Podcasts about nras

Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease.  I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida.  Our full disclosures are available in the transcript of this episode.  James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary.  But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting.  So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important.  Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission.  In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults.  I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate.  The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it.  The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting.  The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work.  Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved.  One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now.  So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field.  Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it.  And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't.  A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that.  I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results.  There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that.  John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets.  I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can.  I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that.  And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. 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. Find out more about today's speakers:  Dr. John Sweetenham  Dr. James Foran Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn  Disclosures:    Dr. John Sweetenham:    No relationships to disclose Dr. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview

In this week's episode, Sam Gordon is joined by co-host Jimmy Ibrahim and APS strategist Luke Teeuwsen for a deep dive into whether investors should let government policy dictate their property investment strategy. From banking shifts to proposed tax changes, the team explores how to stay informed about policy shifts without letting them derail your portfolio and investing decisions.   They break down the crucial difference between proposed and implemented changes, emphasising why sticking to core fundamentals is key in the ever-evolving property market. The boys discuss the importance of a holistic approach, analysing different markets across states, and making strategic moves for long-term success. From tax cuts to pandemic-driven policies and the latest in policy updates, this episode will arm you with the insights needed to become a more strategic and savvy investor. Strictly limited tickets are available to the Australian Property Scout Summit on Sunday, November 17th at The Star in Sydney. You will leave with actionable steps, expert inspiration and direction to level up your property investing game, along with the opportunity to be surrounded by the APS and SAP community to expand and develop your circle of influence. Tickets are officially available and are selling fast, click here to save your spot!

On this episode of No BS With Birchy, join Nathan Birch as he dishes up some hard truths about one of the most controversial hot topics in property at the moment, the NDIS Housing Scheme and SDA Properties. You won't want to miss Nathan talk about the good, the bad and the ugly of SDA properties for investors and how history demonstrates how damaging schemes like this one can be for those lured into purchasing these properties. Nathan revisits past government schemes and how they almost always fold and negatively impact investors in the long run. Hold onto your hats folks, because Birchy is passionate about this one. A podcast to share with your fellow investors!  Show Notes: 02:30 - What is an NDIS/SDA Property? 03:36 - Nathan's straight facts. Scheme or Scam? 05:50 - The Logan QLD NDIS property example 08:33 - Pink Batts, Solar - there's been countless schemes! 09:06 - Revisiting Tax - It originated as a tax on tea only 09:27 - We're at the Peak of the NDIS housing scheme right now 10:00 - Kevin 07 and NRAS - investors are still trapped and it's tragic 12:33 - Defence housing, the list goes on. History is repeating again with the NDIS scheme 13:42 - Think about your exit strategy & the next buyer. Will it sell? Will it suit your next buyer? 14:51 - For the record, Nathan owns ZERO and has plans on buying ZERO.  Listen to this week's episode while you're running an errand or on the road here. Liked the episode? Why not show it some love by liking it and leaving your thoughts in the comments? Interested in building your property investment portfolio? Chat with our Investor Relations team to see how we can help you grow your investment property portfolio here. Follow and turn on B.Invested's Facebook page notification to know when Nathan's going live every fortnight on Tuesday at 7:00 pm AEDT. *DISCLAIMER* The following videos have been prepared by Binvested.com.au Pty Ltd ACN (154 400 370). The factual information (“information”) provided in this website and the following videos is general in nature only and does not constitute any type of financial advice and is not intended to imply any recommendation or opinion about a financial product. The information has been prepared without considering your personal objectives, financial situation or needs. Before acting on any information provided in this website and in the following videos you should consider the appropriateness of the information having regard to your objectives, financial situation and needs. Binvested.com.au Pty Ltd is not a financial advisor. Before making any decision, it is important that you should seek appropriate legal, tax, financial and other professional advice before you make any decision regarding any information mentioned in this communication, its website and the following videos. Whilst all care has been taken in the preparation of this material, no warranty is given in respect of the information provided and accordingly neither Binvested.com.au Pty Ltd nor its related entities, affiliate companies, employees or agents shall be liable on any ground whatsoever with respect to decisions or actions taken as a result of you acting upon such information. We can provide access to our Investor Relations team should you wish to speak to them. Please contact 1300 367 925 to speak to a member of the Investor Relations team.   

Eric Madry - Managing Director of Post Oak Minerals joins the podcast to walk through the evolution of their portfolio as well as the $475mm worth of deals they have closed thus far in 2024. A big thanks to our 5 Minerals & Royalties Podcast Sponsors: --R. Reese & Associates: If you are interested in outsourcing and/or bolstering your legal department, then please contact Rachel Reese at 832-831-2289 or visit www.rreeselaw.com to learn more. --Riverbend Energy Group: If you are interested in discussing the sale of your Minerals and/or NonOp interests w/ Riverbend, then please visit www.riverbendenergygroup.com for more information --Farmers National Company: For more information on Farmer's land management services, please visit www.fncenergy.com or email energy@farmersnational.com --Opportune: For more information on Opportune's services, please visit www.opportune.com --Oseberg: For more information on the software & data analytics tools that Oseberg has to offer, please visit www.oseberg.io.

In this episode, I talk to Juliette Rayner, CEO of the children's bladder and bowel charity,  E.R.I.C, Dr Steven Cox, CEO of Cardiac Risk in the Young (CRY), Jane Plumb CEO of  Group B Strep Support, Claire Jacklin from the NRAS and Matt Williams from the Samaritans

Hello, and welcome to episode 115 of the Financial Crime Weekly Podcast, I'm Chris Kirkbride. Money laundering takes centre stage this week with Singapore announcing updates to National Risk Assessments (‘NRAs'), and the FATF announcing public consultation on its NRAs. The fall-out from the FATF Singapore Plenary last week with a response from South Africa respecting its timetable for removal from the ‘Grey List'. On sanctions, here is the usual mix of updates to designations and licences, and on bribery and anti-corruption an update on Andorra from GRECO. We then end with a round-up of the cyber-attack news this week. As usual, I have linked the main stories flagged in the podcast in the description. These are: Council of Europe, Andorra: GRECO report on preventing corruption in top executive functions and the police.Department of Justice, Vice President of Kansas Company Pleads Guilty to Crimes Related to Scheme to Illegally Export U.S. Avionics Equipment to Russia and Russian End Users.EU Directorate-General for Trade, EU protects sanctions against Russian and Belarussian investors under Energy Charter Treaty.European Banking Authority, The EBA issues ‘travel rule' guidance to tackle money laundering and terrorist financing in transfers of funds and crypto assets.European Commission, EU further extends the scope of sanctions on Belarus to fight circumvention.European Council, Russia's war of aggression against Ukraine: EU lists two individuals and four entities for circumventing EU sanctions and materially supporting the Russian government.European Council, Belarus' involvement in Russia's war of aggression against Ukraine: new EU restrictive measures target trade, services, transport and anti-circumvention.European Securities and Markets Authority, New MiCA rules increase transparency for retail investors.Federal Bureau of Investigation, Private Industry Notification: Expansion of US Renewable Energy Industry Increases Risk of Targeting by Malicious Cyber Actors.Federal Register, Reimposing Certain Sanctions with Respect to Iran.Financial Action Task Force, Public consultation on FATF Money Laundering National Risk Assessment Guidance Update.Institute of Chartered Accountants in England and Wales, ICAEW joins forces with the International Federation of Accountants and the Basel Institute to offer anti-corruption guidance for accountants.Monetary Authority of Singapore, Singapore Refreshes the Terrorism Financing National Risk Assessment and National Strategy for Countering the Financing of Terrorism.National Health Service, Update on cyber incident: Clinical impact in south east London – Thursday 4 July.Office of Financial Sanctions Implementation, General licences - INT/2024/4423849, INT/2023/3074680, INT/2022/2470156 and INT/2022/2470056.Office of Financial Sanctions Implementation, General Licence – Sale, divestment and transfer of financial instruments held by the National Settlement Depository and payment of safe keeping fees to the National Settlement Depository INT/2024/4919848.Office of Financial Sanctions Implementation, General Licence: Payments for Visa Application Services INT/2024/4907888.Office of Financial Sanctions Implementation, Guidance: Russian Oil Services ban.Office of Financial Sanctions Implementation, General Licence – Oil Price Cap: Exempt Projects and Countries INT/2022/2470156.Office of Financial Sanctions Implementation, General Licence: Payments to Revenue Authorities INT/2024/4881897.Office of Foreign Assets Control, Treasury Sanctions Mexico- and China-Based Money Launderers Linked to the Sinaloa Cartel.South African Government, Treasury on Financial Action Task Force greylisting.The Wolfsberg Group, The Wolfsberg Group Statement on Effective Monitoring for Suspicious Activity.The Wolfsberg Group, The Wolfsberg Group Statement on Effective Monitoring for Suspicious Activity (Document).US Department of State, Imposing Sanctions on Entities and Vessels Trading in Iranian Petroleum or Petrochemical Products.US Financial Crimes Enforcement Network, Financial Action Task Force Identifies Jurisdictions with Anti-Money Laundering, Combating the Financing of Terrorism, and Counter-Proliferation Finance Deficiencies. 

Brent discusses how the sunset of the estate tax exemption in 2026 will also effect non-citizen non-residents of the US significantly (NRAs). He explains how the estate tax treaties work and how the math under some of the treaties could change in 2026 in a way that makes an NRA who is currently safe from estate tax exposed to estate tax thereafter. He also gives an estate tax planning framework for US citizens, NRA's in treaty jurisdictions, and NRA's in non-treaty jurisdictions.

BUFFALO, NY- January 29, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.” In this new paper, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss thyroid cancer. A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short-lived due to multiple compensatory resistance mechanisms. “One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation.” DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. “Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.” DOI - https://doi.org/10.18632/oncotarget.28544 Correspondence to - Luc GT Morris - morrisl@mskcc.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28544 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, thyroid cancer, drug resistance, anaplastic transformation, BRAF inhibitors, PIK3CA About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Research presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics found that a combination of two drugs targeting the nRAS mutation had clinical activity in patients with checkpoint-inhibitor refractory melanoma and had potential for treating other solid tumors with mutated nRAS as their oncogenic driver. Rodabe N. Amaria, MD, from the MD Anderson Cancer Center, Houston, talks with OncTimes Talk’s Peter Goodwin about her group’s Nautilus phase 1b/2 study that added an oral histone deacetylase inhibitor (HDACi), bocodepsin, to therapy with a mitogen-activated protein kinase enzyme (MEK) inhibitor, binimetinib, to target the RAS-pathway in solid tumors. The researchers found the combination of bocodepsin and binimetinib was tolerable in patients with RAS-mutated advanced cancers with manageable adverse events, and that this combination brought clinical responses indicating a potential benefit for patients who have failed immunotherapy.

Dr. Tariq Arshad is the Senior Vice President and Chief Medical Officer at Qualigen Therapeutics, addressing multiple types of RAS-driven cancers. While researchers understand RAS's role in tumorgenesis and have identified which cancers are RAS-driven, RAS has been considered an undruggable target. With a pan-RAS approach inhibiting KRAS, HRAS and NRAS, the three isoforms of RAS, Qualigen is identifying drug candidates showing strong anti-tumor efficacy.    Tariq elaborates, "That was so difficult to do because when you look at the KRAS protein itself, it's a complicated, three-dimensional structure that constantly changes. The opening, or the aperture, where a small molecule can attach and inhibit the G12C moiety or specifically the cysteine amino acid, which is targeted by these inhibitors, it appears for a very, very short period of time. It's nothing short of a miracle of bioengineering, and specifically medicinal chemistry that we've been able to identify these inhibitors that can target that subcomponent, that very small aperture within the overall KRAS protein, without, as you're saying, impacting the function of the overall protein." "The field is moving towards understanding why this lack of durability exists and is trying to understand whether it's due to the emergence of other mutations, whether it's due to the emergence of wild-type RAS, or whether it's due to other factors. One of the theories that is emerging behind the emergence of this KRAS resistance is the fact that there are other RAS isoforms that exist in the same tumor. They allow a mechanism in which the tumorigenesis can bypass KRAS, even though it's inhibited, and signal into the cell to convert it into a cancer cell. It now becomes important for us to understand how we can address that potential mechanism of resistance." #QualigenInc #RAS #KRAS #RASDrivenCancer #Cancer  QualigenInc.com Download the transcript here

