Podcasts about Checkmate

On today's episode, I'm going back to 2020 with a conversation with Curt (Libertarian) from Checkmate the State to discuss his awesome article over on Substack, "How Libertarians can Take on the Duopoly and Win". Curt's article breaks down why libertarians need to take advantage of the current political climate and how they can do it. He also talks about how important it is for libertarians to get involved in the political process, even if they don't want to vote or run for office themselves. I really enjoyed this conversation and I think you will too! OH!! By the way... are you a candidate or thinking of tossing your hat in the ring this coming 2023 election cycle?   Whether it's local, state, or national office, my new Candidate School 101 course will give you weekly strategy sessions, roundtable discussions with other candidates, plus extra resources to help you CRUSH your election!   Try your EXCLUSIVE risk-free trial and get a complimentary "Campaign Messaging Scorecard" of your current campaign messaging with actionable recommendations on how to improve it. Learn more about your ad choices. Visit megaphone.fm/adchoices

When a cop on the verge of shutting down a major drug operation is abducted, Hondo and the squad race to save one of their own before it's too late. Also, Luca grows concerned about sudden changes in Hicks' behavior.

It appears that more srypto firms are failing after the FTX bust. It could affect a LOT of finance. The Globalists announced the rollout of "Operation Checkmate" - a genius plan to destroy the GOP and let the authoritarians Dems and Establishment rule for the next 25-50 years! And Humpday Health! Are diet products CAUSING obesity and diabetes? Yes.

Today we talk about Vic Sage, best known as The Question, a guy who covers his face with fake skin who has followed wildly differing philosophies over his iterations, but over all of them he does a lot of violence. Today's mentioned & relevant media: -Watchmen (1986) -Blue Beetle (1986) #5-7 -The Question (1986) -L.A.W. Living Assault Weapons (1999) -Batman/Huntress: Cry for Blood (2000) -The Question (2005) -52 (2006) -Blackest Night: Rise of the Black Lanterns (2010) -Justice League: Trinity War (2013) -New Suicide Squad (2014) -Convergence: The Question (2015) -The Question: Deaths of Vic Sage (2019) -Lois Lane (2019) #3-4 -Event Leviathan (2019) -Checkmate (2021) -Constantine: Distorted Illusions -The Death of Superman 30th Anniversary Special (2022) #1 -Superman: Son of Kal-El (2021) #17 textless cover -Fantastic Four (2022) #1 -Adversary by Blue Delliquanti Print, Digital -How to Break a Curse by Mapurl Kumoricon (currently unavailable) Thanks to Victoria Watkins for our icon! Support Capes and Japes by: Checking out our Patreon or donating to the Tip jar Find out more on the Capes and Japes website.

Filtered Filtered FilteredBOAbucksKevin Bacon Tremors2020 Christmas Run The Six of Wands brings no justice for the little white marbles. Vivaldi plays, and simple abominations play chess. Callers ask for the King on King. During the break, we play abstract music. Sick of Crypto? Bitcoin? Exchanges? The Bankman's got you covered, him and his sultry wood nymph will bring it all down. Checkmate. ‘Til It's Not BYO3-DG ZOSO'S CORNER (Show Notes) If you like what you heard here, check out our revue show! ms. informed NAtion Follow us on Social Sesame at FeedBag (Facebook), Insta-Groan (Instagram) and The Twits (Twitter)! @behindthesch3m3s https://www.behindthesch3m3s.com/

Grace considers all of your theories about Trump's recent digs at former political allies, but she's formed her own opinion that she shares with listeners. Then, Grace breaks the devastating news that Biden's student debt "forgiveness" plan has been struck down in court. That'll mess with a lot of people's travel and dining plans!

We review the 5-year update of CheckMate 227 and the POSEIDON to generate the hypothesis that CLTA-4 inhibition has a role in PD-L1 negative metastatic NSCLC. CM 227 update: https://pubmed.ncbi.nlm.nih.gov/?term=36223558 POSEIDON: https://pubmed.ncbi.nlm.nih.gov/?term=36327426 Editorial: https://pubmed.ncbi.nlm.nih.gov/?term=36331243

Checkmate is WILD, Bob Dylan, Black Panther, Time Machine, The Creeper - get ready for a WILD ONE! Weekly Comics Deadpool #1 Batman Special #1 Moon knight Annual 1 TRADE OF THE WEEK Checkmate #1-10 Please support the show on Patreon! Every single dollar helps the show! https://www.patreon.com/SignalofDoom Follow us on Twitter: @signalofdoom Dredd or Dead: @OrDredd Legion Outpost: @legionoutpost

