit more, but these are small numbers, and we would really need to explore that in a more rigorous prospective manner. The toxicities were, not surprisingly, there, especially hematologic toxicities. I will say for those of us that use this regimen in practice, we use it a little bit differently than what was done in SWOG 1815, but you can't deny that there were significantly higher grade 3-5 toxicities with anemia neutropenia and thrombocytopenia, though the treatment discontinuation rate did not differ. I think the next steps are really going to be the ongoing biomarker analyses. The study had archival tissue and prospective blood collection and we know that in the space of cholangiocarcinomas and biliary cancers, molecular complexities absolutely play a role in how patients do and how they respond to therapies. So that's going to be an important next step, I think, for this study. Dr. Shaalan Beg: Speaking of biomarkers and an impact on GI cancers, the other malignancy where biomarkers are having a much greater impact than other GI cancers is colon cancer. Another year where we continue to see advances in our understanding of molecularly targeted treatments for colon cancer. What caught your eye? Dr. Rachna Shroff: Well, there were a lot of really interesting studies happening in this space and as a biliary person, one of the first things I got excited about was seeing Abstract 139 that looked at pemigatinib, which is the drug we are very familiar with in cholangiocarcinoma. This was a single-arm phase two study looking at the use of the FGFR inhibitor pemigatinib in metastatic colorectal cancer patients who had FGFR alterations. And so this was a study that was opened through the ACCRU mechanism. It was multicenter with assignment two-stage design and it was specifically for patients with FGF and FGFR-altered metastatic colorectal cancer who had progressed on standard therapies. There was a prespecified interim analysis for futility after 12 evaluable patients and so 14 patients were enrolled in the first stage of the study and evaluated for the primary endpoint of objective response. What was seen and the study was subsequently stopped is that there was really not much efficacy, there was no evidence of safety signals, but this did not seem to be a very active drug in patients with FGFR alterations with no objective response noted. So, the study was stopped with the recognition that perhaps the FGFR translocation or fusion patient population may be something to explore since they did not look at that in this study. The other kind of study that I think is really important was important work of Dr. Raghav and colleagues through SWOG. This was SWOG 1613 Abstract 140. This was the first real study that was investigating targeting HER-2 overexpressed and amplified metastatic colorectal cancer who had RAS wild-type tumors. And it was based on, obviously, some early signals of the effectiveness of HER-2 targeting in metastatic colorectal cancer. And this was a large study looking at pertuzumab and trastuzumab in these patients. They were compared to cetuximab and irinotecan, and the initial plan was for a much larger study. Unfortunately, accrual was really slow so the study was really kind of reformatted and a total of 54 patients were randomized, 26 to the trastuzumab arm and 28 to the CetIri or cetuximab and irinotecan arm. What was seen was that you can absolutely use HER-2 targeting therapies with trastuzumab and pertuzumab in these patients. It was safe and there were some obvious signs of efficacy in terms of overall response rate with an overall response rate of 31% compared to the CetIri arm. Crossover was allowed from the CetIri arm to trastuzumab and pertuzumab. So just that's important to keep in mind when they start to follow out the survival data. But unfortunately, because this study did not accrue, it was stopped early and it's really hard to understand in terms of power calculations the impact of trastuzumab pertuzumab. Of course, we can't talk about this without recognizing that the FDA approval based on the MOUNTAINEER study for tucatinib and trastuzumab came through during GI ASCO. So clearly HER-2 targeting is here to stay in colorectal cancer. Dr. Shaalan Beg: So technology is advancing every year and it's important that we are aware of these advances and how they impact our patients. Probably one of the most exciting technologies in oncology in general is the evolution of ctDNA. And it's been amazing to watch that field unfold as we understand how to use circulating biomarkers for early detection of cancer, for minimal residual disease detection, even as a biomarker of response. What caught your eye when it comes to the use of ctDNA in GI cancers, and how do you see this space develop in the next couple of years? Dr. Rachna Shroff: I completely agree. I think the technology of ctDNA is so incredibly exciting and as somebody who does not actively see and treat colorectal cancer, I'm a little bit envious of my colleagues in that space because the strides that have been made in terms of understanding the utility of ctDNA, especially in colorectal cancer, has just been tremendous and even for the last two to three years. One perfect example of integrating that sort of technology into treatment paradigms is the PARADIGM trial, Abstract 11, which was looking at the concept of hyperselection of patients with RAS wild-type metastatic colorectal cancer who were on the PARADIGM trial which basically looked at frontline FOLFOX with panitumumab versus bevacizumab in patients with RAS wild type left-sided metastatic colorectal cancer. So, you know, the initial data from PARADIGM had demonstrated a longer median overall survival 37.9 months versus 34.3 months, but very smartly, the investigators had also collected baseline plasma ctDNA in the biomarker component of this study and used a custom panel that looked at gene alterations for hyperselection and that included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations HER-2 and MET amplifications, as well as some fusions like ALK, RET, and NTRK. And so out of the 802 patients in the full set, 91% - 733 patients - actually had pretreatment samples for ctDNA, which is really in and of itself, I think, tremendous. And when you break it down, about 28% had at least one gene alteration, and that was across each of those different genes that they were looking at. In the 72% of patients who were defined as hyperselected without any gene alterations, the OS was actually longer with panitumumab versus bev, and that actually was independent of sidedness with hazard ratios that kind of ranged from 0.76 to 0.82. And OS was similar or inferior with panitumumab versus bevacizumab again, regardless of sidedness in patients with any of these gene alterations. And so I think it's a really interesting concept that you can use ctDNA to define negative hyperselection rather than looking at left sided and right sided to really help select patients with frontline therapy in terms of using panitumumab versus bevacizumab. And with the speed with which ctDNA can be obtained, this actually seems like something that could be implemented into clinical practice, which is, I think, really the important component of that. There were a number of other really interesting abstracts. Abstract 5, presented by Dr. Cohen and colleagues, really looked at the kinetics of circulating cell-free DNA and how that kind of relates to minimal residual disease detection rates. And this was in patients with resected stages one through three colorectal cancer. And so, this was a retrospective study, so we have to keep that in mind. And it was multi-institutional in really over 16,000 patients with stages 1 through 3 colorectal cancer. But the complete dataset had about 417 patients and basically the patients' circulating cell-free DNA levels, the total cfDNA, were compared to the ctDNA MRD positivity rates and they looked at very specific time points after surgery. What the authors generally found was that the postoperative cfDNA correlated well with ctDNA positivity and that there was really the ability to see plasma cfDNA levels kind of track and follow with the very specific MRD windows that were being looked at, which really, again, just kind of talks about leveraging this technology in terms of real-world and real-time application and better understanding and informing us of minimal residual disease post what is thought to be curative resection. The last one that I thought was really interesting in relation to ctDNA was actually looking at anal cancer and following ctDNA in patients who were treated with definitive chemoradiation. This was a study that was looking at 31 patients with anal squamous cell carcinoma who were treated with definitive chemo radiation and underwent ctDNA response. The majority of these patients had stage 3 disease and the majority of them received the standard 5-FU Mitomycin with radiation. The patients had ctDNA testing performed in 25 of these patients at baseline and then a smaller number over the course of time, some during chemoradiation. And then they looked again at 30 days post chemoradiation. And at baseline, 88% of patients had detectable ctDNA with those with stage three disease having numerically higher baseline ctDNA levels. And basically what they found was that over the course of treatment, ctDNA levels decreased among the patients with detectable ctDNA. And then ctDNA that tested during chemo radiation showed a drop in decline and were going into molecular remission at a time point in which it was subsequently confirmed that they had a clinical complete response. So, the suggestion here is that the time to molecular ctDNA remission was significantly shorter than being able to see that clinical complete response, which suggests that using surveillance ctDNA monitoring could be an earlier response assessment for patients with anal squamous cell carcinoma who are undergoing definitive therapy. Now, obviously this needs to be confirmed in a larger manner, but again, really suggests that we could be understanding how we're doing with treatment in more of a real-time fashion, which I just think is incredible for those of us who are making sure that we are doing and taking the right approaches for these patients. Dr. Shaalan Beg: One of the major transformative announcements that took place only a couple of months before the GI Cancer Symposium was the announcement of ChatGPT. And we heard a lot of discussion on how it can be used for improving cancer care, improving drug development, and in general, artificial intelligence and machine learning. We've been hearing these buzzwords for such a long time, to the point that a lot of people are probably just filtering it out and then this tool comes up and it makes it real. And we're seeing different people apply these technologies in different ways. But there is tremendous potential in how this technology can improve clinical trials, drug development, and early diagnosis. And luckily, we had already secured a keynote speaker, Dr. Matthew Lundgren from Nuance Communications, and he was invited to talk about artificial intelligence, machine learning, and how it applies to cancer care. I'm really curious to hear what your highlights were from his address and how you see this impacting your day-to-day, or just the ecosystem of which we're all part of. Dr. Rachna Shroff: Yeah, I will say that his keynote was really one of the highlights of the entire meeting for me. And that is coming from somebody who doesn't really know– I know who I'm speaking to, but somebody who does not truly understand the way AI is moving. And so, I was joking with him that it was like AI 101. And I really, really appreciated the way he was able to kind of speak to a crowd that he doesn't normally speak to and help us really understand the way in which artificial intelligence can be integrated into healthcare, and specifically oncology. To me, I think what were the most salient takeaways from his address was really about how this is just a rapidly evolving field and we need to be a little bit ahead of the eight ball when it comes to thinking how we can smartly leverage artificial intelligence like you mentioned, to improve our clinical research efforts, to improve access, and to improve fully integrating AI into our EMR, so that we can really leverage that technology and ensure that we are capturing every potential patient for a clinical trial and be smarter about how we're even approaching things. I mean, I loved him talking about the prior authorizations and that sort of thing, and the ways in which we can decrease the burden on health care providers and really let us focus on the areas that we need to focus on. The one thing that I thought was a really important point, though, and I think a number of people asked him, was about how using this technology has the potential to create more gaps and disparities and how can we be smart to ensure that we don't broaden those gaps. And I think that is a really important point that we all need to think about because we know that especially when we think through clinical trials, there's already underrepresentation of certain populations and certain geographic regions. And so, I think that was a really important takeaway for me is how can we make sure that we work and partner with those who are creating these technologies to ensure that we aren't taking two steps forward and four steps back. Dr. Shaalan Beg: It really calls into question how we define productivity and what our value in the entire delivery system really is. And I think from people who are in middle school or high school to people who are in college and even folks who are in the field as you and I are, it's forcing us to rethink what we bring to the table in a way that we've never been challenged to ask that question ever before. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: So, thank you very much, Dr. Shroff. This was wonderful. Thank you for sharing your insights with us today. And we thank you and Dr. George Chang, the chair of the ASCO GI Cancers Symposium, and everyone who worked so hard to develop a robust program this year.  Dr. Rachna Shroff: Thank you. It was so wonderful to be able to speak about it. And thank you to all of the attendees for making it such a memorable meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics        