Dr. Tariq Arshad is the Senior Vice President and Chief Medical Officer at Qualigen Therapeutics, addressing multiple types of RAS-driven cancers. While researchers understand RAS's role in tumorgenesis and have identified which cancers are RAS-driven, RAS has been considered an undruggable target. With a pan-RAS approach inhibiting KRAS, HRAS and NRAS, the three isoforms of RAS, Qualigen is identifying drug candidates showing strong anti-tumor efficacy.    Tariq elaborates, "That was so difficult to do because when you look at the KRAS protein itself, it's a complicated, three-dimensional structure that constantly changes. The opening, or the aperture, where a small molecule can attach and inhibit the G12C moiety or specifically the cysteine amino acid, which is targeted by these inhibitors, it appears for a very, very short period of time. It's nothing short of a miracle of bioengineering, and specifically medicinal chemistry that we've been able to identify these inhibitors that can target that subcomponent, that very small aperture within the overall KRAS protein, without, as you're saying, impacting the function of the overall protein." "The field is moving towards understanding why this lack of durability exists and is trying to understand whether it's due to the emergence of other mutations, whether it's due to the emergence of wild-type RAS, or whether it's due to other factors. One of the theories that is emerging behind the emergence of this KRAS resistance is the fact that there are other RAS isoforms that exist in the same tumor. They allow a mechanism in which the tumorigenesis can bypass KRAS, even though it's inhibited, and signal into the cell to convert it into a cancer cell. It now becomes important for us to understand how we can address that potential mechanism of resistance." #QualigenInc #RAS #KRAS #RASDrivenCancer #Cancer  QualigenInc.com Listen to the podcast here

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.14.549027v1?rss=1 Authors: Yasue, S., Ozeki, M., Nozawa, A., Endo, S., Ohnishi, H. Abstract: Recently, a low-level somatic mutation in NRAS gene (c.182 A greater than G, Q61R) was identified in the specimens of patients with kaposiform lymphangiomatosis (KLA). However, it is unknown how these low-frequency mutated cells can affect the characterization and surrounding environment of their lesions. To understand the pathogenesis and association of these gene abnormalities, we established NRASQ61R mutated lymphatic endothelial cells (LECs) transfected with lentivirus vector and undertook morphological and functional characterization, protein expression profiling, and metabolome analysis. NRASQ61R human dermal LECs showed poor tube formation and high cell proliferation and migration ability with increasing ratios of mutated cells. Analysis of signaling pathways showed inactivation of the PIK3/AKT/mTOR pathway and hyperactivation of the RAS/MAPK/ERK pathway, which was improved by MEK inhibitor treatment. This study may show the theoretical circumstances in vitro induced by NRASQ61R-mutated cells in the affected lesions of KLA patients. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Special guest Wonder Woman (also known as Jackie Skein) has jumped into the shark cage with Hosts Sammy Gordon & Jimmy Ibrahim to tackle one of the hottest topics in real estate, Property Management. In today's episode, we will get in-depth knowledge on how to form great relationships with property managers, how to select a great PM for your properties and some incredible stories from the team which will give you some great insight on what not to do. Intro guest - [00:31] Jackie how do you pick it - [01:37] People are experts at different things - [02:59] There are no kickbacks - [03:58] Jackie give us your background - [4:40] Jackie's level of service - [08:09] Why do property managers hate this conversation - [09:40] What is your ideal amount - [10:48] Your days are numbered - Jimmy - [11:24] Something Jackie noticed property managers didn't have - [12:20] The incentive - [14:45] - The first question you should ask Do certain property managers get kickbacks - [16: 38] - Jackie's story - The common problem Jimmy's fugazi forms - [20:45] Do you get any kickbacks - [ 21:18]  - Be mindful of realistic prices - Are we being too hard What answer do you want to look for - [24:10] - CMA's - How a property manager will reveal how good they are - What's your process around lease renewals Management fees - [31:00] - Understand costs - Dusty pockets Cheapest rate... you're gonna get burned - [36:34] Throwing some heat - [38:00] Are there people in the industry trying to take advantage of you - [40:33] - The flat fee - Don't get caught out on the additionals - The resident upgrade The big push in the industry - [43:47] Average days on market - [45:30] - Here's a take-home gem The fine line - [47:51] How do you manage granny deals & teething issues - [50:13] Important to have a good relationship and bond - [53:54] Give us a horror story Jackie [55:24] NRAS story - [57:05] Sammy's got one - [58:48] If you're taking tremendous value from these episodes why not share them with your mate? If you want your question answered on our podcast DM us on our socials or email us at apsteam@australianpropertyscout.com.au Send us your questions to: Instagram: @australianpropertyscout Want to book a call with us: Website: https://australianpropertyscout.com.au Any information, comments, opinions or content that we provide in this podcast is our general observations and information only and it is not to be taken as, or in any way, considered to be financial advice, accounting advice, superannuation advice or legal advice. We strongly recommend all and any listener and participant to obtain their own independent financial advice, accounting advice, superannuation advice and legal advice before acting in any way in relation to any investment at all including any investment in property such as what we might be discussing in this podcast. No warranty, guarantee or representation is to be taken and you cannot reproduce it in any way. Every persons financial or investment situation is different and you must consider your own circumstances before undertaking any investment and be sure to obtain independent advice. Australian Property Scout Pty Ltd | License Number: 10094798 | ABN: 64 638 266 369

A new research paper was published in Oncotarget's Volume 14 on May 26, 2023, entitled, “Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment.” The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK, and ERK in melanoma is largely unknown. In this study, researchers Valentin Feichtenschlager, Yixuan James Zheng, Wilson Ho, Linan Chen, Ciara Callanan, Christopher Chen, Albert Lee, Jose Ortiz, Klemens Rappersberger, and Susana Ortiz-Urda from the University of California San Francisco and Medical University Vienna demonstrated the impacts of antisense oligonucleotide (ASO)-based MALAT1-inhibition on MAPK-pathway gene regulation in melanoma. “Our results showed that MALAT1-ASO treatment decreased BRAF RNA expression and protein levels, and MALAT1 had increased correlation with MAPK-pathway associated genes in melanoma patient samples compared to healthy skin.” Additionally, drug-induced MAPK inhibition upregulated MALAT1-expression, a finding that resonates with a paradigm of MALAT1-expression presented in this work: MALAT1 is downregulated in melanoma and other cancer types in which MALAT1 seems to be associated with MAPK-signaling, while MALAT1-ASO treatment strongly reduced the growth of melanoma cell lines, even in cases of resistance to MEK inhibition. MALAT1-ASO treatment significantly inhibited colony formation in vitro and reduced tumor growth in an NRAS-mutant melanoma xenograft mouse model in vivo, while showing no aberrant toxic side effects. “Our findings demonstrate new insights into MALAT1-mediated MAPK-pathway gene regulation and a paradigm of MALAT1 expression in MAPK-signaling-dependent cancer types. MALAT1 maintains essential oncogenic functions, despite being downregulated.” DOI - https://doi.org/10.18632/oncotarget.28447 Correspondence to - Valentin Feichtenschlager - valentin.feichtenschlager@ucsf.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28447 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - MALAT1, MAPK-pathway, BRAF, melanoma, antisense oligonucleotides About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  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.  Find out more about today's speakers: Dr. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

