Podcasts about novel therapies

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances, discusses a recently published original research paper on Novel Therapies to Reduce Rehospitalization Risk in Worsening Heart Failure: Systematic Review and Network Meta-Analysis.

Featuring perspectives from Dr Sagar Lonial, Prof Philippe Moreau, Dr Robert Z Orlowski, Dr Noopur Raje and Dr Paul G Richardson, moderated by Dr Lonial, including the following topics: Introduction (0:00) Management of Newly Diagnosed Multiple Myeloma (MM) — Dr Orlowski (1:26) Integration of Novel Therapies into the Management of Relapsed/Refractory MM — Dr Richardson (26:53) Chimeric Antigen Receptor T-Cell Therapy for MM — Dr Raje (48:48) Bispecific Antibodies for the Treatment of MM — Prof Moreau (1:12:52) Other Novel Agents and Strategies Under Investigation for MM — Dr Lonial (1:36:32) CME information and select publications

Discover key updates on emerging immunotherapy combinations in relapsed/refractory (R/R) follicular lymphoma (FL) from the hematology congress in San Diego. Credit available for this activity expires: 12/18/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1002061?ecd=bdc_podcast_libsyn_mscpedu

CME credits: 0.25 Valid until: 21-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/optimizing-outcomes-in-patients-with-igan-novel-therapies-and-evolving-guidelines/26627/ Given that IgA nephropathy is a leading cause of kidney failure, early diagnosis and treatment are essential. In the landscape of the many evolving treatment guidelines, how can nephrologists apply emerging evidence and utilize newer therapies to achieve proteinuria remission and maintain eGFR to improve the outcomes of their patients? Hear the experts answer these questions by reviewing a real-world clinical patient case.=

Carla M. Nester, MD, MSA, FASN - Novel Therapies in Focus: Updates in C3 Glomerulopathy and IC-MPGN

Richard Lafayette, MD, FACP - Novel Therapies in Focus: Updates in IgA Nephropathy

Carla M. Nester, MD, MSA, FASN - Novel Therapies in Focus: Updates in C3 Glomerulopathy and IC-MPGN

Richard Lafayette, MD, FACP - Novel Therapies in Focus: Updates in IgA Nephropathy

Novel therapies for IgA nephropathy are discussed in this ASN Kidney Translation podcast episode, including efficacy and safety of ravulizumab, selective endothelin receptor antagonist SC0062, and long-term results from a study of atacicept as treatment.

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

Bruce A C Cree, MD, PhD, MAS - BTK Inhibition & Beyond: Novel Therapies in MS

CME credits: 0.50 Valid until: 18-10-2025 Claim your CME credit at https://reachmd.com/programs/cme/new-horizons-unraveling-novel-therapies-for-enhanced-cardiovascular-outcomes-in-patients-with-heart-failure/26966/ There are limited therapeutic options for patients with heart failure with mid-range or preserved ejection fraction (HFmrEF/HFpEF). Recently, new data were released on the efficacy and safety of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in patients with HFmrEF/HFpEF. What are the outcomes of the FINEARTS-HF trial with finerenone in this patient population, and what do these findings mean for clinical practice? Three cardiologists discuss the topic of novel therapies, with a focus on nonsteroidal MRAs, to improve cardiovascular outcomes in patients with HFmrEF/HFpEF. =

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Send us a textBen Zimmer is CEO of Priovant Therapeutics ( https://www.priovanttx.com/ ), a clinical-stage biotechnology company focused on delivering novel therapies for autoimmune diseases associated with the greatest morbidity and mortality. Priovant is developing oral brepocitinib, a potential first-in-class dual inhibitor of TYK2 and JAK1, across multiple severe autoimmune indications, unlocking new treatment options for patients who are underserved by existing therapies.Ben joined Priovant from Roivant, where he was a member of the founding team in early 2015 and held multiple leadership roles across the organization, including President, Roivant Health, Chief Operating Officer, and Head, Public Affairs. As President, Roivant Health, Ben led and oversaw the launch of Roivant's Chinese biopharmaceutical subsidiaries, healthcare technology companies (including Datavant), and computationally powered drug discovery platform (including VantAI). Earlier in his career, Ben was a consultant at McKinsey & Co and co-founded and led a public policy non-profit. He holds a BA magna cum laude from Harvard College and a JD from Yale Law School.#BenZimmer #PriovantTherapeutics #AutoimmuneDiseases #Brepocitinib #TYK2 #JAK1 #Dermatomyositis #NonInfectiousUveitis #Pfizer #Roivant #VivekRamaswamy #ProgressPotentialAndPossibilities #IraPastor #Podcast #Podcaster #STEM #Innovation #Technology #Science #ResearchSupport the show

On this episode we talk with experts Dr. Amy Shapiro, Dr. Maria Elisa Mancuso, Dr. Steve Pipe, Dr. Johnny Mahlangu, and Dr. Lynn Malec to delve into the ongoing evolution of hemophilia therapies. The discussion highlights recent advancements in treatments such as emicizumab, extended half-life factor VIII therapies, and investigates medications in clinical trials like Concizumab, Marstacimab, and Fitusiran. The episode also reflects on the role of treatment individualization and the need for more inclusive research data.   Contributors: Johnny Mahlangu, MBBCh, MMed, FCPath Lynn Malec, MD, MSc Elisa Mancuso, MD Steven Pipe, MD Amy Shapiro, MD   Senior Advisor: Donna DiMichele, MD   Hosted & Written by: Patrick James Lynch   Featured Advertiser: Sanofi   Subscribe to the Global Hemophilia Report   Show Notes: Connect with the Global Hemophilia Report Global Hemophilia Report on LinkedIn Global Hemophilia Report on Twitter Global Hemophilia Report on Facebook   Connect with BloodStream Media: BloodStreamMedia.com BloodStream on Facebook  BloodStream on Twitter   

In this ICS podcast, Shannon Wallace interviews Dr. Luca Cindolo about his team's upcoming workshop at ICS 2024 in Madrid. Scheduled for October 23rd, this workshop, "Novel Therapies for Benign Prostatic Obstruction: Technologies and Practical Instruction," will feature minimally invasive surgical techniques for benign prostatic obstruction. Dr. Cindolo emphasizes the workshop's interactive nature and its relevance for both young and experienced urologists, physiologists, and nursing staff. Highlighted experts include Feras Al Jaafari, Riccardo Bertolo, and Dr. Socarrás. The workshop promises comprehensive education and practical insights for attendees, aiming to enhance patient care through multidisciplinary collaboration.Find out more at https://www.ics.org/2024/session/7695 Early registration for ICS 2024 Madrid is now open at www.ics.org/2024The ICS annual meeting is the must-attend, multidisciplinary event for clinical and research scientists interested in: Urology Urogynaecology Female and functional urology Gynaecology Bowel dysfunction Neurourology Pure and applied science Physiotherapy Nursing Geriatrics The ICS 2024 Madrid conference fosters collaboration between all disciplines involved in continence care.