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.09.522931v1?rss=1 Authors: Ngo, A. T., Sarkar, A., Yarovoi, I., Levine, N., Bochenek, V., Zhao, G., Rauova, L., Kowalska, M. A., Eckart, K., Mangalmurti, N., Rux, A., Cines, D. B., Poncz, M., Gollomp, K. Abstract: Neutrophil extracellular traps (NETs) are abundant in sepsis, and proposed NET-directed therapies in sepsis prevent their formation or accelerate degradation. Yet NETs are important for microbial entrapment, as NET digestion liberates pathogens and NET degradation products (NDPs) that deleteriously promote thrombosis and endothelial cell injury. We proposed an alternative strategy of NET-stabilization with the chemokine, platelet factor 4 (PF4, CXCL4), which we have shown enhances NET-mediated microbial entrapment. We now show that NET compaction by PF4 reduces their thrombogenicity. In vitro, we quantified plasma thrombin and fibrin generation by intact or degraded NETs and cell-free (cf) DNA fragments, and found that digested NETs and short DNA fragments were more thrombogenic than intact NETs and high molecular weight genomic DNA, respectively. PF4 reduced the thrombogenicity of digested NETs and DNA by interfering, in part, with contact pathway activation. In endothelial cell culture studies, short DNA fragments promoted von Willebrand factor release and tissue factor expression via a toll-like receptor 9-dependent mechanism. PF4 blocked these effects. Cxcl4-/- mice infused with cfDNA exhibited higher plasma thrombin anti-thrombin (TAT) levels compared to wild-type controls. Following challenge with bacterial lipopolysaccharide, Cxcl4-/- mice had similar elevations in plasma TAT and cfDNA, effects prevented by PF4 infusion. Thus, NET-stabilization by PF4 prevents the release of short fragments of cfDNA, limiting the activation of the contact coagulation pathway and reducing endothelial injury. These results support our hypothesis that NET-stabilization reduces pathologic sequelae in sepsis, an observation of potential clinical benefit. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Raja Dandamudi summarizes the results of his study "Longitudinal Evaluation of Donor-Derived Cellfree DNA in Pediatric Kidney Transplantation," on behalf of his colleagues.