Dr. Shaalan Beg and Dr. Mohamed Salem discuss novel therapies in gastrointestinal cancers, including CAR T therapy and the CodeBreak-101 trial in mCRC, new advances in uHCC in the HIMALAYA trial, and an exciting update from the NAPOLI-3 trial in pancreatic cancer, ahead of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. My guest today is Dr. Mohamed Salem, a GI oncologist at the Levine Cancer Institute at Atrium Health. We'll be discussing key posters and oral abstracts in GI oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Mohamed, thanks for coming on the podcast today.  Dr. Mohamed Salem: Thanks, Shaalan.  Dr. Shaalan Beg: There's some interesting studies in colorectal cancer that I'd like to get us started with today. Abstract 3547 is titled “A Phase I Dose-escalation Study of GCC19 CAR T: A Novel Coupled CAR Therapy for Patients with Metastatic Colorectal Cancer.” What are your thoughts on the study? Dr. Mohamed Salem: Actually, this was a very exciting study to see coming out in GI cancer, especially colorectal cancer. As you know, CAR T made its way to the treatment of lymphoma and other heme malignancies. In fact, we saw a fascinating response and outcome using that technique and that niche in the immunotherapy module. The challenge we had was that we could not replicate this in solid tumors until very recently. I'm sure you had the same thing in your clinic, too. A lot of patients with GI cancer or colorectal cancer come to you and say, "Okay, why can't I have CAR T?" And the response was, "We don't know if it's effective or if it's going to work yet." Here at our center, we had a phase 1 study, I think that was looking also at CAR T and solid tumors, particularly prostate cancer. So that I think was very exciting to see that technology is making its way to the solid tumor. I was very pleased to see this CAR T study coming out from the work of our Chinese colleagues looking into this in the CRC space.  Obviously, as you know, in colorectal cancer, we made a significant advancement, but I don't think we made enough advancement yet, and especially for refractory patients, patients with refractory disease who have underwent multiple lines of therapy. And this study actually addressed the need for those patients. So in this study, that was a phase I escalation dose, very much is we looked at about 13 patients who had metastatic CRC, they had at least two lines of therapy. So in what we say is a "refractory setting," unfortunately for those patients, we don't have large treatment options. And they used two doses, the first dose and the second dose that was a little bit higher. And the interesting part is that they were able to see very nice responses on this patient population. In the lower dose, I think the response was the PFS was about 1.9 months. But when they went up on the dose, actually the PFS was 6.3 months, which I think in the refractory setting is very meaningful.   And also the median overall survival for the first group was 13 months, which in the refractory setting is something we don't see often, and the higher dose was 18 months, which was even better. So there was a trend that higher doses are perhaps more effective or have better efficacies than lower doses, but also in terms of side effects, actually patients were relatively able to tolerate it well, and there were no surprising adverse events. So again, yes, that's 13 patients in total. So it's a very small study, but like everything else, the proof of concept sometimes is the first step and it's very important to see that data to suggest that this technology now can be utilized in solid tumors and CRC, especially now there is an unmet need for those patient populations. I'm sure you and I will see a lot of patients at the clinic with good progress status, and just looking for the next option, and I'm glad to see that. Hopefully, we can continue to build on that work.  Dr. Shaalan Beg: Another key abstract in colorectal cancer is Abstract 3513, the CodeBreak 101 study. This is a phase 1b safety efficacy trial of sotorasib plus panitumumab and chemotherapy with FOLFIRI for previously treated KRAS-G12C mutated colorectal cancer. And this is a really important study because even though KRAS-G12C represents a minority of KRAS mutated colorectal cancer, we know that this treatment can cause meaningful improvement in disease for other cancers like non-small cell lung cancer. And when sotorasib was tested as monotherapy in colorectal cancer, it saw an objective response rate of 9.7% that increased to 30% when added to panitumumab.   So in this trial, they took sotorasib plus panitumumab and added it to chemotherapy to see how it's tolerated and what its effectiveness is going to look like. And they enrolled people who had more than one or more lines of prior therapy for metastatic disease. They treated 33 patients. The most common side effect was dermatologic, which is probably related to EGFR-based therapy, and they saw a confirmed overall response rate of 58%. Side effects are those that we look to expect with this specific regimen. I don't see any additional safety concerns here, but this can be a big step forward for KRAS-G12C-altered colorectal cancer. What do you think? Dr. Mohamed Salem: I totally agree. And again, it was very exciting to see that abstract and that result. I totally believe now, and I'm sure you would agree with me too, Shaalan, that we're moving from an era of one size fits all to a precision oncology and tailored treatment. And the fact now we have a treatment option for patients with a KRAS mutation is very exciting because before, we didn't have much that we can do about that mutation. So now it's not just a proof of concept. Now you're hitting that target with the chemotherapy and you're getting a 50% response rate. That's something interesting also to see for this patient population and as you highlighted as safety also, and the adverse event was not high and patients were able to tolerate it, which makes it more doable for us to use it. Dr. Shaalan Beg: Yeah. And one of the challenges in the precision oncology space, which I'm sure you're experiencing in clinic as well, are the real-world applications of precision oncology and the drop-offs that happen that are preventing us from universal precision oncology - meaning the drop-offs that we see on eligible patients receiving the appropriate genomic testing, those who have genomic testing receiving the appropriate treatment. And we've seen a couple of fairly high-profile studies that are describing this in non-small cell lung cancer where the rates are not as encouraging as we would want it to be, which to me, as a physician, makes me worried that there are people out there who we don't know are carrying these mutations or have these mutations, and it hasn't been acted upon.   And related to that, there is an abstract at ASCO23, which is Abstract 3602, that looked at the real-world rates of FDA-approved targeted therapy and immunotherapy for people with metastatic colorectal cancer. They used the VA's National Precision Oncology Program data to study the prevalence of these mutations and how many of the folks ended up receiving the treatment that would be appropriate for those mutations. And this is a very exciting study. They looked at 908 metastatic colorectal cancer patients who underwent genomic profiling, 81% were colon and the rest were rectal. They found that 34% of patients harbored NRAS, KRAS, BRAF mutations, 9.6% were TMB-high, 7.7% had BRAF V600E, and 5.6% were MSI-high, which kind of puts the overall actionable variant prevalence in colon cancer at 47% and for rectal cancer at 44%.  And then they went down to see amongst those 424 eligible patients, how many ended up on appropriate therapy. And these were their numbers: for MSI-high 70%, TMB-high 47%, NRAS, KRAS, BRAF, wild-type 38%, BRAF V600E 17%. So nearly 30% of patients with MSI-high colorectal cancer did not receive immune checkpoint inhibitor therapy, and again, other aspects in terms of EGFR use, and I know that there are other challenges that may affect the use of EGFR inhibitors in colorectal cancer, but it really begs the point on aspects related to implementation science, on getting the testing and acting on those results. And I'm curious to what you're seeing that's being done on these initiatives nationally.  Dr. Mohamed Salem: I totally agree with you, Shaalan. This is a big problem we're facing day in and day out because we struggle to find treatment options for our patients. And I think if we're missing patient with targetable or actionable mutations and we're not utilizing that, I don't think that's a good situation to be in. And I think that's just a group effort. You have to work with the pathologist, you have to work with your team at the clinic. And as an oncologist treating this patient, we have to pay close attention to those markers. And frankly, just look for them. At least  the ones that you know are going to have therapeutic implications.  I do also think patient advocacy has a huge role here and huge opportunities that they can contribute. I am sure you are familiar with the pancreatic study that was published by our colleague Mike Pishvaian in Lancet a year or two ago. I think he named it the Know Your Tumor Type. I think that should be the way forward now, not just for pancreatic but for any cancer. Patients should ask their oncologists what my tumor is. Is it MSI-high, is it KRAS-G12C, is it BRAF? Because it will affect the treatment. I think it's multi-layer and all of us should work in a cohesive manner to be able to not ever miss those markers which carry therapeutic potential.   Dr. Shaalan Beg: So moving on to hepatocellular carcinoma, Dr. George Lau and colleagues, they'll be sharing data from the phase 3 HIMALAYA study with hepatocellular carcinoma in the Annual Meeting that's Abstract 4004. And he looked at outcomes by occurrence of immune-related events for people who received tremelimumab and durvalumab. What are your thoughts on this study?  Dr. Mohamed Salem: This was a very interesting abstract to see. For a long time, we didn't have many treatment options in hepatocellular carcinoma. So, over the last two or three years now, I think we've made nice advancements in the therapeutic landscape. So, we have multiple options including immunotherapy which is very exciting for all of us to be able to utilize those powerful drugs in that disease. The question that comes out is who actually responds? Obviously, in HCC you don't have a lot of biomarkers like the immune therapy biomarkers like MSI-high and PDL-1, and TMB. It isn't really playing a huge role in HCC. So, as you know, the HIMALAYA study is a phase 3 study and examined the STRIDE regimen which is treme plus durva in the first line of patients with metastatic or unresectable HCC against sorafenib. And the outcome was in favor of the STRIDE regimen with improvement in OS response rate and duration of response and because of that, it became one of the standards of care for that disease. But Abstract 4004 is actually asking a very interesting question - whether immune-related adverse events can predict outcomes. Meaning like those patients who experience immune-related adverse events will likely do better compared to those patients who didn't experience immune-related adverse events or not. The idea of adverse events as a biomarker if you will, for efficacy is not new. I mean we saw that back in the renal carcinoma TKI, hypertension. People who had hypertension were more likely to have a better response. In the GI also there was some data suggesting that rash might be a biomarker in predicting response to EGFR. So the same question we're applying here - immune-related adverse events can function as a biomarker for efficacy for the immune system.  And there are some data out there in other tumors that may be the case, but I think at least to my knowledge in the HCC or GI, this was the first study to address that question. So just to remind our audience that the HIMALAYA was a phase 3 study using the STRIDE regimen as a frontline for patients with hepatocellular carcinoma, either unresectable or metastatic disease. And they compared the STRIDE which is durva-treme compared to the standard of care at that time was sorafenib. The primary endpoint was overall survival and they had secondary endpoint duration of response, response rate, and obviously adverse event.  The study was positive, it met its primary endpoint and OS was in favor of the STRIDE regimen compared to sorafenib. But that part of the abstract now is focusing mainly on those patients who had immune therapy and whether that was a STRIDE regimen or the third arm that durva alone treatment. And they're looking at those patients who had immune-related adverse events, and those who didn't have immune-related adverse events. So basically four groups of patients, the patient who had a STRIDE regimen, about 139 patients had immune-related adverse events, and about 249 didn't have immune-related adverse events. For the cohort who had durva alone, about 64 patients had immune-related adverse events, almost 300 patients had no immune-related adverse events.  And it was very interesting that at least in the STRIDE arm, those patients who experienced immune-related adverse events, their outcome was better than those patients who did not have immune-related adverse events. It's the same trend seen on the durva alone arm, but I think the number was very small to make a statistical value out of it. But I think at least in the STRIDE arm there was a suggestive trend toward the outcome of those patients who experienced immune-related adverse events. So I think this is in a way very interesting because we're always wondering if we give the same dose at least in immunotherapy like for everyone.   What I was wondering is if it's too much, too little, or just right. It's hard to know for sure. But perhaps in my opinion and just me trying to understand why, in my theory, maybe that's just an indication of patients receiving enough drugs and effective drugs that will translate into efficacy. But at the same time, I also wanted to just put a word of caution here because we don't want to see side effects as a good thing. I think we want to make sure that us as oncologists treating these patients and patients also don't see like it's good to have a side effect. Side effects associated with especially those grade 3 or 4 can be associated with significant problems and decreased quality of life. So, definitely should be looking at those side effects and be careful interpreting those data. But I think that is very interesting and I will look for more work on that.   Dr. Shaalan Beg: Let's move on to pancreatic cancer. We heard the results of the NAPOLI-3 clinical trial at GI ASCO and this year in ASCO 2023 we will hear the results of Abstract 4006 by Dr. O'Reilly that are presenting results of the 12 and 18-month survival rates from the study that compared NALIRIFOX or nano-liposomal irinotecan, 5-fluoro/leucovorin, and oxaliplatin versus nab-paclitaxel/gemcitabine for newly diagnosed pancreatic cancer patients. I'm interested to hear what you think about that study. Dr. Mohamed Salem: Thank you, Shaalan. So this also is a very exciting abstract to see, and anyone who treats pancreatic cancer patients realizes that, unfortunately, even in 2023, we don't have a lot of treatment options. And yes, I think over the last decade we're now talking about second-line and third-line, but yet we still don't have a lot of treatment options. So, having more options is always good. But the question now is how do you sequence those chemotherapy options? Most of us obviously use FOLFIRINOX in the first line or gemcitabine and paclitaxel in the first line. Until very recently– because we didn't have a head-to-head comparison– we couldn't tell patients for sure if one is better than the other. I think we had some assumptions, but it wasn't really proven. It was just a cross-trial comparison.  So, the fact is that now we have that phase 3 trial looking at liposomal irinotecan, 5-fluoro/leucovorin and the oxaliplatin comparing to nab-paclitaxel/gemcitabine. To me, that was actually very exciting because now, at least, I can see a triplet chemotherapy drug compared to a doublet chemotherapy drug. And as you mentioned, Shaalan, the first initial read was positive in favor of the triplet regimen compared to the doublet, which I think was an important message to give to our colleagues and all of us that if you can, obviously, the triplet comes with side effects, but if you can deliver the triplet, that's perhaps a better starting point for the treatment. But the study here, we're trying to get more read after more mature or more time-lapsing. So the initial study was initial read was positive. And I think this is good to see, too because it translates that even with a longer follow-up, we're still seeing the same benefit. So the OS rate in 12 months for the triplet was about 45% compared to 39.5% for the doublet, and the 18 months, a year and a half, was 26% compared to 19%. So, definitely, you can see an improvement in every single endpoint. OS in general was 11.1 months compared to 9.2 months, and PFS was also in favor of the triplet. So I think it's a message here to reinforce what we saw a few months ago in the initial presentation that, in fact, the triplet is associated with better outcomes if you can safely manage the toxicity and guide the patient through the process. Dr. Shaalan Beg: Well, thank you very much, Mohamed. This was a lot of fun. Thanks for sharing your valuable insights with us on the ASCO Daily News Podcast. Dr. Mohamed Salem: Thank you for having me and looking forward to the full presentation at the meeting. And please, if you haven't registered for the meeting yet, make sure you attend. It's a wonderful opportunity to learn from an expert in the field and also meet your colleagues and make new friends. I also want to take this opportunity to thank the ASCO Daily News Podcast team for taking the time, and also for our colleagues who reviewed these abstracts. This takes a lot of time and effort, and I think they're doing a wonderful job. So, thank you to all of them, and I'll see you all at ASCO.  Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. I'll be back to cover late-breaking abstracts and other key advances in GI oncology after the annual meeting, so please join us for more key insights from ASCO 23 on the ASCO Daily News Podcast.  Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.  Disclaimer:The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Mohamed Salem @SalemGIOncDoc   Follow ASCO on social media: @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg: Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen Speakers' Bureau: Sirtex Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune  Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck

Formerly known as The Property Planner, Buyer and Professor, we've rebranded to The Property Trio. Our listeners who have subscribed to our show don't need to do a thing. Each week's episode will keep landing in your feed.Got a question for the trio? https://zfrmz.com/0S6ddQ7y4WzaE3qX3xZtShow notes: https://propertyplanning.com.au/the-property-professors-memoirs-part-3-ep-199/This is arguably one of the trio's favourite set of episodes. Taking a trip down memory lane was not only a thrilling chat for Pete, but a wonderful way to share some very important learnings with our listeners.Following on from last week's episode 1 where Pete got started on his property journey in 1984, this week's episode introduces listeners to Pete's learnings as he embarked on value-adding to his investments.Episode 1 - Getting Started. It starts back in 1984 when Pete and his wife purchased their first home in High Street, Ardrossan (SA) and spans the the purchase of their first upgrader home, as well as some early value adds and long-term investments that Pete embarked on.Episode 2 - Property Speculation. Pete branched into purchasing value add properties and wised up to other ways that investors can value add, other than gaining a DA.Episode 3 - Property Development and Construction. Pete started building and retaining properties in this particular investment phase. In Episode Two, Dave delves into Pete's 'mid-journey' property acquisitions and upgrades.In the last of these three special episodes, Cate hosts this episode and looks into the various ways that Pete's skillset and experience have enabled him to achieve success and to have choice as he approaches semi-retirement. Episode Three hinges on Pete's growing expertise in relation to subdivision and building."Two equilateral triangles make a square"... Listen in to find out how Pete optimised two sites for development.Pete also touches on his experience post-GFC with his NRAS scheme properties, and the implication of the benefits that have spanned ten years of his investing journey.Cate reflected with Pete about his growing national brand and his achievements over the years. Pete appeared in almost every API magazine, contributed to journalist articles, authored two books; firstly in 2008 and then in 2013, he's continued his studies, maintained his passion in property as an active investor, and in 2013 Pete had what he describes as a 'landmark year'. His Masters of Urban Regional Planning study commenced, he was teaching full time, he managed authoring his book and he was training for a marathon. No small feat indeed."Knowledge is power in many different fields, and it's no different when it's in property."Pete emphasises the need for investors to take action, because time is only a wonderful thing once you're investing. He considers some of the students he's taught and the people who have asked him for help over the years, and he touches on the sad reality that many didn't take action to actualise their goals. Pete's saga about his daughter bidding for him while he was holidaying in Melbourne. While sitting outside a fashion shop waiting for his wife, he trawled the internet on his phone. Recognising a poor listing on the internet that had previously been incorrectly uploaded, Pete set himself the challenge and geared up for an auction (with his daughter's help) in a tiny space of time. It's a wonderful story! Tune in to hear why this particular property caught Pete's eye.Another great project that Pete shares with our listeners relates to a quadrilateral shaped block that one of his students identified, and in fact it's one of his favourite developments. Pete built the townhouses and holds them to this day, retaining them as a key piece of his retirement plan."You don't need to be a genius to do well in property. You just need to know a bit more than the last person".The trio ponder the properties they've sold, the losses they've averted and the reasons why they sold at the time. Pete's sensible words of wisdom shine through as he reminds listeners that sometimes we make decisions that were the right decisions to make *at the time*.To sign off the episode, Pete happily sits in the hot seat and answers Cate and Dave's questions. From his best performer, to his tips for success, this episode can't be missed.And... our gold nuggets!Pete Koulizos, the Property Professor's Gold Nugget: "Surround yourself with like-minded people to help you on your property journey."David Johnston, the Property Planner's Gold Nugget: Dave asked Pete a fantastic, burning question that he wanted to bring to light for the listeners; was Pete's property journey the right journey for *him*?Cate Bakos, the Property Buyer's Gold Nugget: Pete's success can be attributed to his passion, continuous learning and his willingness to take action, but a significant ingredient that Pete had on his side was all about time. He got started early.