As 1945 began the greatest conflict in human history was drawing to a close. But with the war in the west almost over, a new question was increasingly being asked. It was one to which Joseph Stalin, Winston Churchill and Franklin D Roosevelt all had different answers. What was going to happen next? In this episode the million-copy bestselling author Giles Milton takes us back to some key moments in 1945. At Yalta on the Crimean peninsula and later in the ruins of Berlin, the shape of the post war world – the world we know today – was beginning to take shape. What is clear now was not so then. Were the Allies really friends or were, as Anthony Eden worried, they hurtling towards a third world war? Arriving in Berlin at the start of July 1945, the US army colonel Frank Howley feared much the same. As Milton explains, it was Howley who saw before almost anyone else that the Germans had ceased to be enemies and the Russians had ceased to be friends. The characters and stories that feature in this episode of Travels Through Time form part of Milton's latest book. Checkmate in Berlin: The Cold War Showdown That Shaped the Modern World. Show notes Scene One: 4 February 1945. Yalta. Opening of the Crimea Conference Scene Two: 2 May 1945. Berlin. Yevgeny Khaldei takes a photograph of the Soviet flag being raised over the Reichstag Scene Three: 1 July 1945. Berlin. Colonel Howley arrives Memento: A little of the Schliemann Gold People/Social Presenter: Peter Moore Guest: Giles Milton Production: Maria Nolan Podcast partner: Ace Cultural Tours Theme music: ‘Love Token' from the album ‘This Is Us' By Slava and Leonard Grigoryan Follow us on Twitter: @tttpodcast_ Or on Facebook See where 1945 fits on our Timeline

Dr. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors.   TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these noble new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan's really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury's still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid's lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you'd still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great having us. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. 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. Follow today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer.    Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen 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. Benjamin Neel: None disclosed Dr. John Heymach: None disclosed    

In this podcast we examine a recent argument for the view that chess is not, in fact, a game. We discuss the Grasshopper's claim that all games must have a prelusory goal, as well as Skepticus' objection to the giant Grasshopper concerning chess. We then turn to a broader analysis of the Suitsian account of games. Does the existence of illusory checkmates offer Grasshopper an avenue for replying to Skepticus? Should we bite the bullet and agree that chess is not a game? What is a lusory attitude? Is Tamler losing his mind? Why is David so giddy? Plus – how should Arthur C. Clarke's novel "2001: A Space Odyssey" affect our understanding of Kubrick's movie? And a little more on Kanye.

Are you ready for Shofar-Blowing, Jesus praising, Power-Packed Wednesday Morning session with Stacy Whited?! If not, then get your mind right because we are LIVE at 11:11AM CST.Videos and Resources Referenced in the Show -FOR ALL WRITTEN PROPHETIC WORDS: https://flyoverconservatives.com/resources-2/prophetic-words/ Amanda Grace Given on 10.6.22 and Released 10.10.22 “A Powerful and Timely Word From the Lord”15:52-24:3325:01-28:2828:38-31:28https://youtu.be/3RTkFJrO2nE Hank Kunneman 9.16.22 Open the Heavens Conference https://youtu.be/Y_ruIVBqraM Julie Green Given 10.3.22 Released 10.11.22“Soon You Will See a Checkmate”2:17-13:49https://rumble.com/v1nh6hs-soon-you-will-see-a-checkmate.html  Robin Bullock 11th Hour 10.11.2233:56-40:39 https://youtu.be/Lxy-SE7RYy0 See a Victoryhttps://youtu.be/YNd-PbVhnvA  Notes: See a Victory by Elevation WorshipPsalms 35Psalms 91TO WATCH ALL OF THE PROPHETIC REPORTS -https://banned.video/playlist/61e604428362a67d2b03e4b7SPONSORS FOR TODAY'S VIDEO►  ReAwaken America- text the word EVENTS to 40509(Message and data rates may apply. Terms/privacy: 40509-info.com)►  Kirk Elliott PHD - http://FlyoverGold.com ►  My Pillow - https://MyPillow.com/Flyover►Z-Stack - https://flyoverhealth.com Own Your Own Business As An Option To Avoid The Jab- https://TipTopK9.com/Want to help spread the Wake Up • Speak Up • Show Up -https://shop.flyoverconservatives.com/Support the show► ReAwaken America- text the word FLYOVER to 918-851-0102 (Message and data rates may apply. Terms/privacy: 40509-info.com) ► Kirk Elliott PHD - http://FlyoverGold.com ► My Pillow - https://MyPillow.com/Flyover ► ALL LINKS: https://sociatap.com/FlyoverConservatives

We strongly recommend you listen to our previous episodes metastatic lung cancer (Episodes 0032 and 0033) to better be able to follow along with this conversation. Key trials mentioned in this episode include:CHECKMATE 227KEYNOTE 024Q:Do you send molecular testing (PDL1 and NGS) on the biopsy, peripheral blood or both?* Yield is highest from the tissue sample* Peripheral blood (circulating DNA) samples are dependent on the burden of disease and so often the yield is lower ** One of the benefits is that it can be sent quickly and having a fast turn-around; Tissue samples are dependent on being able to schedule a biopsy* Dr. West says he definitely sends this on a non-smoker with non-squamous lung cancer, as they are more likely to have molecular targets* Dr. West has not personally adopted the idea of sending peripheral and tissue samples for NGS testing for everyoneQ: Do you ever use Ipi/Nivo in patients with PDL1