Let's talk about cfDNA and how a new test is soon to be coming to a PCP office near you to screen healthy patients for all cancers in a single blood test.

"There's an entire field of fragmentomics with a whole lot of people working on it. The DNA which is shed into the bloodstream has a certain length. The length of ctDNA is shorter than cfDNA, and depending on where the cancer cell is located, the fragment size and pattern is different. So you can actually deduce information about the tissue of origin from the fragment length and pattern. And that's just the beginning."

In this episode we discuss the new Jada postpartum hemorrhage device. More importantly, we discuss the process for choosing to utilize new interventions in clinical practice. Then we discuss a recent New York Times article detailing the problem of false positives in the noninvasive prenatal screening tests. 

In this episode, we are honored to have Sheetal Parmar, who is here to chat about genetic counseling, something new to many of us and something other people may have heard about. Sheetal is a board-certified genetic counselor and the vice president of medical affairs at Natera. Natera is a global leader in cell-free (cfDNA) testing focusing on women's health, oncology, and organ health. Sheetal shares with us that genetic counseling is the process of helping people understand and adapt to the medical, psychological, and family implications of genetic diseases and their contribution of genetic disease to their families. Also, what a genetic counselor is and how their skills are used across any medical field. She tells us how genetic counselors work throughout Natera in patient and health care provider management. Sheetal also dives deep into how beneficial genetic testing can be to understand one's health. This episode is incredibly insightful regarding the many benefits of genetic testing and genetic counselors, tune in and enjoy! Click this link to the show notes, transcript, and resources: outcomesrocket.health