Did you know that more than 20% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) do not respond to current first-line treatments?    Credit available for this activity expires: 5/30/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1000839?ecd=bdc_podcast_libsyn_mscpedu

Our panel of subject matter and lived experience experts engage in a data-driven discussion about caregiver burden in hemophilia, historically, and how the rapidly evolving treatment landscapes impacts that burden. Contributors: Michelle Witkop, DNP, FNP-BC Kate Khair, PhD Beatriz Caceres, MD Kasha Lumsden, BSN, RN, RAC-CT Yasmin Pavri    Senior Advisor: Donna DiMichele, MD   Special Episode Advisor: Michelle Witkop, DNP, FNP-BC   Hosted & Written by: Patrick James Lynch   Featured Advertiser: Sanofi   Subscribe to the Global Hemophilia Report   Show Notes: Presenting Sponsor: Sanofi   Subscribe to the Global Hemophilia Report   Connect with the Global Hemophilia Report Global Hemophilia Report on LinkedIn Global Hemophilia Report on Twitter Global Hemophilia Report on Facebook   Connect with BloodStream Media: BloodStreamMedia.com BloodStream on Facebook  BloodStream on Twitter   

In this episode of Medsider Radio, we had a fascinating chat with Dmitri Leonov, co-founder and CEO of Taopatch USA. The company is commercializing a range of wearable nanotechnology light therapy devices aimed at managing neurological conditions including pain management and sports performance.  Dmitri is also an advisor in a number of transformative technology projects. After seven fruitful years at Overture and later at Yahoo, he dove into the startup world. He went on to found several companies, including Sanebox.com, but was intrigued by frequency medicine and started his current venture by bringing Taopatch to the United States from Italy, where it was first invented.In this interview, Dmitri shares how the company was able to garner unique publicity and how strategic partnerships with holistic practitioners, authentic user testimonials, and a creative money-back guarantee strategy were instrumental in Taopatch USA's market success.Before we dive into the discussion, I wanted to mention a few things:First, if you're into learning from medical device and health technology founders and CEOs, and want to know when new interviews are live, head over to Medsider.com and sign up for our free newsletter.Second, if you want to peek behind the curtain of the world's most successful startups, you should consider a Medsider premium membership. You'll learn the strategies and tactics that founders and CEOs use to build and grow companies like Silk Road Medical, AliveCor, Shockwave Medical, and hundreds more!We recently introduced some fantastic additions exclusively for Medsider premium members, including playbooks, which are curated collections of our top Medsider interviews on key topics like capital fundraising and risk mitigation, and a curated investor database to help you discover your next medical device or health technology investor!In addition to the entire back catalog of Medsider interviews over the past decade, premium members also get a copy of every volume of Medsider Mentors at no additional cost, including the latest Medsider Mentors Volume V. If you're interested, go to medsider.com/subscribe to learn more.Lastly, if you'd rather read than listen, here's a link to the full interview with Dmitri Leonov.