A new research paper was published in Oncotarget's Volume 14 on March 24, 2023, entitled, “Polyisoprenylated cysteinyl amide inhibitors deplete singly polyisoprenylated monomeric G-proteins in lung and breast cancer cell lines.” Finding effective therapies against cancers driven by mutant and/or overexpressed hyperactive G-proteins remains an area of active research. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are agents that mimic the essential posttranslational modifications of G-proteins. It is hypothesized that PCAIs work as anticancer agents by disrupting polyisoprenylation-dependent functional interactions of the G-Proteins. In their new study, researchers Nada Tawfeeq, Jassy Mary S. Lazarte, Yonghao Jin, Matthew D. Gregory, and Nazarius S. Lamango from Florida A&M University College of Pharmacy Pharmaceutical Sciences and Imam Abdulrahman bin Faisal University tested this hypothesis by determining the effect of the PCAIs on the levels of RAS and related monomeric G-proteins. “To investigate the hypothesized anticancer mechanisms of the PCAIs through disruption of G-protein function, we checked the effects of the PCAIs on the G-protein levels in lung cancer (A549 and NCI-H1299) and breast cancer (MDA-MB-231 and MDA-MB-468) cell lines.” Following 48 hours of exposure, they found significant decreases in the levels of KRAS, RHOA, RAC1, and CDC42 ranging within 20–66% after NSL-YHJ-2-27 (5 μM) treatment in all four cell lines tested, A549, NCI-H1299, MDA-MB-231, and MDA-MB-468. However, no significant difference was observed on the G-protein, RAB5A. Interestingly, 38 and 44% decreases in the levels of the farnesylated and acylated NRAS were observed in the two breast cancer cell lines, MDA-MB-231, and MDA-MB-468, respectively, while HRAS levels showed a 36% decrease only in MDA-MB-468 cells. Moreover, after PCAIs treatment, migration, and invasion of A549 cells were inhibited by 72 and 70%, respectively while the levels of vinculin and fascin dropped by 33 and 43%, respectively. Their results show that PCAIs deplete the protein levels of some significant G-proteins which are known to be involved in the migration and invasion of cells (i.e., metastasis) such as RAC1, RHOA, and CDC42. These findings implicate the potential role of PCAIs as anticancer agents through their direct interaction with monomeric G-proteins. “The initial findings presented here indicate how PCAIs can be used as potent agents in developing new anticancer therapeutics, therefore, more extensive studies need to be done to elucidate on its potency. Although we cannot conclusively explain the exact mechanism of action of PCAIs on how they affect the levels of some G-proteins yet, but we can say that these PCAIs have the ability to affect the progression of cancer.” Research paper: DOI: https://doi.org/10.18632/oncotarget.28390 Correspondence to: Nazarius S. Lamango - nazarius.lamango@famu.edu Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords: PCAIs, G-proteins, KRAS, RHOA, RAC1 About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

More than 36,000 properties have been part of the National Rental Affordability Scheme since its inception

Today I'm going into some of the questions that are getting asked in our Perth Property Investment Facebook Group and it's going to be interesting! You may not be in the same specific situation, however, what I think is valuable is for you to see my thinking, my strategy, and how I approach decisions. There's potentially a lot to be gained by adapting this process to your situation. That's why I'm sharing and that's why these episodes have been so popular in the past.  I have some juicy questions today! "Should we buy in a certain area we're looking at?" "Can you purchase a property anonymously without the person selling it knowing who you are?"  Also, looking at some sequencing when you're trying to upgrade your home and "Do you keep your property as an investment?"  And some advice as to how I look at that situation when to sell, when to buy, and should you hold.  Then we look at Joondalup as a suburb. Whether it's worth buying an apartment or not.  Going into some of the comparisons between units and houses and how they performed in the past.  We're going into some of the options that a lot of investors weigh up. Buying a newer home or an established property, and the pros and cons of each. Then I'm going over paying off your mortgage VS. investing and paying off a mortgage later.  And finally, I'm covering my thoughts on NRAS properties. And it should be something that you consider when you're looking at investment options.  So let's go inside.   Resource Links: Episode 111: Strategies for Transitioning to Retirement and Greater Passive Income (https://www.youtube.com/watch?v=lfp7fxf1Dus)  Join the Perth Property Investment Facebook Group (https://www.facebook.com/groups/perthpropertyinvestors) Join Jarrad Mahon's Property Investor Update (https://www.investorsedge.com.au/join) For more info on our award-winning and highly rated Property Management services that give you guaranteed peace of mind (https://www.investorsedge.com.au/perth-property-management-specialists/) For more info on how our Property Sales services can ensure you get the best selling price while handling all the stress for you (https://www.investorsedge.com.au/selling-your-perth-property/) Get Jarrad's strategic advice towards your property purchase and development plans (https://www.investorsedge.com.au/invest-in-perth-property/)   Episode Highlights: Intro [00:00] My thoughts about buying in Girraween [03:02] Is It Possible to Purchase a Property Completely Anonymously? [08:38] What's a Bare Trust? [09:46] Consider the change over costs and focus on what is most important [14:21] Should I buy an apartment in Joondalup [17:20] Higher Maintenance is inevitable but worth it [23:05] Stay Away From Buying NRAS properties [27:14] Outro [31:34]   Thank you for tuning in! If you liked this episode, please don't forget to subscribe, tune in, and share this podcast.   Connect with Perth Property Insider: Subscribe on YouTube: https://www.youtube.com/channel/UCgT9-gB6RS69xSgc8J9KrOw Like us on Facebook: https://www.facebook.com/investorsedge See omnystudio.com/listener for privacy information.

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

Renters are at an increasing risk of housing stress in 2023 as Australians face significant rises while thousands of properties are being wiped from an affordable housing scheme. This year more than 6,600 affordable homes will be lost under the scrapped National Rental Affordability Scheme (NRAS) and advocacy groups are asking for a commitment to build more homes. - 住宅支援スキームから数1,000戸の不動産が一掃され、2023年には住居についの借家人のストレスが高まるリスクがあります。放棄されたNRAS、ナショナル・レンタル・アフォーダビリティー・スキームのもとで今年、6,600戸余りの安い住宅がなくなり、支援団体は住宅建設を増やすコミットメントを求めています。

Người đi thuê có nguy cơ gặp căng thẳng về nhà ở ngày càng tăng vào năm 2023, khi người Úc phải đối mặt với sự gia tăng đáng kể, trong khi hàng ngàn bất động sản đang bị xóa sổ khỏi chương trình nhà ở giá rẻ. Năm nay, hơn 6.600 ngôi nhà giá rẻ sẽ bị mất theo Chương trình Quốc gia về Cho thuê Giá cả phải chăng (NRAS) đã bị hủy bỏ và các nhóm vận động đang yêu cầu xây dựng thêm nhà. Các nhóm ủng hộ nhà ở và các dịch vụ cộng đồng đang yêu cầu chính phủ cam kết xây dựng số lượng nhà ở nhiều hơn, so với dự đoán hiện tại.

This week on the Active Self Protection Podcast we sit down with Kendra Hook and discuss the day she was trying to prevent a drunk family member from driving and was attacked for her trouble. Then we sit down with investigative reporter Stephen Gutowski of the reload.com and discuss the NRAs recent ad push ahead of the 2022 mid-term elections. Active Self Protection exists to help good, sane, sober, moral, prudent people in all walks of life to more effectively protect themselves and their loved ones from criminal violence. On the ASP Podcast you will hear the true stories of life or death self defense encounters from the men and women that lived them. If you are interested in the Second Amendment, self defense and defensive firearms use, martial arts or the use of less lethal tools used in the real world to defend life and family, you will find this show riveting. Join host and career federal agent Mike Willever and the rest of the ASP staff as they talk to real life survivors and hear their stories in depth. You'll hear about these incidents and the self defenders from well before the encounter occurred on through the legal and emotional aftermath. Music: bensound.com

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    

El Dr. Jerónimo Rodríguez Cid, oncólogo médico adscrito al Instituto Nacional de Enfermedades Respiratorias en la Ciudad de México, México, junto con la Dra. Florencia Cuadros, oncóloga clínica del Hospital Eva Perón en Rosario, Argentina, nos comentan algunos de los estudios más destacados sobre el tratamiento del melanoma presentados durante el Congreso Anual de ESMO 2022 en París, Francia. Enfermedad temprana SWOG S1801: Estudio fase II, que aleatorizó 1:1 a 313 pacientes con melanomas cutáneos, acrales y mucosos en estadio IIIB-IV (confirmados histológicamente, medibles, clínicamente detectables y resecables) sin metástasis cerebrales, para recibir pembrolizumab como terapia adyuvante (cirugía seguida de 18 dosis del anti-PD-1) o neoadyuvante (3 dosis preoperatorias seguida de cirugía y luego 15 dosis del anti-PD-1). Se permitió la radioterapia después de la cirugía. El objetivo primario fue la supervivencia libre de eventos. IMMUNED: Resultados informados de supervivencia global (SG) del estudio fase II, multicéntrico, aleatorizado 1:1:1, doble ciego, que evalúa el tratamiento de nivolumab adyuvante solo o en combinación con ipilimumab vs. placebo en pacientes ≥18 años con melanoma primario desconocido o cutáneo en estadio IV sin evidencia de enfermedad (los pacientes fueron estratificados por sitio del estudio, sitio de metástasis y estado de PD-L1). El objetivo primario fue supervivencia libre de recaídas en la población con intensión de tratar, el tiempo hasta la progresión, la SG y, como objetivo secundario, la seguridad. Enfermedad avanzada SECOMBIT: Resultados actualizados de SG y una evaluación preliminar de biomarcadores del estudio secuencial, fase II, que aleatorizó a 251 pacientes con melanoma metastásico BRAF V600 no tratado, a tres brazos paralelos: encorafenib + binimetinib como terapia dirigida (brazo A), ipilimumab + nivolumab como inmunoterapia (brazo B) y la estrategia de "sándwich" con la terapia dirigida primero, cambiando a la inmunoterapia después de 8 semanas y volviendo a la terapia dirigida después de la progresión (brazo C). La SG fue el objetivo primario y los secundarios incluyeron la supervivencia libre de progresión total, la tasa de supervivencia a 4 años y una evaluación preliminar de biomarcadores. PIVOT IO 001: Datos de eficacia y seguridad del estudio fase III, aleatorizado 1:1 y abierto que evaluó bempegaldesleukina + nivolumab vs. nivolumab en 783 pacientes con melanoma no tratado previamente, no resecable o metastásico. Los objetivos primarios fueron la tasa de respuesta objetiva, la supervivencia libre de progresión (SLP), ambos por revisión central independiente ciega según RECIST v1.1, y la SG. Abstract LBA40: Estudio fase II, abierto, que aleatorizó a pacientes con melanoma irresecable/metastásico, con mutación BRAF V600 o NRAS, previamente tratado, a recibir múltiples combinaciones del fármaco naporafenib (LXH254). Se exploró la combinación con LTT462 (inhibidor de ERK1/2), con trametinib (inhibidor de MEK1/2) o con ribociclib (inhibidor de CDK4/6). El objetivo primario fue evaluar la eficacia de las combinaciones de naporafenib en función de las tasas de respuesta globales y los objetivos secundarios fueron la seguridad y la tolerabilidad. Abstract LBA3: Estudio fase III, aleatorizado 1:1, multicéntrico y abierto, que evaluó el tratamiento con infiltrado de linfocitos tumorales (TIL, por sus siglas en inglés) vs. ipilimumab, en 168 pacientes con melanoma irresecable en estadio IIIC-IV (86% eran refractarios al tratamiento anti-PD-1). El objetivo primario fue la SLP según RECIST 1.1 y los objetivos secundarios fueron la tasa de respuesta general y completa, la SG y la seguridad. Fecha de grabación: 22 de

La Dra Nuria Gago López forma parte del Grupo de Investigación sobre el Melanoma del Centro Nacional de Investigaciones Oncológicas (CNIO), Grupo dirigido por la Dra. Marisol Soengas. El melanoma es el tumor de piel más letal que existe y tiene una intensa relación con la exposición solar, habiendo aumentado en su incidencia en los últimos años. A pesar de su gravedad, este tumor puede ser curable si es diagnosticado y tratado en fases iniciales. Incluso en casos avanzados con metástasis, nuevos tratamientos de inmunoterapias y terapias dirigidas, han aumentado mucho la supervivencia de los pacientes. Estos avances se deben en gran parte a investigaciones y avances tecnológicos como la secuenciación del DNA tumoral, que ha permitido conocer las mutaciones que aparecen en este tumor, cómo se va desarrollando y como el organismo se defiende frente a las células tumorales del melanoma. En este episodio la Dra. Gago nos explica los cambios iniciales (mutaciones) que se han descubierto y que son las responsables de que una celula melanocítica normal se transforma en una célula cancerosa que comienza a proliferar de forma descontrolada dando lugar al melanoma, tumor que tiene gran avidez para diseminarse a otras partes del organismo. Con la Dra Nuria Gago charlamos tambien sobre la investigación en España y el papel de la mujer en la ciencia española. 00:00 Mis inicios. Tesis Doctoral Ander Izeta. USA Cardiologia Macllelan 04:00 CNIO. Psoriasis. Erwin Wagner. Grupo de Melanoma. Marisol Soengas 06:00 Melanoma: Introducción. Daño solar en el DNA del melanocito 09:30 Melanocitos en Folículos Pilosos. Melanoma cuero cabelludo. 14:30 Mutaciones. Clasificación molecular del Melanoma. BRAF, NRAS, NF1 24:30 El Sol como causa del cancer de piel 27:30 Los lunares (nevus) también tienen mutaciones. Melanocitos senescentes. 31:30 Estadios iniciales del Melanoma. Estrategias de estudio. 39:00 Microambiente. Sistema inmunológico. Neoantígenos. 45:00 Inmunoterapia. Proteinas PD1 y CTLA4. 49:30 Por que el melanoma metastatiza tanto y respuestas a la Inmunoterapia 53:00 Reflexiones sobre la Investigación en España y extranjero 58: 00 Hay que mejorar relación entre Centros de Investigación y la Universidad 1:02:00 Consejo al Investigador novel. 1:04:00 Hay que divulgar la ciencia. 1:06:00 La mujer y la Ciencia en España. Escasez en puestos directivos. 1:11:30 Mis aficiones: pintura y familia 1:12:30 Libros: Por mil millones de dólares. Vazquez-Figueroa 1:16:30 Países para viajar: España. Costa Californiana.