Welcome to Season 3 of the Personalized Medicine Podcast! We hope you all head a good start in 2022 and are ready to dive deep into the world of personalized medicine with us again.In this first episode of Season 3, we address a very important and, frankly speaking, underappreciated topic of sepsis, commonly known as bacterial blood poisoning. Did you know that last year, sepsis killed more people than 5 most common types of cancer combined? For this episode, our host Oleksandr Yagensky sat down with the co-founder and CEO of Noscendo, Dr. Philip Stevens. Philip and his team are developing diagnostic workflows based on detection of bacterial and fungal cell-free DNA from blood to detect infections.Listen to this episode to learn more about: ◦ The founding story of Noscendo ◦ Building a successful diagnostics startup in Europe ◦ Generation of clinical evidence for early stage startups ◦ Misconceptions about sepsis and sepsis diagnostics ◦ How NGS can help detect sepsis early ◦ Role of DNA sequencing in determining antibiotic resistance ◦ Philip's advice to aspiring life science entrepreneursGet in touch with Philip: ◦ LinkedIn: https://www.linkedin.com/in/philip-stevens-4ab68213b/ ◦ Twitter: https://twitter.com/noscendo ◦ Web: https://noscendo.com/Make sure to download the full show notes with our guest's bio, links to their most notable work, and our recommendations for further reads on the topic of the episode at pmedcast.com

In this episode, we are privileged to feature the amazing Dr. Paul Billings. Paul is the Chief Medical Officer and Senior Vice president of Medical Affairs for Natera. Natera is a global leader in cell-free (cfDNA) testing with a focus on women's health, oncology, and organ health. The company is an expert at the process and measurement of cell-free DNA and at providing that in context with genetic information as well. Dr. Billings educates us on cell-free (cfDNA) testing. He discusses how his company develops millions of testing opportunities in genetics that have given them incredible expertise in measuring very small amounts of cell-free DNA. He shares how Natera has developed a series of products to cast light on things like the health of a fetus, recurrence of cancer, and health of an organ transplant. Dr.l also shares his hypothesis on how a drug post organ transplant is working through constant monitoring of cfDNA. He talks about the three indications Natera is working on, providing clear explanations of how they add enormous value to genetics and healthcare, and specific examples of how Natera works. There are so many things to learn from this insightful and exciting conversation with Paul, so please tune in! Click this link to the show notes, transcript, and resources: outcomesrocket.health

Imagine a liquid biopsy test whose results would allow physicians to evaluate chemotherapy for every patient in real time. Richard Brand, CFO of DiaCarta, Inc., a translational genomics and personalized diagnostics company, discusses a recent data publication in "Nature Scientific Reports" that validates their cell-free DNA biomarker detection pre-treatment (chemotherapy) can predict how much treatment a patient needs. Their QuantiDNA™ cfDNA test, studied in this paper, is used to quantify the total amount of cfDNA directly from a plasma sample while the patient is undergoing cancer therapy. #DiaCarta #LiquidBiopsyTest Richard Brand is the Chief Financial Officer at DiaCarta Inc., a company delivering precision diagnostics. In his previous role, he helped raise $86 million as CFO for a private diagnostics company, Laboratory for Advanced Medicine, Inc. Over 2 years, helped generate 2x return and best performing biotech IPO for most of 2017 as CFO. Managed one-third of an institutional investment fund's portfolio, helping it grow to $1 billion from $400 million. Managed Robertson Stephens's biotech private placement business to number two ranking. Richard holds a MBA from the University of Chicago and is a former Board member for the University's and Booth School's NYC Alumni Clubs.

The Oncology Journal Club - Delivering Oncology News DifferentlyThe Oncology Podcast, brought to you by Oncology News Australia, is proud to present Episode 34 in our series The Oncology Journal Club.This week we have another great episode for you in our usual format. Craig Underhill gets us started by talking us through primary tumour resection plus chemotherapy versus chemotherapy alone for metastatic colorectal cancer patients.Hans Prenen gets stuck into the use of tipifarnib in head and neck squamous cell carcinoma with HRAS mutations and Eva Segelov continues to guide us through what she calls a ‘manifesto for good study design' – a key paper from our friend Bishal Gyawali, addressing biases in study design that distort the appraisal of clinical benefit.Just a quick note – Eva started her analysis of this paper in last week's episode so I recommend listening to Episode 33 if you've not already. Today's quick bites are as diverse as ever covering estimates for cancer incidence and death to 2040, plasma cfDNA genotyping, the CROSS trial, targeting metabolism to enhance immunotherapy and an excellent paper by our friend Heidi Probst on the patient experience of radiotherapy for breast cancer. If you're not familiar with Heidi check out Episode 32 ‘When the Oncologist gets cancer'.With the usual top quality banter, papers you won't hear of anywhere else and expert analysis from our Hosts, you are in for another great episode of The Oncology Journal Club!Full bios and the list of all papers discussed are available on our website.For the latest oncology news visit www.oncologynews.com.au and for regular oncology updates for healthcare professionals, subscribe for free to get the weekly The Oncology Newsletter.The Oncology Podcast - An Australian Oncology Perspective

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

Go online to PeerView.com/KXM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this case-based activity, experts in oncology and primary care examine how to best integrate future blood-based cancer screening tools into clinical practice in order to reduce cancer-related morbidity and mortality. Upon completion of this activity, participants should be better able to: Explain the scientific principles behind cfDNA-based liquid biopsy as a tool for early cancer screening, including the strengths and limitations of liquid biopsy compared with those of conventional screening methods, Identify the diagnostic/screening role of novel cfDNA-based screening assays for early cancer detection in the primary care setting, Adapt current cancer screening protocols based on recent evidence on emerging cfDNA-based multicancer screening assays in order to improve sensitivity, specificity, and tumor localization accuracy, Employ patient-centered strategies to integrate novel cancer screening methodologies in the primary care setting, including as part of educational and screening protocols.