This episode features our favorite toe-headed kid, his best friend, and a guy made of fire, invading a toy store owned by a guy with a bow tie and featuring an alien who pops. In honor of that, I would like to review some of the excellent offerings in this years Amazon Holiday Kids Gift Book: Share the Adventure. I was surprised to get a toy catalog in the mail this year. It moved me back to my childhood at the same time as shocking me to see something so analog in the digital age. But my cynical nature took a back seat when I turned to page 49 and I saw a transforming Lego version of Optimus Prime. I mean, c'mon folks. This book is the dreams of my childhood today! Actually, if we want to move a page prior to the last one, we have even more Lego sets. One flavor for every child. You have sets that cover fantasy, history, magic...and popular franchises that ask us to buy everything associated with it. But I digress into negativity as I review this trove of treasures. Let us turn to page 42. Since that is the answer to Life, the Universe, and Everything, I would expect to find some truly inspiring toys, and I was not mistaken. Batman takes this page, and a bit of the next with He-Man and other. What we are given is a treat of awesome action. Not only can you fulfill your desire to explore a Bat-Cave, but you can also carry a Lego Havoc staff that stands 40.5 inches tall. One moment, I need to add something to my wish list. Sometimes you have to think about more than just the kids in the world, sometimes we need to think about the adults, especially the really cranky ones, like Maestro. In those cases, I would suggest page 51. There is an amazing selection of plushys from teeturtle. I mean, who would say no to and Octopus plushy. And there is also the Care Bears....THE CARE BEARS. Caring is in their name! Everyone loves to play a game. And this catalog has some ideas for you. On page 65, they dare to ask the question, what Monopoly variations have we not done? My question back to Hasbro, where is my Power Pack Monopoly game? Checkmate! No Love for the Human Torch in this book, it is all about the wall-crawler on page 37. Spidey and his Amazing friends (not featuring Iceman or Firestar, cowards!) have an entire page to entice the kids. you have these cute little characters and vehicles, and of course more Lego. There is always room for more Lego. There is so much more in this book that we can talk about, but I really do not have time. I kinda chose this as a framing device because I thought it would make writing this page go faster, but instead I am looking up pages that I find interesting and not getting this podcast out. Besides, you stopped reading a while ago. We need to just sit back and thank Amazon for giving us a catalog. As children, we used these as a gateway to imagine all of the wonderful things we wanted, and then to have the crushing weight of reality destroy us as we opened presents. We should pass on that tradition to our children.   If you want to see some images, check out our webpage for this episode at: https://jeffandrickpresent.wordpress.com/2022/10/23/fantastic-four-580-the-frank-tastic-four/ You can also subscribe and listen to us on YouTube!  We also have some merchandise over at Redbubble. We have a couple of nifty shirts for sale. https://www.redbubble.com/people/jeffrickpresent/?asc=u Our show supports the Hero Initiative, Helping Comic Creators in Need.  http://www.heroinitiative.org/ Eighties Action by Kevin MacLeod Link: https://incompetech.filmmusic.io/song/3703-eighties-action License: http://creativecommons.org/licenses/by/4.0/ Tides Of Iron by Alexander Nakarada Free download: https://filmmusic.io/song/8382-tides-of-iron License (CC BY 4.0): https://filmmusic.io/standard-license Artist website: https://www.serpentsoundstudios.com/

How God 'flipped the script' on Haman; learning that God will give victory no matter what it takes; a summary of Esther chapters 5-7. CLICK HERE to ORDER this full message on MP3! To support this ministry financially, visit: https://www.oneplace.com/donate/1213/29

How God 'flipped the script' on Haman; learning that God will give victory no matter what it takes; a summary of Esther chapters 5-7. CLICK HERE to ORDER this full message on MP3! To support this ministry financially, visit: https://www.oneplace.com/donate/1213/29

How God 'flipped the script' on Haman; learning that God will give victory no matter what it takes; a summary of Esther chapters 5-7. CLICK HERE to ORDER this full message on MP3! To support this ministry financially, visit: https://www.oneplace.com/donate/1213/29

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we begin to round out our NSCLC series with the first of two episodes where we interview Dr. Jack West from City of Hope!We strongly recommend you listen to our previous episodes on early stage lung cancer (Episodes 026 and 029) to follow along in this discussion. Key trials mentioned in this episode include:ADAURA Trial IMPOWER010CHECKMATE816Q: We've previously discussed that adjuvant cisplatin doublet chemotherapy is used for tumors > 4cm and/or nodal involvement. Given that PD-L1 status and EGFR status can also potentially change adjuvant therapy choices, how do you employ these tests in your practice?* Different approaches at every center/with different thoracic oncologists. * Dr. West does NOT recommend sending broad NGS testing on everyone if it is not going to change management. * It it may influence management, at the very least, PDL1 and EGFR should be performed because of implications on adjuvant treatment options (See Episode 026 for treatment discussions): ** ADAURA Trial: Adjuvant Osimertinib x3 years for EGFR+ patients** IMPOWER010: In patients with PDL1 >50%, patients did better with 1 year of immunotherapy (atezolizumab) after adjuvant therapy* In patients with higher risk disease, can consider sending broad NGS, particularly looking for ALK and other mutations; remember that EGFR and ALK+ patients do NOT respond to immunotherapy well. This is important because we don't want to give someone side effects that they would not otherwise had (these patients are getting treatment adjuvantly AKA after their disease is already resected!)Q: What are limitations of the ADUARA Trial? * The ADUARA suggested disease-free survival advantage with use of osimertinib, but we don't know final overall survival data yet.*Limitations:** Three years of therapy** Very expensive drug** More data presented at ESMO 2022 on efficacy; Dr. West stated that there appears to be drop off in survival after stopping drug. Overall survival data not yet available * Just because patients can get osimertinib does NOT mean that they are not eligible for chemotherapy**Adjuvant chemotherapy for patients provides long-term benefit** JBR.10 Trial: Older trial, but showed that patients who got adjuvant treatment (in this case vinorelbine plus cisplatin) had prolonged disease-free and overall survival in early-stage non–small-cell lung cancer.** Follow up study suggested that EGFR+ patients trended towards longer survival Q: What are your thoughts on Checkmate 816 with the use of neoadjuvant nivolumab in addition to the platinum doublet? Do you think pathologic CR was an appropriate surrogate endpoint for the trial?* Complete path CR is a new end-point, but it does correlate with PFS. We cannot always for traditional endpoints, such as overall survival data, to mature because doing so may result in us withholding therapy that may be very beneficial. * Biggest benefit to neoadjuvant treatment is that more patients are able to get the full regimen. Many have complications after surgery and never are able to then get/benefit from chemotherapy. Supported by data from NATCH trial Q: What are your thoughts on induction chemoradiation vs. chemotherapy alone?* Dr. West prefers to not use radiation pre-operatively, with some exception (for instance, pancoast tumor) Tune in next week for part 2 of this discussion!About our guest:Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women's Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD References:https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext - IMPOWER 010 Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2027071- ADAURA Trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032958/ - NATCH Trial https://www.nejm.org/doi/pdf/10.1056/NEJMoa043623 - JBR.10 Trialhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033998/ - Follow up to JBR.10 Trial looking at influence of EGFR status on chemotherapy responsehttps://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s - Episode 026https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s-6xae9-ws6nt-ntn8g - Episode 029Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