Doctors Vamsi Velcheti, Sandip Patel, and Michael Zervos discuss recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for patients and the role of surgery in the era of targeted therapy and immuno-oncology in lung cancer. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. On today's episode, we'll be discussing recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for our patients, and the evolving role of surgery in the era of targeted therapy and immuno-oncology in lung cancer.  Today, I am delighted to be joined by two renowned experts in this space, Dr. Sandip Patel and Dr. Michael Zervos. Dr. Patel is a professor of medicine and a medical oncologist specializing in lung cancer at UCSD. Dr. Mike Zervos is the clinical chief of the Division of Robotic Thoracic Surgery and Director of General Thoracic Surgery at NYU Langone. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod. Dr. Patel and Dr. Zervos, it's a great honor to have you on the podcast today. Welcome aboard. Dr. Sandip Patel: Great to be joining you.  Dr. Vamsi Velcheti:  Let's get started with Dr. Patel. As you know, over the last decade we've had dramatic advances in systemic therapy options for patients with metastatic non-small cell lung cancer, in both the realms of targeted therapy and immunotherapy. These have significantly improved outcomes for our patients with metastatic lung cancer. What's exciting is that more recently, we've seen the incorporation of these agents, both targeted therapies and immunotherapies, in early-stage non-small cell lung cancer. Dr. Patel, can you tell our listeners about these exciting recent advances and why do you think it's so important to incorporate these personalized systemic therapy options for our early-stage patients? Dr. Sandip Patel: I think it's a great point and a great question. And so, I think one thing to understand is that non-small cell lung cancer is actually multiple diseases. We give it one name based on how it looks under the microscope, but the vast majority of our advances to improve outcomes for patients have come from our ability to understand specific subgroups.  Many of our therapies have had activity in the advanced setting. We have our patients with metastatic or more widespread disease, which naturally led to the thought that could we utilize these therapies in earlier stage disease and potentially increase the rate of cure for many of our patients, lung cancer being the most common cancer killer worldwide. And so to your point, trying to understand how to best treat a patient really involves personalized medicine, typically driven by understanding the genomic profile of their tumor and two of the genes that have graduated from being tested for in the metastatic setting and now in the localized setting are EGFR and ALK. And these in particular are mutations that confer sensitivity to small molecule inhibitors, EGFR with osimertinib, ALK in the localized setting with alectinib based on the data that we've seen.  And so, one of the areas that's been particularly exciting is our ability to maximize a patient's chance for durable remissions by integrating these therapies after surgery, after chemotherapy when appropriate, and continuing generally for a finite amount of time, two to three years depending on the agent in the study we're discussing for these patients. Additionally, immunotherapy, which has revolutionized our treatment of patients with metastatic disease, may be particularly well-suited for the localized setting of non-small cell lung cancer as well. Dr. Vamsi Velcheti: Excellent points, Sandip. You're absolutely right, in the metastatic setting, we've all come to accept molecular testing, sequencing, and biomarker profiling as a standard, but unfortunately, that hasn't quite yet percolated into the early-stage setting. Can you talk about some of the challenges that we face as we have these therapeutic options available now for more early-stage patients? Dr. Sandip Patel: So, I think there are 3 flavors of localized therapy in non-small cell lung cancer. One is the advanced, unresectable stage 3, for which the approach is often concurrent chemo-radiation followed by some form of consolidated therapy. We're about to hear the results of LAURA, which is the study looking at EGFR-mutated non-small cell lung cancer.  For other patients, historically, the treatment has been durvalumab, an anti-PD-L1 directed immunotherapy. The other two are operative treatment of localized cancer: adjuvant treatment after surgery, or neoadjuvant or perioperative, in which chemoimmunotherapy begins before surgery. And testing depends on the settings. For the stage 3 patient who's likely getting concurrent chemo-radiation, they may have a very small amount of tissue, and so often these are done by pulmonary EBUS biopsies and that's how we pathologically confirm that advanced stage 3B. There may not be a lot of tissue available for molecular testing. In fact, if you look at the PACIFIC analysis, just looking at PD-L1, which is just an IHC off a single slide, a third of patients weren't able to even get a PD-L1, let alone a genomic result. And so, I think that's one of the areas of LAURA that's going to be particularly interesting to see as we try to implement it into our practice after seeing the full data.  I think in the adjuvant setting, we're lucky because our surgeons, Dr. Mike Zervos here, will get us a large amount of tissue in the surgical resection specimen, so we tend to get enough tissue to do genomics while they're under chemotherapy, there tends to be time to wait for their genomic result. Where this really gets complicated is in the neoadjuvant or perioperative setting, where time is everything.  The most important thing we can do for a patient in the localized space is get them to the operating room, get them started on radiation, their curative local modality, and that's where we have a time pressure but also a sample pressure because that is a diagnostic biopsy. It's a very small piece of tissue. Initially, there are multiple stains that have to be done to identify this lung cancer as opposed to another tumor. And so that's an area that I think we're going to need additional approaches given that cell-free DNA tends to have lower yield in lower stage disease in giving us a result. Dr. Vamsi Velcheti: Great points, Sandip. How do you deal with this issue in San Diego? The challenge is now we have a lot of trials, we'll talk about those neoadjuvant immunotherapy trials, but we know that immunotherapy may not be as effective in all patients, especially those with EGFR or ALK or some of these non-smoker, oncogene-driven tumors. So, we don't want to be giving patients treatments that may not necessarily be effective in the neoadjuvant space, especially when there is a time crunch, and we want to get them to surgery and all the complications that come with giving them targeted therapy post-IO with potential risk for adverse events. Dr. Sandip Patel: Absolutely. It is a great point. And so, the multidisciplinary team approach is key, and having a close relationship with the interventional pulmonary oncs, interventional radiology surgery, and radiation oncology to ensure that we get the best treatment for our patients. With the molecularly guided therapies, they are currently more on the adjuvant setting in terms of actually treating. But as you mentioned, when we're making a decision around neoadjuvant or perioperative chemo IO, it's actually the absence of EGFR now that we're looking for because our intervention at the current time is to give chemoimmunotherapy. Going back to the future, we used to use single gene EGFR within 24 hours, which was insufficient for a metastatic panel, but it often required five slides of tissue input. ALK can be done by IHC, and so some of these ‘oldie but goodie' pathologic techniques, and that pathologists, if I haven't emphasized, understanding what we're trying to do at a different context is so key because they are the ones who really hold the result. In the neoadjuvant and perioperative setting, which many of us favor, especially for stage 3A and stage 2B disease, understanding how we can get that result so that we can get the patient to the operating room in an expeditious way is so important. There is a time pressure that we always had in the metastatic setting, but I think we feel much more acutely in the neoadjuvant and perioperative setting in my opinion. Dr. Vamsi Velcheti: Fascinating insights, Dr. Patel.  Turning to Dr. Zervos, from a surgical perspective, there has been an evolution in terms of minimally invasive techniques, robotic approaches, and enhanced recovery protocols, significantly improving outcomes in our patients post-surgery. How do you see the role of surgery evolving, especially with the increasing complexity and efficacy of these systemic therapies? How do you envision the role of surgery in managing these early-stage patients, and what are the key considerations for surgeons in this new era? Dr. Michael Zervos: Thanks, Vamsi. Thanks, Sandip. Thank you for having me on the podcast. Obviously, it's an honor to be a part of such a high-level discussion. I have to say, from a surgeon's perspective, we often listen to you guys talk and realize that there's been a lot of change in this landscape. And I think the thing that I've seen is that the paradigm here has also changed. If we were having this discussion 10 years ago, a lot of the patients that I am operating on now, I would not be operating on. It really has been amazing. And I think the thing that stands out to me the most is how all of this has changed with neoadjuvant chemotherapy checkpoint inhibition. I think, for us as surgeons, that's really been the key. Whether it's CheckMate 816 or whatever you're following, like PACIFIC, the data supports this. And I think what we're seeing is that we're able to do the surgery, we're able to do it safely, and I think that the resectability rates are definitely high up there in the 90% range. And what we're seeing is pretty significant pathologic responses, which I think is really amazing to me.  We're also seeing that this has now shifted over to the oligometastatic realm, and a lot of those patients are also being treated similarly and then getting surgery, which is something that we would not have even thought of ever. When you look at the trials, I think a lot of the surgery, up to this point, has been done more traditionally. There's a specific reason why that happens, specifically, more through thoracotomy, less with VATS, and less with robotic. Sandip, I think you guys have a pretty robust robotic program at UCSD, so I'm sure you're pretty used to seeing that.   