FDA 批准降钙素基因相关肽单抗用于预防偏头痛和丛集性头痛的发作JAMA Neurology 妊娠与临床孤立综合征发病的关系J Am Coll Cardiol 复杂的颈动脉斑块是引起隐源性卒中的一个原因Nature子刊 颅内恶性肿瘤的无创检测Nature子刊 合成纳米颗粒治疗胶质母细胞瘤加那珠单抗（galcanezumab）降钙素基因相关肽（CGRP）受体位于疼痛信号通路、颅内动脉和肥大细胞中，其活化被认为在偏头痛的病理生理学中起着因果作用。加那珠单抗（galcanezumab）是一种CGRP单克隆抗体。和此前在《神经科星期四 Episode 4》中介绍的治疗急性偏头痛的CGRP受体拮抗剂包括：瑞美吉泮（rimegepant）和乌布吉泮（ubrogepant）；以及《神经科星期四 Episode 14》中介绍的预防偏头痛发作的依替尼单抗（eptinezumab）属于一类药物。2018年9月，FDA批准加那珠单抗用于预防偏头痛发作；2019年6月，FDA批准加那珠单抗用于预防丛集性头痛发作。《CONQUER研究：加那珠单抗预防偏头痛的安全性和有效性的3b期临床研究》Lancet Neurology，2020年10月 (1)这项多中心、随机、双盲、安慰剂对照的3b期研究，纳入2到4类偏头痛预防药物无效的患者655例，患者年龄在18-75岁之间，有发作性或慢性偏头痛，在50岁之前发生偏头痛，入组后随机接受安慰剂或加那珠单抗（120mg q1m * 3m）。在1-3个月期间，加那珠单抗治疗的患者偏头痛发作天数比安慰剂显著减少。与基线相比，加那珠单抗组每月平均少4·1天，而安慰剂组每月平均少1·0天（p < 0·0001）。加那珠单抗和安慰剂之间治疗紧急不良事件的类型和数量相似。结论：加那珠单抗在偏头痛的预防治疗方面优于安慰剂，并且在以前的多个标准预防治疗失败的患者中有良好的耐受性。 《加那珠单抗预防发作性丛集性头痛的临床研究》New England Journal of Medicine，2019年7月(2)阵发性丛集性头痛是一种神经功能障碍，其特征是每天头痛发作，持续数周或数月。共招募患者106人，随机分配接受加那珠单抗（300mg）或安慰剂组。基线期每周丛集性头痛的平均发作次数，加那珠单抗组为17.8，安慰剂组为17.3。在第1至3周中，加那珠单抗组每周平均减少为8.7次，而安慰剂组为5.2次（P =0.04）。在第3周，头痛频率降低≥50%的患者，加那珠单抗组为71%，安慰剂组为53%。除了加那珠单抗组8%的患者有注射部位疼痛外，不良事件发生率在组间没有实质性差异。结论：与安慰剂相比，在首次注射后的1-3周内，加那珠单抗300mg ip降低了偶发性丛集性头痛的发作频率。多发性硬化多发性硬化（multiple sclerosis，MS）是以中枢神经系统白质炎性脱髓鞘病变为主要特点的自身免疫病。本病最常累及的部位为脑室周围白质、视神经、脊髓、脑干和小脑，主要临床特点为中枢神经系统白质散在分布的多病灶与病程中呈现的缓解复发，症状和体征的空间多发性和病程的时间多发性。 多发性硬化症主要的模式和病程可以分为以下几种临床亚型：临床孤立综合征（CIS）、复发缓解型（RR）、继发进展型（SP）、和原发进展型（PP）。 《前瞻性队列研究：妊娠与临床孤立综合征发病的关系》JAMA Neurology，2020年12月 (3)多发性硬化症常诊断于育龄妇女，但妊娠是否能延迟脱髓鞘或临床孤立综合征（CIS）的首次发作尚无共识。研究的目的是探讨妊娠与CIS发病时间的关系。这个国际、多中心、前瞻性研究纳入2557名女性，CIS发病的平均年龄为31岁，发病前46%至少有1次怀孕，43%至少有1次分娩。首次怀孕的平均年龄为23.3岁，首次分娩的平均年龄为23.8岁。与从未怀孕过的女性相比，有过怀孕和分娩经历的女性发生CIS的时间较晚，延迟3.3年（P < 0.001）。与从未分娩过的女性相比，分娩过的女性发病年龄也较晚，延迟3.4年（P < 0.001）。孕产次数与发病延迟无关。结论：发病前怀孕和分娩与CIS发病时间之间存在关联，但与次数无关。需要进一步的研究来帮助解释怀孕和多发性硬化症发病之间关联的机制。《前瞻性观察性队列研究：持续免疫治疗与活动性继发进展性多发性硬化症患者残疾结果的相关性》JAMA Neurology，2020年11月 (4)研究旨在评价继发进展性多发性硬化的患者中残疾累计发生率，及是否能够通过治疗延缓残疾累积的进展。这项观察性队列研究中， 招募53680例多发性硬化的患者，其中4997例继发进展型，在1621例符合纳入条件的患者中，女性患者68.0%，发病时的平均年龄为33.9岁。共有661例（40.8%）患者在继发进展性多发性硬化期间经历了叠加性复发。早期治疗方案和残疾累计发生无关。继发进展期的高复发率与轮椅依赖的残疾风险增加有关（P = 0.009）。在继发进展性多发性硬化期间经历反复复发的患者中，抑制疾病进展的治疗与残疾进展率的降低和轮椅依赖风险的降低显著相关。结论： 继发进展型多发性硬化症患者中，残疾进展率与早期病程和治疗方案无关，但是与疾病复发相关。多发性硬化的治疗多发性硬化治疗的主要目的是抑制炎性脱髓鞘病变进展，防止急性期病变恶化及缓解期复发，晚期采取对症和支持疗法，减轻神经功能障碍带来的痛苦。疾病修正治疗（disease-modifying therapy，DMT）主要包括：抗整合素α-4单抗（那他珠单抗 natalizumab），抗CD20单抗（奥瑞珠单抗 ocrelizumab、奥法木单抗 ofatumumab、利妥昔单抗 rituximab），抗CD52单抗（阿伦单抗 alemtuzumab）、干扰素（干扰素β-1a、干扰素β1-b）、富马酸类（富马酸二甲酯 dimethyl fumarate、富马酸单甲酯 monomethyl fumarate）、鞘氨醇调节剂（芬戈莫德 fingolimod、西尼莫德 siponimod、奥扎莫德 ozanimod）、免疫抑制剂（克拉屈滨 cladribine），还可使用其他免疫抑制剂如特立氟胺（teriflunomide）、硫唑嘌呤、环磷酰胺、米托蒽醌等。《OPERA I和OPERA II研究：复发相关的恶化与复发无关的进展对典型复发性多发性硬化症总体确认残疾积累的贡献》JAMA Neurology，2020年9月 (5)奥瑞珠单抗（ocrelizumab）是一种靶向CD20+B细胞的单克隆抗体，于2017年被批准用于多发性硬化的治疗。研究旨在评价复发相关的恶化（relapse-associated worsening，RAW）和复发无关的进展（progression independent of relapse，PIRA）对证实的残疾累积（confirmed disability accumulation，CDA）的影响，并评估两种治疗方法对预后的影响。这2个相同的、3期、多中心、双盲随机临床试验中，1656人纳入分析，两组平均年龄37.2-37.1岁，随机奥瑞珠单抗组（奥瑞珠单抗 600mg ivgtt q24w）或干扰素组（干扰素 ip q3w）共96周。12周后，干扰素组和奥瑞珠单抗组的残疾累积事件发生率分别为29.6%和21.1%；24周发生率分别为22.7%和16.2%。复发无关的进展事件是12周和24周复合残疾累积事件的主要影响因素，分别占干扰素组的78.0%和80.6%，占奥瑞珠单抗组的88.0%和89.1%。结论：大部分的残疾积累事件与明显的疾病复发无关，这挑战了目前多发性硬化复发和进展形式的临床区别。《ORATORIO研究的事后分析：奥瑞珠单抗治疗原发性进行性多发性硬化症的长期随访》Lancet Neurology，2020年12月 (6)ORATORIO研究是一项国际、多中心、双盲、随机对照的3期试验，招募年龄18-55岁的、原发性进行性多发性硬化症患者，随机分配奥瑞珠单抗（600mg ivgtt q24w）或安慰剂，至少120周，之后可以选择进入开放标签阶段。共451人进入完成6.5年的随访。在早期使用奥瑞珠单抗的患者，残疾进展比例较低（51.7% vs 64.8%，P=0.0018），复合进展率较低（73.2% vs 83.3%；p = 0.0023）；需要轮椅的比例较低（11.5% vs 18.9%；p = 0.0274）。在研究结束时，奥瑞珠单抗组患者T2病变体积更小（0.45% vs 13.00%， p