How God 'flipped the script' on Haman; learning that God will give victory no matter what it takes; a summary of Esther chapters 5-7. CLICK HERE to ORDER this full message on MP3! To support this ministry financially, visit: https://www.oneplace.com/donate/1213/29

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. Brittany Harvey: First. 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 full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation? Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts. So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course. Brittany Harvey: Great. Thank you for providing that information. So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases? Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery. Brittany Harvey: Thank you, Dr. Eng for going over those recommendations. So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended? Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation. So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations. But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion. Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90. While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians. Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration. And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases? Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process. Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline. So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice? Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients. And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer. Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline. And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer? Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better. Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng. Dr. Van Morris: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes 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.  

Crabb and Sales are in beautiful Albany, having completed a white-knuckle drive from Perth along with Gwen Blake, a cello and three kg of fresh cheese. Basketball legend and Nicest Man In The World Luc Longley makes Sales' life by turning up.   (0.30) Boom! Shake the Room by DJ Jazzy Jeff and The Fresh Prince | Spotify (7.10) Albany Community Hospice | Website (8.35) Emu Point Cafe | Website (9.51) Williams Woolshed | Website (10.15) Mount Barker Bakery | Website  (14.00) Albany Entertainment Centre | Website (14.16) Australian Story, Luc Longley: One Giant Leap | ABC iview (19.20) Vannella Cheese Marrickville | Website (19.24) Two Providores Marrickville | Website (21.00) The Last Dance | Netflix | Trailer (22.30) Best of Larry Bird | Youtube (22.37) When The Game Was Ours by Earvin Johnson, Larry Bird, Jackie MacMullan | Booktopia (35.15) Luc Longley Speaking tour | Tickets  (38.40) The Hitler Diaries by Charles Hamilton | Booktopia (38.40) The Hoax by Clifford Irving | Booktopia (39.15) The Phantom of the Open | Trailer | Youtube (45.00) Checkmate by Leigh Sales | The Monthly (46.16) “Trap. Dominate. Fuck.” by Julian Barnes | Granta (50.00) Killing Eve Season 3 | Trailer | Stan (50.45) Prima Facie | Dendy Theatre  (55.57) Wrong Time, Wrong Place by Gillian Mcallister | Booktopia (1.01.00) Ian Mckewan - Author | Wiki   (1.03.00) The Cutting by Ian McHugh | Booktopia (1.10.00) Tree Top Walk | Website (1.10.30) Torndirrup National Park | Website (1.11.00) Margaret River Region | Website (1.11.13) Miki's Open Kitchen | Website   Produced by DM PodcastsSee omnystudio.com/listener for privacy information.

911 Free Fall with Andy Steele Aiming for Checkmate: Ted Walter on defeating the 9/11 cover-up This week on 9/11 Free Fall, AE911Truth Director of Strategy Ted Walter joins host Andy Steele to discuss the organization's forthcoming book, Debunking Popular Mechanics, and several other ongoing efforts to take down the official story of 9/11

It is all these weeks later, the RHOBH reunion has come and has almost gone, and we are still a BravoVerse divided over whether Lisa Rinna is telling the truth, the whole truth and nothing but the truth when it comes to Aspen and one Miss Kathy Hilton. We break that down, Rinna's constant social media posts that she knows EXACTLY what she is doing and whether we are as confident as her that she is the LeBron James of Real Housewives and will definitely be back next season. In other West Coast Housewives news, Vicki was seen filming the other week with the other two Tres Amigas - Shannon and Tamra. Is Vicki's filming a last ditch effort to hold onto her Housewives' fame of yesteryear or a brilliant play at getting the franchise and Bravo to realize they need the OG of the OC more than we ever knew. We also break down the rumors that the franchise has got off to a slow start, the rumors that Heather Dubrow has not filmed in weeks and the rumors that Taylor Armstrong has come in hot ready to exchange her once diamond for an orange in an attempt to officially be upgraded to full time status. Finally, Jim Edmonds marries, David Beador plans to divorce, TomKat divorces and Straight Up With Stassi returns! All this and more in another jam packed episode! @thesarahfrasershow @behindvelvetrope @davidyontef BONUS & AD FREE EPISODES Available at - www.patreon.com/behindthevelvetrope BROUGHT TO YOU BY: ORGANIFI - www.organifi.com/velvetrope (Use Code velvetrope at Checkout for 20% Off Your Entire Order) ETHOS - www.ethoslife.com/VELVET (Get a Free Personalized Life Insurance Quote Today) TALKSPACE - www.talkspace.com/velvet ($100 Off Your First Month) The REWATCHER: BUFFY THE VAMPIRE SLAYER (Listen on Amazon Music, Apple Podcasts, or Listen Early and Ad-Free by Subscribing to Wondery Plus in Apple Podcasts or the Wondery App) ADVERTISING INQUIRIES - Please contact David@advertising-execs.com MERCH Available at - https://www.teepublic.com/stores/behind-the-velvet-rope?ref_id=13198 Learn more about your ad choices. Visit megaphone.fm/adchoices