As you guys have become so much more sophisticated with the treatments, we have also had to modify what we do operatively to be able to step up to the plate and accept that challenge. But what we are seeing is yes, these treatments work, but the surgeries are slightly more complicated. And when I say slightly, I'm minimizing that a little bit.  And what's complicated about it is that the treatment effect is that the chemo-immune check inhibition actually has a significant response to the tumor antigen, which is the tumor. So it's going to necrose it, it's going to fibrose it, and wherever there is a tumor, that response on the surgical baseline level is going to be significant. In other words, there are going to be lymph nodes that are stuck to the pulmonary artery, lymph nodes that are stuck to the airway, and we've had to modify our approaches to be able to address that.   Now, fortunately, we've been able to innovate and use the existing technology to our advantage. Personally, I think robotics is the way we have progressed with all this, and we are doing these surgeries robotically, mainly because I think it is allowing us, not only to visualize things better, but to have sort of a better understanding of what we're looking at. And for that matter, we are able to do a better lymph node dissection, which is usually the key with a lot of these more complicated surgeries, and then really venturing out into more complicated things, like controlling the pulmonary artery. How do we address all this without having significant complications or injuries during the surgery? Getting these patients through after they've successfully completed their neoadjuvant treatment, getting them to surgery, doing the surgery successfully, and hopefully, with minimal to no morbidity, because at the end, they may be going on to further adjuvant treatment. All of these things I think are super important. I think although it has changed the landscape of how we think of things, it has made it slightly more complicated, but we are up for the challenge. I am definitely excited about all of this. Dr. Vamsi Velcheti: For some reason, like medical oncologists, we only get fixated on the drugs and how much better we're doing, but we don't really talk much about the advances in surgery and the advances in terms of outcomes, like post-op mortality has gone down significantly, especially in larger tertiary care centers. So, our way of thinking, traditionally, the whole intergroup trials, the whole paradigm of pneumonectomies being bad and bad outcomes overall, I think we can't judge and decide on current treatment standards based on surgical standards from decades ago. And I think that's really important to recognize.  Dr. Michael Zervos: All of this stuff has really changed over the past 10 years, and I think technology has helped us evolve over time. And as the science has evolved for you with the clinical trials, the technology has evolved for us to be able to compensate for that and to be able to deal with that. The data is real for this. Personally, what I'm seeing is that the data is better for this than it was for the old intergroup trials. We're able to do the surgery in a better, more efficient, and safer way. The majority of these surgeries for this are not going to be pneumonectomies, they are going to be mostly lobectomies. I think that makes sense. I think for the surgeons who might be listening, it doesn't really matter how you're actually doing these operations. I think if you don't have a very extensive minimally invasive or robotic experience, doing the surgery as open is fine, as long as you're doing the surgery safely and doing it to the standard that you might expect with complete lymph node clearance, mediastinal lymph node clearance, and intrapulmonary lymph node clearance. Really, I think that's where we have to sort of drive home the point, really less about the actual approach, even though our bias is to do it robotically because we feel it's less morbidity for the patient. The patients will recover faster from the treatment and then be able to go on to the next phase treatments. Dr. Vamsi Velcheti: In some of the pre-operative trials, the neoadjuvant trials, there have been some concerns raised about 20% of patients not being able to make it to surgery after induction chemo immunotherapy. Can you comment on that, and why do you think that is the case, Sandip?  Dr. Sandip Patel: Well, I think there are multiple reasons. If you look, about half due to progression of disease, which they might not have been great operative candidates to begin with, because they would have early progression afterwards. And some small minority in a given study, maybe 1% to 2%, it's an immune-related adverse event that's severe. So, it's something that we definitely need to think about. The flip side of that coin, only about 2 in 3 patients get adjuvant therapy, whether it be chemotherapy, immunotherapy, or targeted therapy. And so, our goal is to deliver a full multimodal package, where, of course, the local therapy is hugely important, but also many of these other molecular or immunologically guided agents have a substantial impact.  And I do think the point around neoadjuvant and perioperative is well taken. I think this is a discussion we have to have with our patients. I think, in particular, when you look at higher stage disease, like stage 3A, for example, the risk-benefit calculus of giving therapy upfront given the really phenomenal outcomes we have seen, really frankly starting with the NADIM study, CheckMate816, now moving on into studies like KEYNOTE-671, AEGEAN, it really opens your eyes in stage 3. Now, for someone who's stage 1/1b, is this a patient who's eager to get a tumor out? Is there as much of an impact when we give neoadjuvant therapy, especially if they're not going to respond and may progress from stage 1 and beyond? I think that's a reasonable concern. How to handle stage II is very heterogeneous. I think two points that kind of happen as you give neoadjuvant therapy, especially chemo-IO that I think is worth for folks to understand and this goes to Mike's earlier point, that is this concept if they do get a scan during your neoadjuvant chemo immunotherapy, there is a chance of that nodal flare, where the lymph nodes actually look worse and look like their disease is progressing. Their primary tumor may be smaller or maybe the same. But when we actually go to the OR, those lymph nodes are chock-full of immune cells. There's actually no cancer in those lymph nodes. And so that's a bit of a red herring to watch out for.   And so, I think as we're learning together how to deliver these therapies, because the curative-intent modality is, in my opinion, a local modality. It's what Mike does in the OR, my colleagues here do in the OR. My goal is to maximize the chance of that or really maximize the long-term cure rates. And we know, even as long as the surgery can go, if only 2 or 3 patients are going to get adjuvant therapy then 1 in 10, of which half of those or 1 in 20, are not getting the surgery and that's, of course, a big problem. It's a concern. I think better selecting towards those patients and thinking about how to make these choices is going to be hugely important as we go over. Because in a clinical trial, it's a very selective population. A real-world use of these treatments is different. I think one cautionary tale is that we don't have an approval for the use of neoadjuvant or perioperative therapy for conversion therapy, meaning, someone who's “borderline resectable.” At the time at which you meet the patient, they will be resectable at that moment. That's where our best evidence is, at the current time, for neoadjuvant or perioperative approaches.  Dr. Vamsi Velcheti:   I think the other major issue is like the optimal sequencing of immune checkpoint here. Obviously, at this point, we have multiple different trial readouts, and there are some options that patients can have just neoadjuvant without any adjuvant. Still, we have to figure out how to de-escalate post-surgery immunotherapy interventions. And I think there's a lot of work that needs to be done, and you're certainly involved in some of those exciting clinical trials. What do you do right now in your current clinical practice when you have patients who have a complete pathologic response to neoadjuvant immunotherapy? What is the discussion you have with your patients at that point? Do they need more immunotherapy, or are you ready to de-escalate?  Dr. Sandip Patel: I think MRD-based technologies, cell-free DNA technologies will hopefully help us guide this. Right now, we are flying blind along two axes. One is we don't actually know the contribution of the post-operative component for patients who get preoperative chemo-IO. And so this is actually going to be an ongoing discussion. And for a patient with a pCR, we know the outcomes are really quite good based on CheckMate816, which is a pure neoadjuvant or front-end only approach. Where I actually struggle is where patients who maybe have 50% tumor killing. If a patient has only 10% tumor killing ... the analogy I think in clinic is a traffic light, so the green light if you got a pCR, a yellow light if you have that anywhere from 20%-70% residual viable tumor, and then anything greater than that, you didn't get that much with chemo-IO and you're wondering if getting more chemo-IO, what would that actually do? It's a bit of a red light. And I'm curious, we don't have any data, but my guess would be the benefit of the post-op IO is because patients are in that kind of yellow light zone. So maybe a couple more cycles, we'll get them an even more durable response. But I am curious if we're going to start relying more on MRD-based technologies to define treatment duration. But I think it's a very complicated problem. I think folks want to balance toxicity, both medical and financial, with delivering a curative-intent therapy. And I am curious if this maybe, as we're looking at some of the data, some of the reasons around preferring a perioperative approach where you scale it back, as opposed to a neoadjuvant-only approach where there's not a clean way to add on therapy, if you think that makes sense. But it's probably the most complicated discussions we have in clinic and the discussion around a non-pCR. And frankly, even the tumor board discussions around localized non-small cell lung cancer have gone very complex, for the benefit of our patients, though we just don't have clean data to say this is the right path.   