Nonprofit news: In Wake Of Uvalde School Shooting, Gun Rights Advocacy Groups Fill Void Left By NRA   On May 24 a gunman opened fire at Robb Elementary School in Uvalde, Texas killing 19 students, two teachers, and wounding 17 others. The horrific shooting has rekindled the decades-long debate in the United States between gun control and gun rights advocates. Within economically developed countries, the United States by far outnumbers other countries in terms of both gun ownership and gun deaths per capita. Among gun rights advocacy groups, however, the infighting and reputationally-damaged NRA has provided an opportunity for other organizations (many tax-exempt) to fill the void, according to reporting from The Washington Post. The National Association for Gun Rights, a 501(c)4 group that often criticizes the NRA for being too compromising, saw revenue increase to $15 million, up from $6 million in 2019. Other gun rights groups have seen similar increases in revenue and capacity. Read more ➝ Summary Nonprofit Begins Tracking Anti-Asian Hate Crimes in the Midwest | NBC Chicago Nonprofits Fighting Gender Violence Have Struggled Since Losing Buffetts' Funding. They Urgently Need More Support. | The Chronicle of Philanthropy Coloradans asked to take water conservation pledge | 9News.com KUSA Tax breaks aren't prime reason for high-net-worth philanthropy, study finds | CNBC  Nonprofit keeps taps Memorial Day tradition alive | Military | kdhnews.com | The Killeen Daily Herald   Rough Transcript:   [00:00:00] George: This week on the nonprofit news feed we have got in the wake of the Uvalde, the school shooting information about how gun rights advocacy is actually increasing for some nonprofits and a number of other summary articles. Following coming after, uh, this Memorial day weekend, NEC. [00:00:21] Nick: It's going good, George. We have a lot to cover this week. Of course, the first story we're going to talk about is. Uh, around what happened in your Uvalde and better conversations about gun rights and gun control advocacy groups. So last week on May 24th government opened fire the Robb elementary school in , Texas killing 19 students to teachers. [00:00:46] And wounding 17 others. And this terrific shooting has rekindled a decades long debate in the United States between gun control and gun rights advocates. Uh, now within economically developed countries, the United States by far outnumbers others in terms of both gun ownership and gun deaths per capita. [00:01:06] Um, but along the debate about how to solve. You have gun rights, advocacy groups on one side and gun control advocacy groups on the other. Uh, we wanted to highlight an article from the Washington post, which is talking about a little bit of the landscape change on the side of the gun rights advocacy groups. [00:01:30] We've talked about those on this podcast before how the NRA has suffered from lots of infighting and legal challenges. As a whole has seen its reputation damage quite significantly over the past couple of years. Um, but as the Washington post points out, a lot of other tax exempt organizations now seem to be filling the void, um, and potentially taking the lead on the gun rights. [00:01:59] Side of the issue here. The national association for gun rights is a 5 0 1 C4 group that often criticizes the NRA for being too compromising saw revenue increase to 15 million up from just 6 million in 2019 on the article sites that lots of other gun rights groups have seen similar increases in revenue and capacity. [00:02:25] So the takeaway here is that what was. Very consolidated. Uh, landscape in terms of advocacy with one go-to group is now splintering and other groups are taking the place, uh, and serving the role once filled by the NRA. But George, this comes as the NRA held its annual conference in Texas, just three days after the shooting. [00:02:51] Um, this conference was on last Friday and it's a fraught moment in the United States. And, um, You know, personally, I think that that gun control and gun safety needs to be acted upon and legislative upon. And unfortunately that were happened, but interesting, nonetheless, to see the landscape on the gun rights side, change in pretty significant. [00:03:12] George: Yeah, it's sort of inevitable the thought that tamping down the NRAS ability to sort of fundraise and operate effectively to assume that that would stop. The progress of guns in this country. And it's unbelievable power in terms of putting money into politics is, is errand, right? It is. It's sort of targeting your energy at the, the wrong enemy because like a hydro, when you cut off its head to more show up in its place, inevitably the source of the money is not going away. [00:03:51] The amount of guns purchased after an event like this inevitably increases, and that simply puts more money in the hands of manufacturers, which then finds its way inevitably into any functioning non-profit willing to carry the flag of, of gun rights over human. And so, you know, in a moment like this, there's a, you know, a rare opportunity to get the country's attention and to focus on something. [00:04:18] I am having a hard time finding faith in Congress that immediately chose the bold action of going on vacation and leadership that has just polar polar views. Interesting narratives that I've seen coming out here are, is around the fact that we actually had a ban on assault. Right. Had a band. And if you look at the number of mass shootings prior to 2004, when it went out of the fact where he was put into place in 1994, by president than bill Clinton, the number of mass shootings go up. [00:04:52] The question that is just hard to reconcile is why, you know, 18 year olds or frankly anyone needs access to high capacity, uh, firearms, if not to kill it. It makes zero sense other than to line the pockets of [00:05:08] these manufacturers under this like misconceived notion of the right to bear arms and it's absurd extent, you know, why, why draw the line of dissolves? Shouldn't we all have, uh, you know, explosives, why am I put on Dara's watchlist? If I buy a extreme amounts of. It's because you have intent to do harm to large amounts of people. [00:05:32] There are potential solutions being talked about that that could work. And you mentioned the sort of larger fact of how America has more guns than other countries. You said, uh, a lot more though, you know, and I think it's important to note that our, our guns, our guns per a hundred people are 120 guns per people. [00:05:52] The next closest is Candace at 34 guns for people. You know that there are more guns than there are people here. Um, and somehow we continue to purchase more. And then that inevitably leads to gun murders per a hundred thousand, which is 30 times worse than Australia's. And a number of times worse than Canada's we're at 3.4 deaths per and Canada is at 0.6. [00:06:14] So, you know, I think what needs to happen differently this time than the last time we had a tragedy. This magnitude, which was Sally and, you know, Sandy hook, December of 2012 is a reasonable step forward. It's easy to respond extreme to extreme, but I think you, what I'm saying, you, I think. Progressive legislators advocates. [00:06:43] Non-profits people speaking to this need to couch, the anger and rage and focus on small wins, which feels just painful to say, but small wins and steps toward reasonable controls on. Anywhere that you can gain this, and I'm not going to list the number of policies out there, but there are areas where Americans all can agree and should agree. [00:07:08] So I think I'm, I'm being a sort of moderate in my expectation, uh, and also analyzing some Google trends and seeing. That so far, we actually haven't hit the overall searches search volume that we saw about a decade ago. Um, in 2013, far from it, in terms of Google trends, searches for gun control as a topic. [00:07:30] So I haven't seen it take off as high as it probably needs to, to actually move the needle. And again, Congress going on a brave vacation. During this time, uh, is going to slow any potential policy. So the question is for, for how long can the state in the media narrative and hopefully not get taken over also by a counter narrative, which is going to be incredibly attractive to take, which is why the sheriff overseeing this, uh, this, this tragedy chose to wait for. [00:08:06] Over 15 minutes to take action. And that's, that's not the point. The point is there's an 18 year old who needed medical help and instead he got help from a local gun store. [00:08:17] Nick: I definitely agree with you. I think to your point for too long folks on the side of the policy debate about wanting stricter gun control have propped up the NRA as this kind of buggy man. But the truth of the matter is. Is ideological divide in this country. And there are a lot of people who repeatedly vote in candidates who are. [00:08:45] Pro gun. And that, that ideological messaging on the right is, is extreme. And I think it's beyond just money and lobbyist. It's a genuine ideological, perhaps demagogues, but it's an ideological difference. And I think that for folks who are looking for solutions need to understand that it's not just countering dark money and politics, it's actually. [00:09:09] Changing minds and having those debates and meeting people where they're at to your point about small wins. Um, but something, something we'll continue to watch. And unfortunately I'm not super hopeful as well, but that being said, um, you have to try and, and we'll keep trying. And this year we have a chance to try again. [00:09:33] So, uh, something, a story and a narrative will continue to be. [00:09:37] All right, shifting gears a little bit. I can take us into the summary. This one comes from NBC in Chicago, and it's about a nonprofit beginning to track anti Asian hate crimes in the Midwest. So over the course of the pandemic, uh, organizations that track statistics of, um, Uh, hate crimes against Asian Americans have seen in over 300% increase. [00:10:03] And this particular organization that Asian American foundation is setting up a program to track hate crimes and AAPI violence while providing legal and other support to victims. Um, To build trust, um, and break down barriers with communities, particularly immigrant communities or non native English speaking communities, um, to, to help these folks feel supported in a time where unfortunately, they're seeing a surge in violence against them. [00:10:33] And I live in New York and there's been really tragically high profile, um, hate crimes against. Asian folks in the New York city area. So there's just something that's, that's very close to us. And I know a lot of here, all of us here at Holwell. So, um, just awesome. Worked from a nonprofit, stepping up to fill that dough, that void when it comes to data and reporting, and that is hugely important when it comes to creating policy decisions and other sorts of interventions to address such violence. [00:11:05] George: Yeah, I think it's important that. Sir, not the qualitative, but the quantitative on this one, trying to document and get the data of what's going on. So you can really understand the scope of the problem. There's one thing to say, one-off events and like it's easy then for the public to say, oh yeah, but that's just like one lone actor as opposed to the larger incidents going up. [00:11:28] So yeah, I like this. [00:11:30] Nick: Okay. All right. Our next story is interesting one, and this comes from the Chronicle of falling anthropy and it talks about how the buffets, um, have stopped funding programs that support women and girls, particularly in the United States. So this article talks about, um, the foundation, um, the, the Novo foundation. [00:11:55] Uh, quote unquote stunned the nonprofit world by announced thing at the height of the pandemic, that it was halting funding for critical programs, focused on women and girls. And the article goes on to talk with some of the, uh, uh, grant recipient organizations that have been on the receipt had been on the receiving end of such funding, seeing it suddenly dry off. [00:12:17] And, uh, the, the, the TLDR of this article is. When it comes to corporate philanthropy, single similarly split second decisions can have really lasting and unfortunate ramifications. And, uh, the article kind of goes on to talk about the need for organizations to diversify funding, which is of course easier said than done. [00:12:40] Um, but George, what's your take on this? [00:12:42] George: No, we covered the Nova foundation out and shift, and this is just the second order or logical next order effect of that, where, you know, the Nova foundation accounted for or reported 96% of funding for that type of work. And it's. It's it's unfortunate because it does then a cliff and raises questions about, you know, was this? [00:13:04] you know, especially if they're trying to turn long-term impact, it's hard to do when your funding can drive overnight. [00:13:09] So, you know, we'll call for much more responsible philanthropy and just, just a warning for anyone who's funding relies heavily 70%, 50% more on one story. [00:13:19] Nick: All right. Our next story comes from nine news.com K USA. And it's about Coloradans being asked to take a water conservation pledge. This is kind of a cool one. It's called the water 22 pledge, and it includes 22 ways for every Coloradan to save 22 gallons of water every day. And according to this nifty infographic, um, Each Colorado and saves 22 gallons per day. [00:13:49] That's 8,000 gallons per year, or approximately 48 billion gallons per year for the statewide. So, uh, this of course addressing the, some, uh, climate concerns around, uh, drought and lack of, uh, clean water, um, and, and really, really dangerously low water levels out there. Um, so, uh, I love it. I love this, this kind of educational approach to addressing environmental impacts. [00:14:19] And of course it takes much more than that, but the fact that this is just one kind of component of that I think is really cool and something we're going to need a hell of a lot more of as we start and continue to tackle the climate crisis. [00:14:33] George: Yeah. I like stories like these sort of, non-profits stepping up for water crises, which are absolutely going to happen across the west Midwest. This. Based on what they're reporting. I think those, those points are incredibly important, but the practical environmental scientist. That I once potentially wanted to be in, in college, uh, has to also point to the fact that in terms of water consumption, agricultural water use is 89% of Colorado state wide usage. [00:15:07] So, you know, the, the individuals, you know, cutting back certainly helps, but I think there's also a lot of room for improved farming practices and, uh, smart irrigation systems that can save quite a bit more if we're just being. Logical about it. So, you know, I, I see stories like this. I'm excited about citizens getting in there, but I hope it doesn't stop there. [00:15:28] And also, you know, allocates for more intelligent, more intelligent ways to save. [00:15:33] Nick: Absolutely. Our next story is from CNBC and it says the tax breaks. Aren't the prime reason for high net worth philanthropy or. So the study conducted by BNI, BNY Mellon wealth management asserts that in fact, tax benefits are not the primary reason that people donate to charity, um, including, um, hyper wealthy people. [00:16:03] Um, and the top reasons for charitable giving include they're donated to a special cause they wanted to see impact they, or they want to give back or increase their legacy. Um, so. Maybe the folks who are a little bit too cynical about, uh, charitable giving. So take a look at this and, and of course, you know, there's exceptions well, um, but it restores your faith a little bit, and it talks about interestingly and perhaps more importantly trends amongst younger people, millennials and gen Z while still building up. [00:16:37] For, as you talk a lot about the greatest wealth transfer in history is about to come our way, um, increasing trends in terms of young people, uh, donating and caring about, uh, social. [00:16:49] George: Yeah, quoting here. The younger generations are more charitably inclined and they care more about impact and nearly three quarters of high net worth millennials and eight and 10. Gen X-ers investors have a charitable giving strategy according to this report. And I think it's important to note that the, the rising generation and the rising generation of frankly, a million multi-millionaires seem to have that type of lens and probably parked under the effective philanthropy, uh, effective philanthropy, effective altruist type of mantra, where they, you know, the care of where the dollars go in terms of trackable impact into causes and issues that serve a greater. [00:17:28] Systemic solution. I would say, uh, also, you know, notably people like, um, one of the youngest, uh, new billionaires out there in crypto sandbank, then freed is also said to be making money so that he can spend money aggressively, uh, in, um, in his work. And it's a good trend to be aware of as some, you know, one large donor can, can make a, quite, quite a difference, especially as how. [00:17:57] Craft your, your narratives and communications to your general audience, because inevitably there are probably a power law dynamic of 1% of that audience has 99% of the wealth. [00:18:08] Nick: Definitely that's a great analysis and something, I guess we'll see, play out over time, but toward time out, I feel good story to finish. [00:18:18] George: Um, [00:18:19] Nick: All right. This comes from KTH news.com, Kilian daily Herald, and it's about a nonprofit keeping them Memorial day, traditional Latifah playing taps. The Mecca Ts multi educational cross-cultural arts of central Texas is a nonprofit organization dedicated to educating and spreading the awareness of cultural music and dance gathered to play taps. [00:18:46] Veterans grades and honor of their service and sacrifice this Memorial day. And it talks about Mecca Tech's leader and retired us army criminal, Daniel , who was 90, who began this year's remembrance at the grave of his friend. Um, another former board member of this nonprofit retired Sergeant first class Jose land does. [00:19:07] So, uh, music can be an important and valuable way to serve. That part of our life journey and, uh, recognizing, um, friends fallen and war celebrating life morning life and just overall expression. Um, he's like, it's really important to me and I know to a lot of other people, and this is great to see a nonprofit, uh, using it to pay their respects this Memorial day. [00:19:38] George: Beautiful way to remember people that have given the ultimate sacrifice for the freedoms that we enjoy. And so yes, to, to the veterans and to the people that are remembering Memorial day, uh, it's much appreciated and like to see non-profits involved in, in keeping these types of traditions alive. Thanks, Nick. [00:19:59] Nick: Thanks, George.  