In this edition, we have Dr. Teele Kuusk (UK), the associate editor of the UROONCO RCC educational platform discussing kidney cancer highlights at the recent ESMO2022. Dr. Kuusk begins with the reporting of several new trials and the accompanying results, which include: Phase 3 CheckMate-914, Phase 3 COSMIC-313, Phase 2 Keynote-B61, and Cohort 1 of LITESPARK-003 study. After delivering the trial results, Dr. Kuusk shares the possible reasons why the adjuvant trials failed. For more details on the results of the LITESPARK-003 study, you can watch this video  featuring Assoc. Prof. Jaime Merchan (US), who presented at ESMO2022. https://kidney.uroonco.uroweb.org/video/cohort-1-of-litespark-003/ 

This is a pre-release. Full info will come when it is officially out on the video platforms. Recorded: 09 Nov 2021 NB! Optimal Chronological Order:   1. Arrival 2. Dance of the Dead 3. Free for All 4. Checkmate 5. The Chimes of Big Ben 6. Schizoid Man 7. The General 8. A. B. and C 9. Many Happy Returns 10. A Change of Mind 11. The Girl Who Was Death 12. Hammer into Anvil 13. Do Not Forsake Me Oh My Darling 14. Living in Harmony 15. It's Your Funeral 16. Once Upon a Time 17. Fall Out

First in Checkmate 30, Winston and Lionel, continue their battle against Bishop, while Checkmate if falling apart! And more on Harry Stien's situation. And then over in Suicide Squad 46, the Squad continues it's battle against Hayoth!. Feel free to e-mail us at taskforcex@headspeaks.com with your thoughts. Visit us on the web at http://taskforcex.headspeaks.com And let us know what you think.

Banks collapse. It's what they do. But could Credit Suisse collapsible be good for Bitcoin?

Part 10 in a series on the Book of Acts.

Join me for some laughs this week as I discuss the Expectations in Love Songs, the Jewel Cooler, and a Chess Master. --- Send in a voice message: https://anchor.fm/the-amazing-world-of-talkinu2019-shiz/message Support this podcast: https://anchor.fm/the-amazing-world-of-talkinu2019-shiz/support

Quinn comes to you LIVE from Minneapolis, Minnesota to tell you about all the beers he's trying, plus movie sequel trivia, and avoiding the tolls in order to BANKRUPT the State of Illinois. Checkmate bitch

Episode 16 of Hard Money with Natalie Brunell - Headlines this week include intensifying volatility in global financial markets, soaring yields in the bond markets, major selloffs in equities, the Fed's aggressive stance on hiking rates, rising mortgage rates, the British pound plunging to a record low against the US dollar, the election of ultra conservative Girogia Meloni as Italy's new Prime Minister, ruptures in the Nord Stream pipelines likely due to sabotage, Russia granting citizenship to Edward Snowden, Interpol issuing a Red Notice for Terra Luna founder Do Kwon, Alex Mashinsky resigning from Celsius, Federal Reserve Chairman Jerome Powell's criticism of DeFi, Colorado becoming the first US State to allow the payment of taxes in Bitcoin and other cryptocurrencies, and Bitcoin Magazine's upcoming conference in Amsterdam. This week's guest commentator is James Check aka Checkmate, lead on-chain analyst at Glassnode. And for this week's Hard Money Special Report, Natalie spoke to Wyoming Senator, Cynthia Lummis about the regulation of Bitcoin and cryptocurrencies. Chapters: 00:00:00 "Hard Money" Intro 00:00:35 Bitcoin, Macroeconomic and Political Headlines from this Week 00:11:44 Interview with James Check aka Checkmate, from Glassnode 00:21:46 Special Report: Crypto Regulation featuring Senator Cynthia Lummis 00:28:45 "Hard Money" Outro Watch the full interview with Senator Cynthia Lummis on Coin Stories: https://www.youtube.com/watch?v=IvNm3jW_xnY&t=769s Hard Money with Natalie Brunell features weekly headlines and hard hitting interviews from the world of Bitcoin and Finance, a macro update with Andy Edstrom, as well as Bitcoin stories from around the world. Hard Money is a production of Swan Studios. Connect with Natalie and Hard Money on Twitter: https://twitter.com/natbrunell https://twitter.com/hardmoneyshow Save the date for the Pacific Bitcoin Conference, November 10th & 11th in Los Angeles, California. Purchase your tickets now before the prices go up: https://pacificbitcoin.com Swan Bitcoin is the best way to accumulate Bitcoin with automatic recurring buys and instant buys from $10 to $10 million. Get started in just 5 minutes. your first $10 purchase is on us: https://swanbitcoin.com/yt Are you a high net worth individual or do you represent a corporation that might be interested in learning more about Bitcoin? Swan Private guides corporations and high net worth individuals toward building generational wealth with Bitcoin. Find out more at https://swanbitcoin.com/private Check out the best place for Bitcoin education, Swan Bitcoin's "Bitcoin Canon". Compiling all of the greatest articles, news sources, videos and more from your favorite bitcoiners! https://www.swanbitcoin.com/canon/ #bitcoin #bitcoinnews #hardmoney