Dr. Vamsi Velcheti: I think that the need for a really true multidisciplinary approach and discussing these patients in the tumor board has never been more significant. Large academic centers, we have the luxury of having all the expertise on hand. How do we scale this approach to the broader community is a big challenge, I think, especially in early-stage patients. Of course, not everyone can travel to Dr. Zervos or you for care at a large tertiary cancer centers. So, I think there needs to be a lot of effort in terms of trying to educate community surgeons, community oncologists on managing these patients. I think it's going to be a challenge. Dr. Michael Zervos: If I could just add one thing here, and I completely agree with everything that has been said. I think the challenge is knowing beforehand. Could you predict which patients are going to have a complete response? And for that matter, say, “Okay. Well, this one has a complete response. Do we necessarily need to operate on this patient?” And that's really the big question that I add. I personally have seen some complete response, but what I'm mostly seeing is major pathologic response, not necessarily CR, but we are seeing more and more CR, I do have to say. The question is how are you going to predict that? Is looking for minimal residual disease after treatment going to be the way to do that? If you guys could speak to that, I think that is just tremendously interesting.  Dr. Vamsi Velcheti: I think as Sandip said, MRD is looking very promising, but I just want to caution that it's not ready for primetime clinical decision making yet. I am really excited about the MRD approach of selecting patients for de-escalation or escalation and surgery or no surgery. I think this is probably not quite there yet in terms of surgery or no surgery decision. Especially for patients who have early-stage cancer, we talk about curative-intent treatment here and surgery is a curative treatment, and not going to surgery is going to be a heavy lift. And I don't think we're anywhere close to that. Yet, I'm glad that we are having those discussions, but I think it may be too hard at this point based on the available technologies to kind of predict CR. We're not there.  Dr. Michael Zervos: Can I ask you guys what your thought process is for evaluating the patient? So, when you're actually thinking about, “Hey, this patient actually had a good response. I'm going to ask the surgeons to come and take a look at this.” What imaging studies are you actually using? Are you just using strictly CT or are you looking for the PET? Should we also be thinking about restaging a lot of these patients? Because obviously, one of the things that I hate as a surgeon is getting into the operating room only to find out that I have multiple nodal stations that are positive. Which really, in my opinion, that's sort of a red flag. And for me, if I have that, I'm thinking more along the lines of not completing that surgery because I'm concerned about not being able to provide an R0 resection or even having surgical staple lines within proximity of cancer, which is not going to be good. It's going to be fraught with complications.  So, a lot of the things that we as surgeons struggle with have to do with this. Personally, I like to evaluate the patients with an IV intravenous CT scan to get a better idea of the nodal involvement, proximity to major blood vessels, and potentially even a PET scan. And though I think in this day and age, a lot of the patients will get the PET beforehand, not necessarily get it approved afterwards. So that's a challenge. And then the one thing I do have to say that I definitely have found helpful is, if there's any question, doing the restaging or the re-EBUS at that point to be particularly helpful.  Dr. Sandip Patel: Yeah, I would concur that having that pathologic nodal assessment is probably one of the most important things we can do for our patients. For a patient with multinodal positive disease, the honest truth is that at our tumor board, that patient is probably going to get definitive chemoradiation followed by their immunotherapy, or potentially soon, if they have an EGFR mutation, osimertinib. For those patients who are clean in the mediastinum and then potentially have nodal flare, oftentimes what our surgeons will do as the first stage of the operation, they'll actually have the EBUS repeated during that same anesthesia session and then go straight into surgery. And so far the vast majority of those patients have proceeded to go to surgery because all we found are immune cells in those lymph nodes.  So, I think it's a great point that it's really the pathologic staging that's driving this and having a close relationship with our pathologists is key. But I think one point that I think we all could agree on is the way that we're going to find more of these patients to help and cure with these therapies is through improved utilization of low-dose CT screening in the appropriate population in primary care. And so, getting buy-in from our primary care doctors so that they can do the appropriate low-dose CT screening along with smoking cessation, and find these patients so that we can offer them these therapies, I think is something that we really, as a community, need to advocate on. Because a lot of what we do with next-generation therapies, at least on the medical oncology side, is kind of preaching to the choir. But getting the buy-in so we can find more of these cases at stage 1, 2 or 3, as opposed to stage 4, I think, is one of the ways we can really make a positive impact for patients. Dr. Vamsi Velcheti: I just want to go back to Mike's point about the nodal, especially for those with nodal multistation disease. In my opinion, those anatomic unresectability is a moving target, especially with evolving, improving systemic therapy options. The utilization for chemo radiation has actually gone down. I think that's a different clinical subgroup that we need to kind of think differently in terms of how we do the next iteration or generation of clinical trials, are they really benefiting from chemo-IO induction? And maybe we can get a subset of those patients in surgery. I personally think surgery is probably a more optimal, higher yield to potentially cure these patients versus chemo radiation. But I think how we identify those patients is a big challenge. And maybe we should do a sequential approach induction chemo-IO with the intent to kind of restage them for surgery. And if they don't, they go to chemo consolidation radiation, I guess. So, I think we need to rethink our approach to those anatomically unresectable stage 3s. But I think it's fascinating that we're having these discussions. You know, we've come to accept chemo radiation as a gold standard, but now we're kind of challenging those assumptions, and I think that means we're really doing well in terms of systemic therapy options for our patients to drive increased cures for these patients. Dr. Michael Zervos: I think from my perspective as a surgeon, if I'm looking at a CT scan and trying to evaluate whether a patient is resectable or not, one of the things that I'm looking for is the extent of the tumor, proximity to mediastinal invasion, lymph nodes size. But if that particular patient is resectable upfront, then usually, that patient that receives induction chemo checkpoint inhibition is going to be resectable afterwards. The ones that are harder are the ones that are borderline resectable upfront or not resectable. And then you're trying to figure out on the back end whether you can actually do the surgery.  Fortunately, we're not really taking many patients to the operating room under those circumstances to find that they're not resectable. Having said that, I did have one of those cases recently where I got in there and there were multiple lymph node stations that were positive. And I have to say that the CT really underestimated the extent of disease that I saw in the operating room. So, there are some challenges surrounding all of these things. Dr. Sandip Patel: Absolutely. And I think for those patients, if upfront identification by EBUS showed multi nodal involvement, we've had excellent outcomes by working with radiation oncologists using modern radiotherapy techniques, with concurrent chemo radiation, followed by their immunotherapy, more targeted therapy, at least it looks like soon. I think finding the right path for the patient is so key, and I think getting that mediastinal pathologic assessment, as opposed to just guessing based on what the PET CT looks like, is so important. If you look at some of the series, 8% to 10% of patients will get a false-positive PET on their mediastinal lymph nodes due to coccidioidomycosis or sarcoidosis or various other things. And the flip side is there's a false-negative rate as well. I think Mike summarized that as well, so I think imaging is helpful, but for me, imaging is really just pointing the target at where we need to get pathologic sampling, most commonly by EBUS. And getting our interventional pulmonary colleagues to help us do that, I think is so important because we have really nice therapeutic options, whether it's curative-intent surgery, curative-intent chemo radiation, where we as medical oncologists can really contribute to that curative-intent local therapy, in my opinion.  Dr. Vamsi Velcheti: Thank you so much Sandip and Mike, it's been an amazing and insightful discussion, with a really dynamic interplay between systemic therapy and surgical innovations. These are really exciting times for our patients and for us. Thank you so much for sharing your expertise and insights with us today on the ASCO Daily News Podcast.   I want to also thank our listeners today for your time. If you value the insights that you hear today, please take a moment to rate, review, and subscribe to the podcast wherever you get your podcasts. Thank you so much. [FH1]   Dr. Sandip Patel: Thank you. Dr. Michael Zervos: Thank you.   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. Vamsidhar Velcheti @VamsiVelcheti Dr. Sandip Patel @PatelOncology Dr. Michael Zervos   Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Sandip Patel: Consulting or Advisory Role: Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca/MedImmune, Nektar, Compugen, Illumina, Amgen, Certis, Eli Lilly, Roche/Genentech, Merck, Pfizer, Tempus, Iovance Biotherapeutics. Speakers' Bureau: Merck, Boehringer Ingelheim Research Funding (Inst.):Rubius, Bristol-Myers Squibb, Pfizer, Roche/Genentech, Amgen AstraZenece/MedImmune, Fate, Merck, Iovance, Takeda   Dr. Michael Zervos: No relationships to disclose