Morse code transcription: vvv vvv How to Murder Your Husband author Nancy Crampton Brophy guilty of hubbys murder Advancing Russian forces reach key highway out of Donbas cities Power of Trumps Endorsements Dims in Governor Races Texas shooting Gunman posted just before deadly US school attack Ukraine war latest news Fighting rages in east of Ukraine Oklahoma governor signs into law strictest abortion ban in the U.S. Ukraine war World Bank boss warns over global recession Kate Moss Johnny Depp never pushed or kicked me How Texas shooter bought guns, hatched sinister plans Texas shooting Where does US gun control go from here How two Texas newspapers broke open the Southern Baptist sex scandal Orphaned elk calf rescued by Montana crew battling NM wildfire KRTV NEWS New BBC film shows the Queens unseen family videos This is Us stars bid farewell with final flashbacks Severodonetsk Battle for key road as fighting reaches Ukraine city Texas shooting Uvalde tragedy opens painful memories for Sandy Hook parents Partygate PM says he will not resign following Sue Gray report Analysis Donald Trump had a rough night in Georgia What to know about the NRAs annual meeting in Houston After Texas school shooting, teachers weigh in on how to stop the violence

Morse code transcription: vvv vvv Advancing Russian forces reach key highway out of Donbas cities Texas shooting Gunman posted just before deadly US school attack Ukraine war latest news Fighting rages in east of Ukraine Orphaned elk calf rescued by Montana crew battling NM wildfire KRTV NEWS Ukraine war World Bank boss warns over global recession Partygate PM says he will not resign following Sue Gray report Kate Moss Johnny Depp never pushed or kicked me Oklahoma governor signs into law strictest abortion ban in the U.S. How to Murder Your Husband author Nancy Crampton Brophy guilty of hubbys murder How Texas shooter bought guns, hatched sinister plans What to know about the NRAs annual meeting in Houston This is Us stars bid farewell with final flashbacks Severodonetsk Battle for key road as fighting reaches Ukraine city After Texas school shooting, teachers weigh in on how to stop the violence Power of Trumps Endorsements Dims in Governor Races Texas shooting Uvalde tragedy opens painful memories for Sandy Hook parents New BBC film shows the Queens unseen family videos Texas shooting Where does US gun control go from here How two Texas newspapers broke open the Southern Baptist sex scandal Analysis Donald Trump had a rough night in Georgia

Morse code transcription: vvv vvv Kate Moss Johnny Depp never pushed or kicked me Texas shooting Where does US gun control go from here Power of Trumps Endorsements Dims in Governor Races Advancing Russian forces reach key highway out of Donbas cities Orphaned elk calf rescued by Montana crew battling NM wildfire KRTV NEWS How two Texas newspapers broke open the Southern Baptist sex scandal How Texas shooter bought guns, hatched sinister plans Texas shooting Uvalde tragedy opens painful memories for Sandy Hook parents Texas shooting Gunman posted just before deadly US school attack This is Us stars bid farewell with final flashbacks Severodonetsk Battle for key road as fighting reaches Ukraine city Oklahoma governor signs into law strictest abortion ban in the U.S. Partygate PM says he will not resign following Sue Gray report What to know about the NRAs annual meeting in Houston Analysis Donald Trump had a rough night in Georgia New BBC film shows the Queens unseen family videos Ukraine war latest news Fighting rages in east of Ukraine Ukraine war World Bank boss warns over global recession How to Murder Your Husband author Nancy Crampton Brophy guilty of hubbys murder After Texas school shooting, teachers weigh in on how to stop the violence

Morse code transcription: vvv vvv Severodonetsk Battle for key road as fighting reaches Ukraine city Sue Gray report Drunken No 10 party culture in lockdown laid bare Trump Said to Have Reacted Approvingly to Jan. 6 Chants About Hanging Pence This is on you Beto ORourke confronts Abbott, Cruz at Texas school shooting press conference What to know about the NRAs annual meeting in Houston Nancy Brophy, romance novelist who wrote How to Murder Your Husband, found guilty of murder 4 years after chef spouse found dead in kitchen Josh Duggar sentenced to 12 years in federal prison for child pornography conviction Michigan Republicans block votes on gun storage, background check bills after Texas shooting Brad Raffensperger defied Trump. Georgia voters rewarded him for it. Texas shooting Americas gun control debate that never goes away Rep. Paul Gosar tweets, then deletes, unsubstantiated speculation about Texas shooter Texas school shooting Biden makes emotional plea as victims of Texas shooting named Kate Moss Johnny Depp never pushed or kicked me Georgia primaries Trump backed Perdue trounced by Pences chosen Texas school shooting live updates Gunman sent Facebook messages before shooting North Korea fires missiles hours after Biden leaves Asia Anguished Father Says 10 Year Old Was Always Smiling Police injured as Roma fans deported from Albania Burkina Faso missing miners Four dead bodies found Volkswagen to pay out 193m in dieselgate settlement

Morse code transcription: vvv vvv Michigan Republicans block votes on gun storage, background check bills after Texas shooting Volkswagen to pay out 193m in dieselgate settlement What to know about the NRAs annual meeting in Houston Kate Moss Johnny Depp never pushed or kicked me Severodonetsk Battle for key road as fighting reaches Ukraine city Nancy Brophy, romance novelist who wrote How to Murder Your Husband, found guilty of murder 4 years after chef spouse found dead in kitchen Rep. Paul Gosar tweets, then deletes, unsubstantiated speculation about Texas shooter Trump Said to Have Reacted Approvingly to Jan. 6 Chants About Hanging Pence Texas shooting Americas gun control debate that never goes away Georgia primaries Trump backed Perdue trounced by Pences chosen Texas school shooting Biden makes emotional plea as victims of Texas shooting named Brad Raffensperger defied Trump. Georgia voters rewarded him for it. Anguished Father Says 10 Year Old Was Always Smiling North Korea fires missiles hours after Biden leaves Asia Police injured as Roma fans deported from Albania Burkina Faso missing miners Four dead bodies found Sue Gray report Drunken No 10 party culture in lockdown laid bare Texas school shooting live updates Gunman sent Facebook messages before shooting Josh Duggar sentenced to 12 years in federal prison for child pornography conviction This is on you Beto ORourke confronts Abbott, Cruz at Texas school shooting press conference

Morse code transcription: vvv vvv Trump Said to Have Reacted Approvingly to Jan. 6 Chants About Hanging Pence This is on you Beto ORourke confronts Abbott, Cruz at Texas school shooting press conference Texas school shooting live updates Gunman sent Facebook messages before shooting Michigan Republicans block votes on gun storage, background check bills after Texas shooting Nancy Brophy, romance novelist who wrote How to Murder Your Husband, found guilty of murder 4 years after chef spouse found dead in kitchen Volkswagen to pay out 193m in dieselgate settlement Texas shooting Americas gun control debate that never goes away Severodonetsk Battle for key road as fighting reaches Ukraine city Texas school shooting Biden makes emotional plea as victims of Texas shooting named Burkina Faso missing miners Four dead bodies found Brad Raffensperger defied Trump. Georgia voters rewarded him for it. Sue Gray report Drunken No 10 party culture in lockdown laid bare What to know about the NRAs annual meeting in Houston Rep. Paul Gosar tweets, then deletes, unsubstantiated speculation about Texas shooter Kate Moss Johnny Depp never pushed or kicked me Josh Duggar sentenced to 12 years in federal prison for child pornography conviction Police injured as Roma fans deported from Albania Georgia primaries Trump backed Perdue trounced by Pences chosen North Korea fires missiles hours after Biden leaves Asia Anguished Father Says 10 Year Old Was Always Smiling

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. David M. Gershenson to discuss the use of trametinib in low-grade serous cancer. Dr. Gershenson is Professor and former Chair of the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. His major focus is on the clinical and translational research of rare ovarian cancers. Highlights: Trametinib represents a new standard for the treatment of recurrent low-grade serous carcinoma of the ovary/peritoneum. The findings of GOG 281 suggest that women whose tumor harbors a MAPK mutation (KRAS, NRAS, BRAF) may have a greater probability of response to trametinib, but the results are hypothesis-generating, and further studies are needed. Importantly, trametinib should not be withheld from a woman whose tumor lacks MAPK mutations. Based on the findings of GOG 281 and preclinical studies, future trials will include combinations of a MEK inhibitor plus endocrine therapy and novel agents targeting the MAPK signaling pathway or, more specifically, RAS.

Have you thought about the cost of your rent and wondered if there was a cheaper option? The national rental affordability scheme (NRAS) was designed to help low to middle income earners get into the rental market below the market value. Azaria breaks down

Charlie Shufeldt - CEO of Elk Range Royalties recently came onto the podcast to discuss his team's portfolio & acquisition criteria as well as their latest transaction in the Permian, which included 2,000+ NRAs in the core of the Midland & Delaware Basins.