PrizePicks of the Week for Packers-Patriots (plus a few bonus options). Headlines predicting whether Green Bay will handle business against Bellichick and New England. Whoa Nelly! "celebrating" National Chewing Gum Day. And Feel Good Friday painted by Hallman Lindsay Paints.

Chess 2 is finally here. Your loyal subjects have abandoned you and you've taken down your royal shotgun. Rapid arcade developer PUNKCAKE Delicieux created this game within 72 hours and dropped it on Steam within a month. Is it good? We put it to the test on this episode of Garbage Game Night!

Checkmate's shopping tool gathers all the online discount codes, gift cards and personalized deals from your inbox and automatically applies them at checkout. Checkmate captures all of your shopping deals so you don't have to by Christine Hall originally published on TechCrunch

Happy Soccer Podcast Day! On this week's episode of Bone & Beam United, the guys open up by sharing what the podcast schedule will be for this year's World Cup beginning next month, before diving into the story of Barcelona suing the Spanish newspaper El Mundo for releasing the details of Lionel Messi's contract (6:05). Along with that, they discuss how Barcelona's management has a tendency to throw their own players under the bus. Next, they get into Christian Pulisic's upcoming book, where he speaks about Thomas Tuchel misleading him on starting in the 2021 Champions league semifinal and more on his strained relationship with the former Chelsea manager (22:08). On the topic of Pulisic, the guys talk about his insane amount of time spent playing chess (28:18). Next, they discuss Crew2 and the team's upcoming conference semifinal game against Rochester NYFC this Saturday (34:22). Finally, Beam explains why EA Sports FIFA 23 will once again disappoint him, but how it's pretty cool that Ted Lasso and AFC Richmond will be in this year's game (38:13). As always, let us know what you think of the show - on twitter @bonebeamunited

Live Recorded Set from VirtualDJ Radio PowerBase

Pittsburgh has had a hard week, but the boys are here to make it better! The Steelers Offense is breaking our hearts. We need to get rid of Canada, Snoop Dogg wants the job. And Jack has an interesting bathroom experience with a guy and Jeff Reed. A guy whipped his junk out at the Queen's funeral. We learn babies do float. Golf is done. Tik Tokers are marinating chicken with Nyquil. Kanye West is opening a private religious school. And a man uses anal beads to cheat at chess. All that and more on this week's episode of Greenfield's Finest Podcast!

In this episode of Agents Influence podcast, host Jason Cass interviews Mark Engels, CEO of ePayPolicy. Mark discusses the areas in which ePayPolicy has simplified the process of making insurance payments. Mark also highlights ePayPolicy's new service, CheckMate, which is changing the game for paper check payments. Episode Highlights: Mark discusses how ePayPolicy's new service, CheckMate, is making it easy for customers to receive payments and then have them auto reconcile into the back office to make things more efficient. (2:52) Mark explains what a lockbox is and how it helps customers by transforming physical checks into digital files. (6:03) Mark mentions that as ePayPolicy evolves, they are developing a solution for their clients that only take a handful of checks in their office each month and do not require a full-fledged outsourced lockbox service. (8:17) Mark announces that ePayPolicy will launch a product associated with outbound payments for an insurance premium, as well as an invoicing solution that will take it to the next level. (10:14) Jason explains how he became interested in the services and products offered by ePayPolicy. (13:07) Mark shares that ePayPolicy will be attending AI Brainshare in March of 2023 in New Orleans. (15:45) Key Quotes: "If you think about the ecosystem today, and what we do, well, we help our customers accept and auto reconcile inbound payments associated with a premium." - Mark Engels "There's still a lot of paper checks in the ecosystem. And, you know, it causes a lot of pain for the folks that are out there. And so we took a step back and said, Look, why don't we come up with a solution to offload that burden from our customers, we can't force the insurance into a method of payment." - Mark Engels "It's our job to make it easier for our customers to accept those payments, and then make them auto reconcile into the back office to make it more efficient. So that's what CheckMate is all about." - Mark Engels Resources Mentioned: Mark Engels LinkedIn ePayPolicy Reach out to Jason Cass  Agency Intelligence

How many moves ahead is God? When it comes to prophecy and future events to be fulfilled, it is good to realize that God is in control. This podcast looks at the awesome power of God.