Featuring perspectives from Dr Joyce F Liu, Dr Mansoor Raza Mirza and Dr David M O'Malley, moderated by Dr Kathleen N Moore, including the following topics: Introduction (0:00) Current Up-Front Treatment for Advanced Ovarian Cancer (OC) — Dr Liu (2:06) Potential Role of Immunotherapeutic Strategies for Advanced OC — Dr O'Malley (25:12) Incorporation of Novel Therapies into the Management of Relapsed/Refractory OC — Dr Moore (48:23) Diagnosis and Management of Adverse Events Associated with Commonly Employed Therapies for Advanced OC — Dr Mirza (1:06:59) CME information and select publications

Dr. Patel, of the Swedish Cancer Institute in Seattle, Washington, joins Chadi Nabhan, MD, MBA, FACP, on “The HemOnc Pulse” to discuss novel frontline therapies in the lymphoma space, including the bispecific antibody glofitamab. They also discuss bispecifics versus chimeric antigen receptor (CAR) T-cell therapy, fixed duration therapy and step-up dosing, and how to sequence therapy.

Welcome back to The Trip Report Podcast, a production of Beckley Waves, a Psychedelic Venture Studio.This week, I am speaking with Dr. Jackie von Salm, Ph.D., co-founder and Chief Scientific Officer at Psilera, a biotech company pioneering early-stage psychedelic-inspired drug discovery and development for neurological conditions.If you've ever been curious about the intricate and fascinating world of drug discovery, this conversation is a must-listen.Jackie walks me through the entire process, from scaffolds to IND submission and all the steps in between.Along the way, we discuss her background in natural product chemistry, the role of secondary metabolites, and a unique property of adaptive physiology whereby some types of stress actually strengthen organisms.We discuss the origin story of Psilera and the inspiration from 2 Bromo-LSD, a non-hallucinogenic compound that has been successfully used by people suffering from cluster headaches, among other neurological conditions.We discuss the increasing role of AI and computation in the drug discovery process but also the ‘chemical intuition' that one develops after years of practicing chemistry. We dive into the emerging field of neuropsychiatric biomarkers, a toolset that has eluded researchers, clinicians, and patients in this particular field, and how EEG and other brain imaging technologies may be the answer.We discuss the perception of psychedelic drug development in the eyes of the pharma world and much more.And now, I bring you my conversation with Dr. Jackie von Salm.Listen to the episode on Substack, Spotify, Google or Apple.Credits:* Hosted by Zach Haigney * Produced by Zach Haigney, Erin Greenhouse, and Katelin Jabbari* Find us at thetripreport.com* Follow us on Instagram, Twitter, LinkedIn and YouTubeTheme music by MANCHO Sounds, Mixed and Mastered by Rollin Weary This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit www.thetripreport.com

How can novel therapies improve the lives of your patients with epidermolysis bullosa (EB)? Credit available for this activity expires: 3/28/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1000534?ecd=bdc_podcast_libsyn_mscpedu

Welcome to Episode 33 of “The 2 View,” the podcast for EM and urgent care nurse practitioners and physician assistants! Show Notes for Episode 33 of “The 2 View” – Walking Boots, Jones Fracture: A Review, and a Few Procedures: Penile Foreign Body Removal and Keloid Removal. Walking Boots Infraorbital Nerve Block Courtesy of Jessica Mason MD. Dropbox. Accessed January 24, 2024. https://www.dropbox.com/scl/fi/r6ite1ior1wdcg63jcect/Infraorbital-Nerve-Block-Courtesy-of-Jessica-Mason-MD.mp4?rlkey=o5aiz60qmcvpqlnz2z62q8vkz&dl=0 Jones Fracture: A Review Jones J, Datir A. Jones fracture. In: Radiopaedia.org. Radiopaedia.org; 2008. Revised October 20, 2023. Accessed January 24, 2024. https://radiopaedia.org/articles/jones-fracture-1?lang=us Metzl JA, Bowers MW, Anderson RB. Fifth Metatarsal Jones Fractures: Diagnosis and Treatment. J Am Acad Orthop Surg. Published February 15, 2022. Accessed January 24, 2024. https://journals.lww.com/jaaos/Fulltext/2022/02150/FifthMetatarsalJonesFracturesDiagnosisand.6.aspx Michigan Foot Doctors. 5th Metatarsal Jones Fracture [Recovery, Treatment & Surgery]. YouTube. Published April 22, 2020. Accessed January 24, 2024. https://www.youtube.com/watch?v=8f0ECP1FtCc A Few Procedures: Penile Foreign Body Removal and Keloid Removal Memariani H, Memariani M, Moravvej H, Shahidi-Dadras M. Emerging and Novel Therapies for Keloids: A compendious review. Sultan Qaboos Univ Med J. NIH: National Library of Medicine, National Center for Biotechnology Information. Published February 2021. Accessed January 24, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968901/ Roberts JR. Roberts and Hedges' Clinical Procedures in Emergency Medicine and Acute Care, 7th Edition; 2018. Accessed January 24, 2024. https://www.us.elsevierhealth.com/roberts-and-hedges-clinical-procedures-in-emergency-medicine-and-acute-care-9780323354783.html Roberts JR, Roberts M. The Curse of the Keloid. Emergency Medicine News. Published February 28, 2018. Accessed January 24, 2024. https://journals.lww.com/em-news/blog/theproceduralpause/pages/post.aspx?PostID=79 The Proceduralist. Foreign body in the shaft of the penis removal using dorsal nerve block. YouTube. Published January 11, 2024. Accessed January 24, 2024. https://www.youtube.com/watch?v=71PesnLDl-0 The Proceduralist. Keloid. YouTube. Published February 9, 2018. Accessed January 24, 2024. https://www.youtube.com/watch?v=wRBstgCULBc Weech D, Ameer MA, Ashurst JV. Anatomy, Abdomen and Pelvis, Penis Dorsal Nerve. StatPearls Publishing. NIH: National Library of Medicine, National Center for Biotechnology Information. Updated August 8, 2023. Accessed January 24, 2024. https://www.ncbi.nlm.nih.gov/books/NBK525966/ Recurring Sources Center for Medical Education. Ccme.org. http://ccme.org The Proceduralist. Theproceduralist.org. http://www.theproceduralist.org The Procedural Pause. Emergency Medicine News. Lww.com. https://journals.lww.com/em-news/blog/theproceduralpause/pages/default.aspx The Skeptics Guide to Emergency Medicine. Thesgem.com. http://www.thesgem.com Trivia Question: Send answers to 2viewcast@gmail.com Be sure to keep tuning in for more great prizes and fun trivia questions! Once you hear the question, please email us your guesses at 2viewcast@gmail.com and tell us who you want to give a shout-out to. Be sure to listen in and see what we have to share!