FDA 批准靶向PDL1抑制剂成为尿路上皮癌的一线治疗Clin J Am Soc Nephr 老年捐赠者单肾和双肾移植的应用和结果LANCET 供氧冷灌注与标准冷灌注保存肾脏的临床研究Am J Kidney Dis ABO血型不匹配的活体肾移植对患者生存的影响Nature子刊 使用血浆和尿液无细胞DNA甲基化模式识别肾细胞癌阿维鲁单抗（avelumab）2020年7月，FDA批准PD-L1抑制剂阿维鲁单抗（avelumab）用于局部晚期或转移性尿路上皮癌患者的一线维持治疗。《JAVELIN Bladder 100研究：阿维鲁单抗用于晚期或转移性尿路上皮细胞癌的维持治疗》New England Journal of Medicine，2020年9月 (1)这项3期试验的目的是阿维鲁单抗用于化疗后尿路上皮癌患者的维持治疗的疗效。研究纳入局部晚期或转移性尿路上皮细胞癌，并且一线化疗（吉西他滨+顺铂或卡铂治疗4~6个周期）后未出现疾病进展的患者共700人，随机分入支持治疗组、或阿维鲁单抗维持治疗组。阿维鲁单抗维持性治疗显著延长了总生存期和无进展生存期。阿维鲁单抗与对照组相比，1年总生存率分别为71.3%和58.4%（中位总生存期，21.4个月vs. 14.3个月；风险比，0.69；P=0.001）；在PD-L1阳性人群中，阿维鲁单抗组和对照组相比，1年总生存率分别为79.1%和60.4%（风险比，0.56；P