It's been a minute! The gang gets into the breaking news about Federer, the return of the NFL, and the cheating allegations that have the chess community in shambles. Plus, an elf at half-field, boxing as a second career and covert texts to send to friends if you're in danger. Did we miss anything? Let us know at 631-397-0403. Rate, review, subscribe and we'll see you next week! Learn more about your ad choices. Visit megaphone.fm/adchoices

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we round out our discussion of early stage lung cancer treatment!* When deciding if a patient can get surgery upfront or not, remember the three “Fellow on Call” criteria for early stage lung cancer: - Mass invading other structures or mediastinum- Central lymph nodes (single digit)- Tumor >7 cm* If surgery is NOT an option at this time, where do we go from here?- Treat with upfront concurrent definitive chemoradiation- Treat with “induction” chemotherapy or induction concurrent chemoradiation**If surgery is/may be possible***What are the goals of “induction” treatments? - Eradicate microscopic disease- Improved local control, possibly shrinkage- Adding radiation may allow you to downstage tumor or lymph nodes to have a possible improvement in surgical outcomes* What sorts of discussions are being had a thoracic tumor board in patients with newly diagnosed early stage NSCLC? - Is the patient a surgical candidate?- If the patient is not a surgical candidate, then what are the options:--Definitive concurrent chemoradiation (usually) followed by immunotherapy---Pearl 1: Always choose this if surgeon thinks the patient is unresectable in general even with an induction approach---Pearl 2: Always choose this if 2 out of 3 criteria we discussed above are met---Pearl 3: Always choose this if N3 disease- “Induction” regimen with either chemotherapy alone or concurrent chemoradiation followed by surgery * What's the idea behind “induction” chemo or chemoradiation? - There is a chance that patients with these high risk features may already have micrometastatic disease, so treatment upfront can help address that- There is a chance that after surgery, patient may suffer deconditioning, which may preclude the use of chemo +/- radiation (up to 90% of patients are often eligible for chemoradiation before surgery; this drops to ~60% after surgery)- Local disease control to achieve the best possible surgical outcome (R0 resection) and also prevent any microscopic residual disease from then having the opportunity to spread systemically, especially in areas where the mass may be adjacent to many blood vessels or lymph nodes* What to treat with in the neoadjuvant setting?- Platinum containing regimens (“platinum doublets”):-- Carboplatin + paclitaxel-- Cisplatin + etoposide-- Cisplatin + gemcitable-- Cistplain + pemetrexed- Can combine this with radiation* How does the data about chemotherapy+IO in the neoadjuvant setting fit in here (CHECKMATE 816)?- In patients with Stage IIB to IIIA (8th edition) WITHOUT EGFR or ALK mutation, treatment with NEOADJUVANT chemotherapy q3w x3 cycles (most got cisplatin based therapy) + nivolumab 360mg q3w x3 cycles resulted in improved event free survival (31.6 months vs. 20.8 months) AND pathological complete response was 24.0% vs. 2.2%- Current NCCN guidelines state that if nivolumab is used in neoadjuvant setting, it should not be used in adjuvant setting- There is still uncertainty about how this fits into treatment compared to “traditional” neoadjuvant approaches with chemo+/-radiation*So after neoadjuvant treatment, does everyone go to surgery?- Always re-assess the status of the disease; if there is progression of disease, then will go to definitive chemoradiation- Discuss with surgeons to confirm if the patient is still a surgery candidate* If patient undergoes surgery, then what?- If patient got neoadjuvant therapy and an R0, then they are done with treatment- If R0 resection was not able to achieved, then either radiation “boost” to the area (if they previously got radiation), a course of radiation (if they just got induction chemo) or re-resection- We discuss the adjuvant setting in more detail in Episode 026 (https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s)** If surgery is not possible*** If patient cannot go through to surgery Definitive chemoradiation:- Same chemotherapy agents as above, but treatment course is longer.- For instance, for NSCLC, total 60Gy in 2Gy divided fractions (5 days/week, 6 weeks of treatment) with chemotherapy* Additional therapy after chemoradiation (PACIFIC Trial) - Found that “consolidation” durvalumab 44% PFS 18 months vs 20% 5year survival benefit 40% vs. ~30% without treatmentReferences:https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 - NCCN Lung Cancer guidelines https://www.nejm.org/doi/full/10.1056/nejmoa1709937 - PACIFIC Trial (NEJM 2017)https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 (NEJM 2022) Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

It was always about controlling free citizens, and here is how they did it. Ushering us into enslavement. Spoon feeding the obvious to the never truthers. A planned event. Hillary, Bill, Jim, James, John and all the others. Think Congress and Senate. So many traitors facilitated and capitalized. Visa corruption in foreign locales. Not about left or right, but good and evil. The 911 perps still rule. Never forget? 20 years later, same questions. Fear is the vehicle for loss of rights. They perfected it all in other countries. Where would a whistle blower have gone? They own the media. Bio-warfare was the next step, now it's VAX weapons. Real press were attacked. Voting systems designed to ensure extended control. Own nothing and be happy. A new 911 review should be about accountability and truth. Bannon talks our strategy. J6 teasers. Lights, camera, insurrection. Stay focused and be strong. Sometimes we have to start way back at the beginning to really fix things. Learn more about your ad choices. Visit megaphone.fm/adchoices

On last episode, I told a story about how I didn't want my son playing football. Well, sometimes desperate times call for desperate measures! Check out this bonus episode! --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