Featuring perspectives from Dr Amrita Krishnan, Dr Sagar Lonial, Dr Robert Z Orlowski, Dr Noopur Raje and Dr Paul G Richardson, including the following topics:    • Introduction (0:00) • Management of Newly Diagnosed Multiple Myeloma (MM) — Dr Richardson (4:47) • Integration of Novel Therapies into the Management of Relapsed/Refractory (R/R) MM — Dr Lonial (30:01) • Chimeric Antigen Receptor (CAR) T-Cell Therapy for MM — Dr Raje (57:22) • Bispecific Antibodies in the Treatment of MM — Dr Krishnan (1:19:54) • Other Novel Agents and Strategies Under Investigation for MM — Dr Orlowski (1:37:56)   CME information and select publications  

Featuring perspectives from Prof Michael Dickinson, Prof Grzegorz S Nowakowski, Prof Gilles Salles, Dr Laurie H Sehn and Dr Jason Westin, including the following topics:    • Introduction (0:00) • Up-Front Management of Diffuse Large B-Cell Lymphoma (DLBCL) — Dr Salles (6:58) • Promising Investigational Approaches to First-Line Therapy for DLBCL — Dr Nowakowski (25:27) • Selection and Sequencing of Novel Therapies for Relapsed/Refractory (R/R) DLBCL — Dr Sehn (48:08) • Incorporation of CAR T-Cell Therapy into the Management of R/R DLBCL — Dr Westin (1:18:15) • Role of Bispecific Antibodies in the Treatment of DLBCL — Prof Dickinson (1:43:27)   CME information and select publications  

Novel therapies targeting the immune system and their combinations are gaining ground in AML. This podcast series, led by expert faculty, will clarify the potential and utility of innovative therapies that harness the immune system and will provide guidance on their applicability into clinical practice, especially for elderly/unfit patients with AML. Launch Date: December 27, 2023Release Date: December 27, 2023Expiration Date: November 30, 2024FACULTY BIOSTapan Kadia, MDMD Anderson Cancer InstituteUniversity of TexasDaniel Pollyea, MDProfessor of MedicineUniversity of Colorado School of MedicineDepartment of HematologyEunice Wang, MDProfessor of OncologyChief, Leukemia/Benign Hematology ServiceDepartment of MedicineMedical Director, Chemo/Infusion ClinicsRosewell Park Comprehensive Cancer CenterThis podcast provides accredited continuing education credits. To qualify for credit, please read all accreditation information at the provided link below prior to listening to this episode.https://www.practicepointcme.com/CMEHome/conversations-in-acute-myeloid-leukemia-novel-therapies-targeting-the-immune-system-for-elderlyunfit-patients-1

Novel therapies targeting the immune system and their combinations are gaining ground in AML. This podcast series, led by expert faculty, will clarify the potential and utility of innovative therapies that harness the immune system and will provide guidance on their applicability into clinical practice, especially for elderly/unfit patients with AML. Launch Date: December 27, 2023Release Date: December 27, 2023Expiration Date: November 30, 2024FACULTY BIOSTapan Kadia, MDMD Anderson Cancer InstituteUniversity of TexasDaniel Pollyea, MDProfessor of MedicineUniversity of Colorado School of MedicineDepartment of HematologyEunice Wang, MDProfessor of OncologyChief, Leukemia/Benign Hematology ServiceDepartment of MedicineMedical Director, Chemo/Infusion ClinicsRosewell Park Comprehensive Cancer CenterThis podcast provides accredited continuing education credits. To qualify for credit, please read all accreditation information at the provided link below prior to listening to this episode.https://www.practicepointcme.com/CMEHome/conversations-in-acute-myeloid-leukemia-novel-therapies-targeting-the-immune-system-for-elderlyunfit-patients-1

Novel therapies targeting the immune system and their combinations are gaining ground in AML. This podcast series, led by expert faculty, will clarify the potential and utility of innovative therapies that harness the immune system and will provide guidance on their applicability into clinical practice, especially for elderly/unfit patients with AML. Launch Date: December 27, 2023Release Date: December 27, 2023Expiration Date: November 30, 2024FACULTY BIOSTapan Kadia, MDMD Anderson Cancer InstituteUniversity of TexasDaniel Pollyea, MDProfessor of MedicineUniversity of Colorado School of MedicineDepartment of HematologyEunice Wang, MDProfessor of OncologyChief, Leukemia/Benign Hematology ServiceDepartment of MedicineMedical Director, Chemo/Infusion ClinicsRosewell Park Comprehensive Cancer CenterThis podcast provides accredited continuing education credits. To qualify for credit, please read all accreditation information at the provided link below prior to listening to this episode.https://www.practicepointcme.com/CMEHome/conversations-in-acute-myeloid-leukemia-novel-therapies-targeting-the-immune-system-for-elderlyunfit-patients-1

The 20th International Workshop on Non-Hodgkin Lymphoma (iwNHL 2023) took place in Miami, FL, and brought together leading experts as... The post iwNHL 2023 Session IV: Novel therapies in NHL: BTK inhibitors, BTK degraders, and bispecific antibodies appeared first on VJHemOnc.

Good morning from Pharma and Biotech Daily, the podcast that gives you only what's important to hear in the Pharma and Biotech world. Today we have some exciting news to share with you. Eli Lilly has recently entered into a collaboration with Tokyo-based Prism Biolab to develop small molecule inhibitors of protein-protein interactions. This partnership aims to target protein-protein interactions, which play a critical role in various disease processes. By developing drugs that can disrupt these interactions, there is potential for novel therapies for diseases such as cancer and autoimmune disorders. Lilly will be paying up to $660 million to gain access to Prism Biolab's proprietary platform.In another partnership, Boehringer Ingelheim has teamed up with Phenomic AI to develop targets for stroma-rich cancers. Stroma-rich cancers are known for their resistance to treatment, so by targeting the stroma, there is hope that the efficacy of cancer therapies can be enhanced. Boehringer Ingelheim will be paying $9 million upfront, with the potential for up to $500 million in milestone payments.Moving on to some interesting research, real-world data suggests that Eli Lilly's tirzepatide may achieve stronger and faster weight loss compared to Novo Nordisk's semaglutide in patients with type 2 diabetes. Healthcare analytics firm Truveta analyzed electronic health records and found promising results for tirzepatide.In regulatory news, the FDA has launched an investigation into malignancies linked to CAR-T therapies. The agency is evaluating the risk of T cell malignancies associated with CAR-T treatment and may take regulatory action if necessary.Shifting gears, we have some updates from the business world. Verve Therapeutics' stock price has recently dropped following a $148 million public offering. On a positive note, Novartis has raised its growth target as part of its "pure-play" strategy and has made adjustments to its pipeline.On a more global scale, a recent comparison of drug prices in the U.S. and other countries reveals significant variations, highlighting the complexities of pricing in the pharmaceutical industry.In our podcast section, we will be discussing recent deals in the industry, drug shortages for Dupixent and GLP-1 drugs, and the challenges faced by contract development and manufacturing organizations in 2023.Thank you for tuning in to Pharma and Biotech Daily. Stay informed, stay curious, and have a great day!