In this podcast episode, Jeffrey S. Weber, MD, PhD; Allison Betof Warner, MD, PhD; and Hussein Tawbi, MD, PhD, discuss recent key data on adjuvant and neoadjuvant therapy and review the latest evidence on therapies for metastatic disease.Link to full program:https://bit.ly/3ogPjMoFollow along with the downloadable slideset:https://bit.ly/2XYNIztPresenters:  Jeffrey S. Weber, MD, PhDDeputy DirectorLaura and Isaac Perlmutter Cancer CenterNYU Langone HealthProfessor of MedicineNYU Grossman School of MedicineNew York, New YorkAllison Betof Warner, MD, PhDAssistant MemberAssistant Attending PhysicianMelanoma ServiceDivision of Solid Tumor OncologyDepartment of MedicineMemorial Sloan Kettering Cancer CenterNew York, New YorkHussein Tawbi, MD, PhDProfessorDepartment of Melanoma Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, Texas 

In this episode of our podcast series about Rheumatoid Arthritis, Mel Brooke, Patient and Public Engagement Programme Director (BIRD) invites Clare Jacklin, Chief Executive of NRAS (National Rheumatoid Arthritis Society) to share an update on their work and campaigns. Did you know you can access all our information podcasts direct from BIRDs website? Simply visit www.birdbath.org.uk/podcasts and scroll down the page to find the one you are looking for. For links mentioned in the podcast you can also visit: NRAS (National Rheumatoid Arthritis Society) and the JIA NRAS website Please note: All content for BIRD's PPE podcasts are created for information purposes only and not intended to be a substitute for individual medical advice, diagnosis, or treatment. Always seek the advice of your physician or health provider with any questions you may have about your medical condition. Reliance on any information provided by BIRD or any of the expert podcast guests is solely at your own risk. Please sign up to our mailing list if you would like to stay in touch and be notified about future podcasts via admin@birdbath.org.uk The Patient and Public Engagement Programme is supported by a hands-off sponsorship from Eli Lilly and Company Limited who have no involvement in the development or running of the programme. This podcast is supported by Healthwatch Bath and North East Somerset and UCB - both of who have no editorial control on the contents. To find out more about BIRD and the PPE Programme visit: The Bath Institute for Rheumatic Diseases

Melanoma Update, Issue 1, 2021 — Part 2: Our interview with Dr Lewis highlights the following topics as well as cases from his practice: Approved and investigational strategies for patients with metastatic melanoma (0:00) Case: A man in his late 70s with metastatic melanoma and an NRAS mutation who receives stereotactic radiosurgery and single-agent pembrolizumab (27:41) Case: A woman in her early 60s with metastatic melanoma and a BRAF V600 mutation who receives encorafenib and binimetinib as first-line therapy (31:04) Case: A man in his early 50s with metastatic melanoma and a BRAF V600 mutation (33:45) Therapeutic options for patients with metastatic melanoma in the first-line setting (37:45) Results and clinical implications of the Phase III IMspire150 trial of atezolizumab in combination with cobimetinib and vemurafenib for previously untreated advanced melanoma with a BRAF V600 mutation (44:25) Mechanism of action and activity of bempegaldesleukin in combination with an immune checkpoint inhibitor; rationale for the investigation of TILs for metastatic melanoma (50:16) Emerging data with pembrolizumab/lenvatinib for patients with advanced melanoma whose disease has progressed on an anti-PD-1/PD-L1 antibody (56:06) Choice of therapy for patients with BRAF wild-type metastatic melanoma (59:43) Activity and tolerability of ipilimumab/nivolumab for advanced melanoma (1:03:48) Selection and sequencing of therapy for patients with metastatic melanoma and BRAF mutations (1:08:12) Therapeutic approach to metastatic melanoma with a BRAF mutation and a high disease burden (1:11:36) Efficacy and side-effect profile of BRAF/MEK inhibitor combinations (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) for metastatic melanoma with a BRAF mutation (1:15:39) CME information and select publications

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391029v1?rss=1 Authors: Covell, D. G. Abstract: A joint analysis of NCI60 small molecule screening data, their genetically defective genes and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-organizing-maps (SOMs) are used to organize the chemosensitivity data. Students t-tests are used to identify SOM clusters with chemosensitivity for tumor cells harboring genetically defective genes. Fishers exact tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. This analysis may contribute towards the goals of cancer drug discovery, development decision making, and explanation of mechanisms. Copy rights belong to original authors. Visit the link for more info

Featuring a discussion on recent clinical trial data on the use of FLT3 inhibitors in the management of acute myeloid leukemia with Dr Keith Pratz, including the following topics: Targeting FLT3 in Acute Myeloid Leukemia (AML) — Keith W Pratz, MD (0:00) Case: A man in his late 50s with AML and a FLT3-ITD mutation receives midostaurin and 7 + 3 chemotherapy followed by an allogeneic transplant and maintenance sorafenib (23:52) Case: A woman in her late 60s with hypertension and diabetes is diagnosed with AML and FLT3-ITD, IDH2, NPM1 and NRAS mutations (25:41) Case: A woman in her early 80s with AML with FLT3-TKD and NPM1 mutations receives single-agent gilteritinib (27:52) CME information and select publications

Volume 11 Issue 25 of @Oncotarget reported that this study aimed to define the mutation profile of SUM in Caucasians. Next-generation sequencing-based genomic analysis was used to identify frequently mutated loci in 50 cancer-related genes in 31 SUM primary tumors. The most abundant mutations in SUM were found in KIT – in 13% of cases and NRAS – also in 13%, while BRAF - only in 3% of cases. The authors' findings confirmed a high frequency of KIT and NRAS mutations in SUM, as well as a low incidence of BRAF mutations. They reported novel KRAS, CTNNB1, TP53, ERBB2, and SMAD4 mutations in SUM. Dr. Aneta Borkowska from The Maria Sklodowska-Curie National Research Institute of Oncology said "Across all human cancers, cutaneous malignant melanoma (MM) genome has one of the highest prevalence of somatic mutations." At the same time, NRAS mutations are detected in approximately 20% of MM and are more commonly reported in melanomas developing in the skin with chronic sun exposure. WHO Classification of Skin Tumours recognizes the most common acral melanoma histotype is acral lentiginous melanoma, followed by nodular cutaneous melanoma and superficial spreading melanoma. Cutaneous MM located on the acral part of extremities - hand and foot melanoma - comprises a rare group within all melanomas in Caucasians. Whole-genome sequencing study shown that structural changes and mutational signature of acral melanomas were dominated by different than other MMs sites. SUM seems to be not related to sun exposure, however, in Australian Melanoma Genome Project UVR signatures on acral melanomas occurred most frequently in subungual parts. The Borkowska Research Team concluded in their Oncotarget Research Paper, "Our study offers new insights into the genetics SUM subtype, for understanding pathogenesis and providing potential biomarkers for future studies. Molecular testing is now widely used in patients with advanced melanoma in the process of therapeutic decisions. Mutations reported in melanoma cells provide starting points for the development of the rational design of novel therapies, including immunotherapy agents. They also may provide to find the molecular pathogenesis and natural history of subtypes of this heterogeneous disease. We confirmed that SUM have different than other cutaneous melanomas genetic profile, which due to its rareness and lack of studies should be subjected to further analyzes in multicenter studies." Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27642 Full text - https://www.oncotarget.com/article/27642/text/ Correspondence to - Aneta Borkowska - anetame@gmail.com Keywords - melanoma, acral melanoma, subungual melanoma, nail apparatus melanoma, SMAD4 About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

PRESS RELEASE: Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study The cover for issue 5 of Oncotarget features Figure 2, "Survival curves in the KRAS, EGFR, and niche mutations cohorts," by Aramini, et al. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that: Niche mutations had higher mortality than EGFR mutations KRAS mutations had higher mortality than EGFR mutations, and Niche mutations presented similar mortality to KRAS mutations. Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations. Dr. Beatrice Aramini from the Division of Thoracic Surgery in Department of Medical and Surgical Sciences at the University of Modena and Reggio Emilia in Modena Italy said in their Oncotarget Research Paper, "In the last century, carcinoma of the lung has progressed from an uncommon and obscure disease to the most common cancer in the world, and the most common cause of death from cancer." In addition to these somatic mutations, which are the most frequent, other mutations in several genes have been discovered, including BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations. Moreover, the prevalence of the RET mutation in adenocarcinoma was estimated to be 1.7%, and the prevalence of DDR2 mutation in lung cancer was 2.2%. With regard to treatment, discoveries of gene mutations have allowed the development of targeted therapies, which are considered more effective for survival than chemotherapy in patients with advanced mutated disease. Considering the potential aggressiveness of niche mutations in this context, the technological advances of next-generation sequencing, which is currently used in clinical practice, represents a precise approach to identifying a large panel of mutations in oncologic patients. The Armini Research Team concluded, "The correct selection of mutations will be helpful in terms of the greater efficacy of treatment in association with better prognosis and a higher quality of life for oncologic patients." Full text - https://doi.org/10.18632/oncotarget.27472 Correspondence to - Beatrice Aramini,beatrice.aramini@unimore.it Keywords - somatic mutations, non-small cell lung cancer (NSCLC), lung cancer treatment, overall survival, target therapy Sign up for free Altmetric alerts about this article About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with: YouTube - http://bit.ly/OncotargetYoutube SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Oncotarget interviews Dr. Beatrice Aramini from the University of Modena and Reggio Emilia in Modena Italy about their Featured Cover Paper for Volume 11 Issue 5 titled "Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study" PRESS RELEASE: The cover for issue 5 of Oncotarget features Figure 2, "Survival curves in the KRAS, EGFR, and niche mutations cohorts," by Aramini, et al. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that: Niche mutations had higher mortality than EGFR mutations KRAS mutations had higher mortality than EGFR mutations, and Niche mutations presented similar mortality to KRAS mutations. Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations. Dr. Beatrice Aramini from the Division of Thoracic Surgery in Department of Medical and Surgical Sciences at the University of Modena and Reggio Emilia in Modena Italy said in their Oncotarget Research Paper, "In the last century, carcinoma of the lung has progressed from an uncommon and obscure disease to the most common cancer in the world, and the most common cause of death from cancer." In addition to these somatic mutations, which are the most frequent, other mutations in several genes have been discovered, including BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations. Moreover, the prevalence of the RET mutation in adenocarcinoma was estimated to be 1.7%, and the prevalence of DDR2 mutation in lung cancer was 2.2%. With regard to treatment, discoveries of gene mutations have allowed the development of targeted therapies, which are considered more effective for survival than chemotherapy in patients with advanced mutated disease. Considering the potential aggressiveness of niche mutations in this context, the technological advances of next-generation sequencing, which is currently used in clinical practice, represents a precise approach to identifying a large panel of mutations in oncologic patients. The Armini Research Team concluded, "The correct selection of mutations will be helpful in terms of the greater efficacy of treatment in association with better prognosis and a higher quality of life for oncologic patients." Full text - https://doi.org/10.18632/oncotarget.27472 Correspondence to - Beatrice Aramini,beatrice.aramini@unimore.it Keywords - somatic mutations, non-small cell lung cancer (NSCLC), lung cancer treatment, overall survival, target therapy Sign up for free Altmetric alerts about this article About Oncotarget Oncotarget is a weekly, peer-reviewed, open-access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with: YouTube - http://bit.ly/OncotargetYoutube SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology. Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.   This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.   At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.   Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.   Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed.    The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.   Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.   As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.   In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.   This concludes this JCO Podcast. Thank you for listening.

A review of the week's major US international tax-related news. In this edition: French President comments on new Digital Services Tax – IRS lists jurisdictions with reporting requirements for interest and OID paid to certain NRAs

In this podcast, Panagiotis Tsangaris, alumnus of the Max Planck Institute for Innovation and Competition, discusses the competition law and regulation issues that arise as a result of capacity withdrawals in the electricity wholesale markets, exploring the application of Article 102 TFEU and the terms of Regulation 1227/2011 (REMIT). visit the Florence School of Regulation website: fsr.eui.eu In electricity wholesale markets, market power is mainly exercised either by withdrawing generation capacity (physical withdrawal) or by pricing it above competitive levels (economic withdrawal) in order to achieve a higher market price and, thereby, increase revenue. Inevitably, capacity withdrawal practices can be damaging for both the market and consumers. Thus, the ability of competent authorities to intervene against practices of physical and economic withholding of capacity is crucial. As with any other form of market abuse, the physical and economic withholding of capacity is subject to the application of competition law, in particular Article 102 TFEU. In addition, Regulation 1227/2011 on wholesale market integrity and transparency (REMIT) also enhances transparency in wholesale energy markets and prohibits any acts of market manipulation on wholesale energy markets and may be turned to in order to deal with capacity withdrawal practices. Panagiotis Tsangaris discusses the scope and application of both, as well as the roles of ACER and the NRAs in monitoring the markets, the definition and geographic delineation of the markets in an increasingly interconnected and integrated market across Europe, and the challenges of determining market dominance. For more, you can see Panagiotis Tsangaris’ recent publication here: https://www.springer.com/de/book/9783662555125?utm_medium=affiliate&utm_source=commission_junction_authors&utm_campaign=3_nsn6445_deeplink_PID8793001&utm_content=deeplink

In the framework of the 7th World Forum on Energy Regulation (WFER), ICER Women in Energy and FSR teamed up to ‘give a voice’ to women professionals actively contributing to the event. Annegret Groebel is Vice-President at CEER and Head of the International Relations Department at BNetzA, Germany’s multisector regulatory authority. In this podcast, she sheds light on BNetzA’s approach and discusses the main similarities and differences when it comes to a ‘multisector regulation’. Network industries under the supervision of BNetzA share similar cost structures and face the problem of recovering sunk costs. The challenge for regulators is then to assess those costs and ensure an adequate structure and level of the network tariff paid by network users. However, regulators like BNetzA play a role also in ensuring the integrity and transparency of the wholesale markets, as mandated in the EU by REMIT. As a concluding remark, Ms Groebel stresses the importance of looking at the regulatory experience of other countries and other sectors. Knowledge sharing, eagerness to learn and cooperation are essential to avoid mistakes and improve the regulation of the industries under the oversight of NRAs. Check out more podcasts like this one and learn more about the Lights on Women Initiative here: medium.com/lights-on-women/