On this episode of Magic Internet Money host Brad Mills invites investment strategist Lyn Alden, and analysts Dylan LeClair, and Checkmate onto the show to get into the thick of the technology of blockchains, namely on the topic of censorship resistance and the potential impact the Ethereum 2.0 merge might have in the world of cryptocurrencies.Time Stamps:00:00:20 - Introduction00:09:49 - Discussing censorship resistance, what if Bitcoin didn't exist?00:32:20 - Are there credible threats to user-activated software in Ethereum?00:41:07 - ETH proof of work vs ETH proof of stake00:57:23 - Institutional adoption, balkanization of treasuries, current events impact01:11:08 - Hypothetical: How do we get back into DeFi summer?01:21:32 - What is redeemable about Ethereum?01:34:28 - Is there any serious threat from regulatory risks?01:54:30 - Outros and PlugsLinks to Mentions in the ShowEthereum 2.0This Machine GreensThe Deep DiveWhy the Ethereum Merge is a BlunderGeyser FundWeb 3.0Freerider ProblemESGGuest Social LinksLyn Alden TwitterLyn Alden Investment StrategyDylan LeClair TwitterBTC IncCheckmate TwitterFind Brad MillsBrad Mills TwitterMIM TwitterBrad Mills Facebook

Blockware Solutions Analyst Joe Burnett (https://twitter.com/IIICapital) speaks with onchain and derivatives expert Checkmate, Lead Analyst at Glassnode. Follow Checkmate at: https://twitter.com/_Checkmatey_ Start Mining Bitcoin with Blockware Solutions: https://www.blockwaresolutions.com/contact?SQF_LEADSOURCE=YouTube

IN THIS EPISODE, YOU'LL LEARN:What is happening between the energy sector and the Bitcoin mining space?Regulator capture with Ethereum.Has Bitcoin reached a tipping point with energy and mining being interlinked?Blackrock endorsing Bitcoin as ESG compliant.Parker's concerns with ESG in general.Taking custody of Bitcoin and why it's so important to its role in the future.Unchained offering final settlement to a person's personal account.Where are energy prices going in Europe from here?BOOKS AND RESOURCESParker's Lewis' Twitter.Will Cole's Twitter.Unchained Capital multi-signature custody.Checkmate's video on why he has concerns with the Ethereum merge.Checkmate's Twitter account.Link to charts from the discussion.Related episode: Bitcoin Retirement Planning & Self Custody w/ Parker Lewis & Jeff Vandrew - BTC069.Related episode: Bitcoin, Supply Chains, Debt Ceilings and More w/ Parker Lewis - BTC047.NEW TO THE SHOW?Check out our We Study Billionaires Starter Packs.Browse through all our episodes (complete with transcripts) here.Try our tool for picking stock winners and managing our portfolios: TIP Finance Tool.Enjoy exclusive perks from our favorite Apps and Services.P.S The Investor's Podcast Network is excited to launch a subreddit devoted to our fans in discussing financial markets, stock picks, questions for our hosts, and much more! Join our subreddit r/TheInvestorsPodcast today!SPONSORSTrade specifically based on your view of concrete events with Kalshi.Enforce strong passwords and make it easy for your teams to securely share credentials with Keeper Security. Sign up for a Keeper free trial for your organization today, and get a free 3-year personal plan.Take the next step in your working-life or get ready for a change, by being a Snooze franchise partner.Confidently take control of your online world without worrying about viruses, phishing attacks, ransomware, hacking attempts, and other cybercrimes with Avast One.Build a plan that helps you strengthen your financial security with RBC Wealth Management. RBC capital markets LLC, member NYSE, FINRA, SIPC.Send, spend, and receive money around the world easily with Wise.Invest in high quality, cash flowing real estate without all of the hassle with Passive Investing.Make backing up and accessing your data astonishingly easy with Backblaze.Make summer dinners stress-free with Freshly. Get $125 off your first five orders today!Get up to 3% Daily Cash back on everything you buy with Apple Card. Apply now in the Wallet app on iPhone and start using it right away. Subject to credit approval. Daily cash is available via an Apple Cash card or as a statement credit. See Apple Card customer agreement for terms and conditions. Apple Cash card is issued by Green Dot Bank, Member FDIC. Variable APRs range from 13.24% to 24.24% based on creditworthiness. Rates as of August 1, 2022.Help empower girls to break free through education, healthcare, child protection, and other wonderful benefits by being a World Vision child sponsor today.Experience a simple way for you to set up a bitcoin IRA while keeping control of your bitcoin keys with Unchained Capital. Schedule a complimentary consultation today.Support our free podcast by supporting our sponsors.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

John and Eric discuss Checkmate #1-6 from 1988. Time Codes: 0:00:00 Intro 0:00:36 Opening comments 0:00:47 Checkmate #1-6 0:28:08 Previews Spotlight reminder 0:28:36 Wrap up 0:29:06 End of episode. Email us at TheGuys@ComicBookPage.com Join the discussion on our forum at: http://forum.comicbookpage.com Join the Comic Book Page Slack channel: http://comicbookpage.com/cbp_slack_request.php This podcast episode originated on the […]

The Crew battle the first of Blue Blood's Commanders

Andy is with Alice Fraser and Aditi Mittal to unpack everything behind the unbearable heat, superhuman chess and who's the new kid inside number 10.Our 15th Birthday Special Tour is coming to the UK and Ireland this year: https://www.thebuglepodcast.com/liveThere's no ads in this show, thanks to you! Cast some cents and pennies our way: https://www.thebuglepodcast.com/donateThis episode was written and presented byAndy ZaltzmanAlice FraserAditi MittalAnd produced by Ross Ramsey-Golding See acast.com/privacy for privacy and opt-out information.