FDA 批准靶向PDL1抑制剂成为尿路上皮癌的一线治疗Clin J Am Soc Nephr 老年捐赠者单肾和双肾移植的应用和结果LANCET 供氧冷灌注与标准冷灌注保存肾脏的临床研究Am J Kidney Dis ABO血型不匹配的活体肾移植对患者生存的影响Nature子刊 使用血浆和尿液无细胞DNA甲基化模式识别肾细胞癌阿维鲁单抗（avelumab）2020年7月，FDA批准PD-L1抑制剂阿维鲁单抗（avelumab）用于局部晚期或转移性尿路上皮癌患者的一线维持治疗。《JAVELIN Bladder 100研究：阿维鲁单抗用于晚期或转移性尿路上皮细胞癌的维持治疗》New England Journal of Medicine，2020年9月 (1)这项3期试验的目的是阿维鲁单抗用于化疗后尿路上皮癌患者的维持治疗的疗效。研究纳入局部晚期或转移性尿路上皮细胞癌，并且一线化疗（吉西他滨+顺铂或卡铂治疗4~6个周期）后未出现疾病进展的患者共700人，随机分入支持治疗组、或阿维鲁单抗维持治疗组。阿维鲁单抗维持性治疗显著延长了总生存期和无进展生存期。阿维鲁单抗与对照组相比，1年总生存率分别为71.3%和58.4%（中位总生存期，21.4个月vs. 14.3个月；风险比，0.69；P=0.001）；在PD-L1阳性人群中，阿维鲁单抗组和对照组相比，1年总生存率分别为79.1%和60.4%（风险比，0.56；P

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.255885v1?rss=1 Authors: Zheng, H., Zhu, M. S., Liu, Y. Abstract: Circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation pat-terns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns. Availability and implementation: FinaleDB service: http://finaledb.research.cchmc.org/. FinaleDB source code: https://github.com/epifluidlab/finaledb_portal and https://github.com/epifluidlab/finaledb_workflow. Copy rights belong to original authors. Visit the link for more info

A liquid biopsy is a minimally invasive alternative to a more traditional surgical solid tumor biopsy. In this episode, Dr. Stephanie Hastings, genomics product lead at Q Squared Solutions, lays out the considerations for liquid biopsy collection and the type of information that can be gathered from circulating free DNA (cfDNA). The main approaches comprise for evaluating cfDNA are: specific mutation detection to help support targeted therapies broader sequencing technologies to enable biomarker evaluations custom sequencing panels to support clinical trial assay development She describes the typical panels for each of the approaches, the sample collection requirements and how these analyses are implemented on a global scale.

In episode 9 we dive deep into the topic that could not be more relevant today - diagnosis of infectious diseases. Our guest on this episode is Tim Blauwkamp, the co-founder and Chief Scientific Officer of Karius, a company that leverages genomics and AI to develop highly-accurate diagnostic tests based on cell-free DNA sequencing. Karius has recently raised a stunning Series B round of $165 million to further the transition of their test to clinic.Tim did his PhD in Biochemistry at the University of Michigan, where he studied genes involved in nitrogen assimilation in bacteria. He then continued as a PostDoc first in Michigan and then at Stanford researching the mechanisms behind WNT signaling and its role in cell differentiation. He then joined Moleculo as a Head of Molecular biology. Moleculo was acquired by Illumina and Tim was responsible for bringing to life the technologies that made it possible to generate long and accurate sequencing reads. About six years ago, Tim co-founded Karius together with Mickey Kertesz. Tim and his team have achieved enormous progress during the last years, bringing the diagnostic tests to clinics that are already changing the lives of patients. Together with Tim, we have talked about:: ◦ The story behind Karius ◦ Cell-free DNA (cfDNA) as a blood biomarker of infection ◦ Why DNA sequencing has an edge over classical microbiology methods ◦ The challenge of isolating microbial cfDNA from blood ◦ Untangling cfDNA sequencing data with AI ◦ Why Coronavirus (SARS-CoV-2) is hard to detect using NGS ◦ Diagnosing sepsis based on microbial cfDNA ◦ Clinical evidence as a key to healthcare innovation ◦ Working with payers to spread the use of innovative diagnostic tests ◦ How cfDNA screening can become a cornerstone of next-generation medicineGet in touch with Tim: ◦ LinkedIn: Tim Blauwkamp ◦ Twitter: @timblauwkamp ◦ Web (Karius): http://kariusdx.com/ ◦ Email: tim.blauwkamp@kariusdx.comMake sure to download the full show notes with our guest's bio, links to their most notable work and our recommendations for further reads on the topic of the episode at pmedcast.com