Ett år efter presidentvalet är USApodden på plats. I Virginia inför det viktiga guvernörsvalet, från NRAs huvudkontor men också från en skogsdunge i Fairfax. Medverkande: Ginna Lindberg, utrikeschef på Ekot Kajsa Boglind, Washingtonkorrespondent för Sveriges Radio Fernando Arias, New York-korrespondent för Sveriges Radio Programledare: Sara Stenholm Pihl Producent: Cecilia Khavar

According to his wife, John Martinovic has turned property investing into a major hobby – but there’s also a more serious side to his wealth-creation efforts. In this episode of The Smart Property Investment Show, John explains why he’s “pedantic” about his property portfolio, but why keeping on top of his finances now will not only safeguard the future of his children, but enable he and his wife to be debt-free by 45. Tune in as he and host Phil Tarrant explore the diversity of his portfolio – from a small unit in Kingsgrove, to NRAS assets, to off-the-plan apartments and the positives and negatives of each, as well as reflect on what he’d do differently if he had his time again. Tune in now to hear all of this and much, much more in this episode of The Smart Property Investment Show! SUBURBS MENTIONED IN THIS EPISODE: *Kingsgrove - http://bit.ly/2udIz25 *Hurstville - http://bit.ly/2tXJhVU *Melbourne - http://bit.ly/2sSXIIZ *Sydney - http://bit.ly/2rjsNSF RELATED ARTICLES OF INTEREST: *Don’t blame high prices on housing shortfall - http://bit.ly/2vcvwT1 *Why were 1 million properties vacant on census night? - http://bit.ly/2vciwwE *Sydney property buyers want expert opinions on development decisions - http://bit.ly/2tYyZ7V *What’s the rate tipping point to stop investors? - http://bit.ly/2f2JLU0 FOLLOW US: Did you like this episode? Show your support by rating us on iTunes (The Smart Property Investment Show) and by liking and following Smart Property Investment on social media: Facebook, Twitter and LinkedIn. If you have any questions about what you heard today, any topics of interest you have in mind, or if you’d like to lend your voice to the show, email editor@smartpropertyinvestment.com.au for more insight! iTunes: apple.co/2tryShe Facebook: bit.ly/2rTJaom Twitter: bit.ly/2sSacBG LinkedIn: bit.ly/2sFIqVd www.smartpropertyinvestment.com.au

The regional approach to the internal energy market: by what means? | Alberto Pototschnig (ACER) At the end of the Annual Conference of ACER near Ljubljana, Nicolò Rossetto (FSR) and Alberto Pototschnig, the Director of the Agency for the Cooperation of the Energy Regulators (ACER), discuss the regional dimension of the internal energy market. Currently, there is a consensus that the EU has to move forward with regional cooperation in the field of electricity and gas. However, it is not yet clear how to implement such regionalisation. Thus far, the experience was mainly based on voluntary initiatives like the Pentalateral Energy Forum. Discussions on the matter are ongoing, with several questions hotly debated: what aspects should be part of the regional dimension? What geographical scope should the regions have? What are the most appropriate governance and regulatory frameworks for the regions? The discussion is particularly lively in the area of electricity, where ENTSO-E and the European Commission have partly diverging opinions on the issue and the legislative proposals presented at the end of 2016. There is an undisputed need for political backing to regional cooperation in electricity: for some, this requires new initiatives by the national policy-makers and regulators (NRAs), while for others the backing is already embedded in the current rules (i.e., Third Energy Package). In the latter case, regionalisation is a merely technical and regulatory issue that must be implemented by TSOs and NRAs, possibly with the contribution of ACER. Indeed, the role of ACER is becoming more important with the shift of the policy level from the Member States to the regions and the whole Europe. A stronger and better staffed ACER is required to support the regional cooperation of NRAs and ensure that regions do not diverge. Eventually, the goal is to have a European single market and not a bunch of poorly integrated regional markets.

How Non-Americans Can Benefit from American Brokerage Accounts By Douglas Goldstein, CFP®, helping people in Israel with their U.S. IRA and investment accounts This past week, my office phone rang several times with non-Americans inquiring about opening American brokerage accounts. Given the hassles of dealing in some of the more popular offshore jurisdictions, and given the many benefits of keeping investments in the United States, these people were happy to see how they could easily invest through a U.S. brokerage firm. Why non-Americans have American investment accounts There are two parts to having a brokerage account: the specific investments and the “custodian” of the funds.  The specific investments include what stocks and shares you own, or which mutual funds or bank deposits you choose. The “custodian” of the assets is normally a major bank or brokerage firm that is responsible for safeguarding the securities, executing the trades, printing the statements, arranging for checkbooks and credit/debit cards for the clients, and other back-office services. Before investing money you must choose both a custodian of your account (the firm) and the individual investments (stocks, bonds, etc.) Non-Americans frequently use a U.S. brokerage firm to custody their assets. Here's why: The unrivaled transparency of the financial system in America The huge number of investment choices The potential for good returns The relatively lower fees The ability to geographically diversify their investments in one account America's political stability Send me an email (doug@profile-financial.com) for a detailed report on the additional benefits of non-Americans having American brokerage accounts. Is it legal for non-Americans to open U.S. accounts? Not only are NRAs (non-resident aliens) allowed to hold their assets in America, they are actively encouraged to do so. From the standpoint of the American government, having foreign investors maintain accounts in the United States helps to keep the U.S. markets as the top trading locations in the world. In fact, the United States doesn't tax the interest and capital gains that foreigners make on their U.S. assets (This is a general discussion. Be sure to speak to your own tax advisor before investing.) If you would like to learn about the advantages of global investments through a U.S. investment firm, please call my office at 02-624-2788. Douglas Goldstein, CFP®, is the director of Profile Investment Services, Ltd. He is a licensed financial professional both in the U.S. and Israel. Call (02) 624-2788 for a consultation about handling your U.S. investments from Israel. Securities offered through Portfolio Resources Group, Inc., Member FINRA, SIPC, MSRB, FSI. Accounts carried by Pershing LLC., Member NYSE/SIPC, a subsidiary of The Bank of New York Mellon Corporation. The opinions expressed are those of the author and not those of Portfolio Resources Group, Inc. or its affiliates.  

Vi pratar om NRAs sagoinspirerade reklam, Eva Witt-Brattström och huruvida man kan vara feminist och offer. Är dessutom feministiska frågor relevanta nu när rasismen är påtaglig runtomkring och varför sålde Batman vs Superman 170 miljoner dollar fösta helgen? Referenser hittar på Filpboard.com och Magnus och Peppes podcast. See acast.com/privacy for privacy and opt-out information.

Dr. Mario Sznol, Yale School of Medicine, provides an overview of melanoma and its treatment, and discusses current melanoma immunotherapies and other agents under investigation.

Dr. Mario Sznol, Yale School of Medicine, provides an overview of melanoma and its treatment, and discusses current melanoma immunotherapies and other agents under investigation.

Dr. Mario Sznol, Yale School of Medicine, provides an overview of melanoma and its treatment, and discusses current melanoma immunotherapies and other agents under investigation.

In this Q&A episode, Bryce and Ben discuss about the intricacies of using a Line of Credit, National Rental Affordability Scheme (NRAS) Program, fixing a broken portfolio, how to start your due diligence and insurances on investment property.... The post Episode 040 | Q&A – Line of Credit, NRAS Program, Fixing a Broken Portfolio, Conducting a Due Diligence and Insurances appeared first on The Property Couch.

What does NRAS stand for? NRAS stands for the National Rental Affordability Scheme which is a scheme created by the Australian government to help increase access to affordable housing for people on lower incomes. What does NRAS stand for? NRAS stands for the National Rental Affordability Scheme, which is a scheme created by the Australian […] The post What Does NRAS Stand For? (Ep275) appeared first on On Property.

Florence School of Regulation: FSR.EUI.eu Event Programme: http://fsr.eui.eu/Events/ENERGY/Workshop/2015/150130CompletionInternalEnergyMarket.aspx Introduction Alberto Pototschnig | FSR/EUI Session 1: Completing the Internal Energy Markets: Consumer Expectation Peter Claes | IFIEC, The expectation of energy intensive consumers Monika Štajnarová | BEUC, Is the internal energy market delivering for smaller consumers? Session 2: Progress Towards the Creation of an Internal Electricity Market Christophe Gence-Creux | ACER, Where do we stand? Roundtable: Priorities for completing the internal electricity market Robert Staschus| ENTSO-E Hans Randen | NordPool Spot/Europex Session 3: Progress Towards the Creation of an Internal Gas Market Dennis Hesseling | ACER, Where do we stand? Roundtable: Priorities for completing the internal gas market Tom Maes | AGWG, (Via conference call, not in video) Vittorio Musazzi | ENTSOG Overview: In the conclusion of its meeting on 4 February 2011, the Council of the European Union set 2014 as the target date for the completion of the Internal Electricity and Gas Markets. This goal was reaffirmed in the conclusions of the meeting on 22 May 2013. Significant progress has been achieved towards meeting this objective, both in terms of the development of the required market and network operation rules and on the ground. In fact, in terms of rulemaking, two network codes have already been adopted, a third one should be adopted soon and ten more have already been recommended for adoption to the European Commission and they could soon enter into the Comitology process. Moreover, a number of the main provisions in these network codes have already been implemented in practice, through the voluntary cooperation of national regulatory authorities (NRAs), transmission system operators (TSOs) and other stakeholders. This early implementation approach has been supported by the Agency for Cooperation of Energy Regulators (ACER), which has coordinated the definition of a number of Roadmaps for the rapid and effective integration of the electricity and gas markets, to deliver tangible benefits to EU energy consumers as soon as possible. In the electricity day-ahead timeframe, a single market-coupling platform operates, since May 2014, to determine prices and cross-border flows on a large part of the EU, from the Straits of Gibraltar to the Barents Sea. Similarly, a single platform is already used for allocating capacity on the majority of internal EU gas interconnection points. However much still remains to be done. The first coordinated auction for long-term electricity cross-border transmission rights is expected to take place in the second half of 2015, on the basis of harmonised auction rules currently being developed. In the intra-day timeframe of the internal electricity market, the development of a single continuous-trading, market-coupling platform has been repeatedly delayed and the go-live is now expected by the end of 2015 at the earliest, more than two years later than originally planned. Liquidity of many gas hubs still needs to be enhanced so that they could provide robust price signals to determine the efficient flow of gas across the EU. A well-functioning internal energy market is also increasingly recognised as an important contributor to the security of energy supply of the EU, as well as a pre-requisite for any additional measure to promote such security. This Workshop aims at reviewing progress in the creation of a single market in electricity and gas across the EU and at identifying what is still missing so that EU consumers can reap the full benefits. The Workshop will be structured in three sessions. Session I will be devoted to assess energy consumers’ expectations from the internal energy market and the benefits already accrued to them. Sessions II and III will aim at reviewing progress towards the creation of a single market in electricity and natural gas, respectively.

Regulation (EU) No. 1227/2011 of the European Parliament and of the Council on wholesale energy market integrity and transparency (REMIT), which entered into force in December 2011, aims at promoting transparency in wholesale energy markets and detecting and deterring market abusive behaviour on these markets. It introduces the explicit prohibition of market manipulation, attempted market manipulation and insider trading, as well as transparency and reporting obligations for market participants and other stakeholders. It also envisages the establishment of an unprecedented market monitoring framework, in which data on wholesale energy market transactions, together with fundamental data, are reported to the Agency for the Cooperation of Energy Regulators (ACER), which is responsible for their screening and initial analysis and assessment. Suspicious events are then notified to national competent authorities (NCAs), typically National Regulatory Authorities for energy (NRAs), for investigation and enforcement.

Prof Peeters talks to ecancertv at ASCO 2014 about the updated analysis of KRAS/NRAS and BRAF mutations in study 20050181 of panitumumab plus FOLFIRI for second-line treatment of metastatic colorectal cancer.

In this podcast, I will discuss first-line usage of anti-EGFR therapies in metastatic colorectal cancer in the context of the PEAK trial findings with a focus on the emerging data surrounding RAS oncogene mutations in treatment selection.

We introduce hybrid solar cells with an architecture consisting of an electrodeposited ZnO nanorod array (NRA) coated with a conformal thin layer (< 50 nm) of organic polymer-fullerene blend and a quasi-conformal Ag top contact (Thin/NR). We have compared the performance of Thin/NR cells to conventional hybrid cells in which the same NRAs are completely filled with organic blend (Thick/NR). The Thin/NR design absorbs at least as much light as Thick/NR cells, while charge extraction is significantly enhanced due to the proximity of the electrodes, resulting in a higher current density per unit volume of blend and improved power conversion efficiency. The NRAs need not be periodic or aligned and hence can be made very simply.

Join me for a lively discussion about the Newton Tradegy and the NRAs response.

In this episode we get all the details of the National Rental Affordability Scheme.  This is a scheme that offers some pretty attractive tax free cash incentives to investors in return for providing reasonably affordable rental accommodation. The scheme has been around for a while, but for those trying to ‘get their head around it’, […]