Dr. Sumanta K. Pal comenta o estudo apresentado por ele na ESMO 2019 que sugere que o cfDNA é uma opção de triagem secundária para estudos que avaliam terapias direcionadas ao FGFR3, como infigratinibe, em pacientes com câncer de bexiga metastático.

In 2011, cf DNA from the maternal serum became commercially available to screen for fetal aneuploidy. Overall, about 3% of test results will detect an aneuploidy, and false positive results are only seen in 0.05% to 0.1% of tests. Evolving data, however, suggest that in women who have more than one aneuploidy suspected by cfDNA testing but who are found by diagnostic testing to carry a genetically normal fetus may harbor a higher risk of occult maternal malignancy. In this session, we will review published data on the risk of maternal malignancy in women who have discordant cfDNA test results.

You have several options during your pregnancy when it comes to testing for chromosome abnormalities in your baby. The most common non-invasive screening tests are the first trimester screen and quad screen and these have been offered to all pregnant women for many years. With better technology comes more options for testing, especially when it comes to examining DNA. The cfDNA (cell free DNA) test, which became available in 2011, is named for the fragments of your baby’s DNA that are freely floating in your blood stream. This simple blood test from you can test for many more chromosome abnormalities than the traditional screen tests, plus the sex of your baby and their Rh factor. This episode breaks down everything you need to know about the cfDNA or NIPT test compared to other options so you can decide whether to opt in to this test and how to understand the results.   Show Notes: http://pregnancypodcast.com/nipt/   Thank you to Zahler for their support of this episode. Zahler makes a high quality prenatal vitamin that has the active form of folate, that I prefer after all of the research I have read on folic acid, plus it has omega 3s and DHA. This is the prenatal vitamin I take and the one I recommend. Zahler is offering an exclusive discount to listeners of the Pregnancy Podcast. To check out the vitamin and find out how you can save 25% when you buy a one month supply on Amazon go to http://pregnancypodcast.com/vitamin/

Prof. Massimo Cristofanilli shares his perspective on the future of liquid biopsy, the complementary purposes of CTC and cfDNA technologies, and when one should expect clinical utility of liquid biopsies. For more information, please visit http://www.NextGenerationDx.com/Circulating-Tumor-Cells/

Dr. Jorg Tost recently spoke to CHI to discuss his work with the ice-COLD-PCR assay and how it is addressing current challenges in cfDNA analysis. He also discusses challenges related to data, new technologies, and including other biomarkers in addition to cfDNA for the most complete and accurate analysis. Dr. Tost is speaking at the Enabling Technologies for Cell-Free DNA Analysis conference, part of Molecular Diagnostics Europe, taking place 22-24 May 2018 in Lisbon, Portugal. For more information, please visit http://www.MolecularDXEurope.com/Cell-Free-DNA-Technology/

Dr Salomon Manier speaks with ecancer at the 16th International Myeloma Workshop about cell-free DNA (cfDNA) and circulating tumour cells (CTCs) sequencing that enable serial temporal sampling. The team looked at whole-exome sequencing (WES) and ultra low pass-whole genome sequencing (ULP-WGS) of cfDNA and CTCs in multiple myeloma. The study demonstrated that WES and ULP-WGS of cfDNA and CTCs are consistently representative of tumour DNA alterations in terms of CNAs and SNVs. This approach could therefore be used to longitudinally follow clonal evolution and minimal residual disease in MM, personalising and improving treatment. It also reduces the need for bone marrow biopsy, greatly improving the patient experience.

Recently, there has been a push to develop alternative methods to traditional invasive techniques, such as solid tissue biopsies, for disease diagnosis and disease progression, as well as therapeutic response. Liquid biopsy is a new, minimally invasive technology for detecting circulating biomarkers without the need for costly or invasive procedures. Liquid biopsy enables users to sensitively, specifically and rapidly analyze circulating free nucleic acids (cfDNA), circulating tumor cells (CTCs) or exosomes from a blood sample. For more information please visit: http://bitesizebio.com/webinar/25528/liquid-biopsy-sample-handling/

Drs. Ben Solomon, Leora Horn, & Jack West assess the utility and limitations of "liquid biopsies", serum-based testing for molecular marker testing in lung cancer.

Drs. Ben Solomon, Leora Horn, & Jack West assess the utility and limitations of "liquid biopsies", serum-based testing for molecular marker testing in lung cancer.

Drs. Ben Solomon, Leora Horn, & Jack West assess the utility and limitations of "liquid biopsies", serum-based testing for molecular marker testing in lung cancer.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.