CME credits: 1.50 Valid until: 05-01-2024 Claim your CME credit at https://reachmd.com/programs/cme/improving-management-of-atopic-dermatitis-in-children-and-adults-with-novel-therapies/16084/ Atopic dermatitis (AD) affects people of all ages, races, and ethnicities. Fortunately, treatment options for AD are expanding. This webcast series focuses on emerging therapies, the transition from pediatric to adult care, and combating healthcare disparities from expert perspectives.=

Drs. Shaalan Beg and Shiraj Sen discuss notable advances in GI cancers featured at the 2023 ASCO Annual Meeting, including the PROSPECT and PRODIGE-23 trials in rectal adenocarcinoma, the MORPHEUS study in uHCC, and the NORPACT-1 trial in pancreatic head cancer. TRANSCRIPT     Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm the vice president of oncology at Science 37, and I'm an adjunct associate professor at UT Southwestern Medical Center. My guest today is Dr. Shiraj Sen. He is a GI medical oncologist and the director for clinical research at NEXT Oncology in Dallas.   Today, we'll be discussing practice-changing studies and other key advances in GI cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available on our transcripts at asco.org/DNpod.   Shiraj, it's great to have you on the podcast today.  Dr. Shiraj Sen: Thanks so much for having me today, Shaalan.  Dr. Shaalan Beg: We saw exciting new data and great progress in GI oncology at the ASCO Annual Meeting. I was hoping we could talk about LBA2. This was the PROSPECT study that was presented during the Plenary Session. It's a randomized, phase 3 trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemo, followed by the selective use of chemoradiation, followed by TME or total mesorectal excision for the treatment of locally advanced rectal cancer. This is the Alliance N1048 trial. What are your thoughts on this study?  Dr. Shiraj Sen: Thanks, Shaalan. It was great to see another GI study presented in a Plenary Session, and I thought this was a great trial that really took us back to thinking about why we do chemoradiation as well as chemotherapy perioperatively in locally advanced rectal cancer. And asking the important question of is there a select patient set or subset where we might be able to safely omit the chemoradiation piece.  To me, the impressive part was this study enrolled from 2012 to 2018. In 2012, when this treatment really started enrolling, the standard of care was long-course chemoradiation for five and a half weeks, followed by surgery, followed by adjuvant chemotherapy with FOLFOX or CAPOX. During this time, a lot of the practices of these patients have shifted from that to giving total neoadjuvant therapy, where we bunch the chemotherapy and chemotherapy upfront prior to the patient undergoing surgery. And this study really asked us to take a look at both practices and ask the question of which one is better and is it possible to de-escalate care for patients who get upfront chemotherapy and omit the chemoradiation and still have similar outcomes.   I thought it was very interesting that this was done in a non-inferiority-type manner, and we can talk more about that in a few minutes as well. But taking that all into context, the fact that in this study, that the non-inferiority endpoints were met for both disease-free survival as well as overall survival in the patients who were able to omit chemoradiation, I think in the big picture sense told us that there truly might be a patient subset where—this is in patients with T2 node-negative disease or T3 node-negative or T3 node-positive disease—where we might be able to safely exclude the chemoradiation and still have similarly effective outcomes for these patients.  Dr. Shaalan Beg: Those are great points, especially when we have started to think about colon cancer and rectal cancer as many different diseases based on their location. And we know that in some instances their biology can be different as well.   Can you talk a little bit about who those patients are that were enrolled on this trial? Because when I think about the German rectal study that led to us using neoadjuvant chemoradiation, the data was really around pelvic control of disease and sphincter preservation. So how did the patients who enrolled in this trial relate to the typical person with rectal cancer who walks through your doors?   Dr. Shiraj Sen: Yeah, great point. I think we should point out the inclusion-exclusion criteria for this study. These patients were only those who were, again, T2 node-positive or T3 node-positive or negative, patients for whom chemoradiation would be indicated in the setting, and patients for whom they'd be good candidates for sphincter-sparing surgeries. So, tumors that are quite up high. These are not for individuals who have tumors requiring an APR. These are not for patients who have clinical T4 tumors. And this is not applied, again, to those high-risk patients who have 4 or more pelvic lymph nodes that are 1 cm in size or larger in the short access. And so, patients who need essentially an APR and the high-risk T4 tumors who are, I think, better suited by something like we'll talk about later in the PRODIGE study.   I think one last point that might be worth making here on the PROSPECT trial is that it was a non-inferiority trial. And in my opinion, this was really a great use of a non-inferiority study. I believe that when there's a new treatment under consideration used in a non-inferiority study, it should be because that therapy or modality of treatment is safer, more cost-effective, or could help increase access to care without compromising efficacy, and ideally maybe more than one of the above. And in this case, I think really all of those checkboxes are met.   In urban settings where we work, we think about access to radiation being quite plentiful, but when we get to more rural areas, or parts of the world where they may not have access to radiation like we may, I think this data can help drive care for a number of patients there. It can certainly be more cost-effective as it allows the omission of radiation. And certainly, from some of the PRO data that they presented, it certainly can be felt to be safer and help omit some toxicities as well.  Dr. Shaalan Beg: Yeah, you mentioned a total neoadjuvant therapy and we seem to be entering this space in rectal cancer where the decision on which modalities an individual person will need for the management of their disease and what sequence they will need is all up for debate, whether that's chemotherapy or radiation, long-form, short-form radiation. And we also heard some results at earlier ASCO meetings around the omission of surgery in people who've had complete clinical responses as well.   And you mentioned total neoadjuvant therapy and at ASCO this year we heard the results from LBA3504, which is a PRODIGE-23 trial. The investigators reported 7-year results of this phase 3 study from the UNICANCER group in France. This study is really pushing the envelope. What are your key takeaways here?   Dr. Shiraj Sen: Great point. I think this study, especially when taken in conjunction with the PROSPECT trial, highlights the fact that these patients really can have heterogeneous diseases and ones that really require careful consideration and discussion at multidisciplinary tumor boards. Unlike the patient population in the PROSPECT trial, the PRODIGE study did treat patients with higher-risk disease. So these were patients with clinical T3, T4 tumors and so higher risk, and asked the question now with more mature 7-year follow-up of, when compared to receiving the standard of care at the time, which was a chemoradiation followed by TME, followed by adjuvant FOLFOX for 12 cycles or the capecitabine, does TNT giving again now modified full FOLFIRINOX for six cycles followed by chemoradiation followed by TME and then adjuvant FOLFOX, do the improvements in both disease-free survival, overall survival, and metastatic relapse rate, do they hold up, and/or are there any differences in local control?   And again, here they demonstrate that even with longer-term follow-up, that the improvements in OFS, DFS, and metastatic relapse rate, really do hold up even with longer-term follow-up. And so, for these patients with higher risk disease, it does seem that giving induction chemotherapy with modified FOLFIRINOX before chemoradiotherapy really might be kind of best practices. The safety profile, even with longer-term follow-up was unchanged. There was not any increase in local recurrences. And again, looking at quality of life metrics there seemed to be similar or maybe improved quality of life for patients who receive the TNT approach. And now again, I think the next step is, as the presenter mentioned, investigating this even in a more tailored fashion, as was done with the PROSPECT study.  Dr. Shaalan Beg: Let's change gears and talk about liver cancer. Abstract 4010 showed the results of the MORPHEUS-liver study. This was a phase 1b/2 randomized trial of tiragolumab in combination with atezolizumab and bevacizumab for people with unresectable locally advanced or metastatic hepatocellular cancer. It's really exciting to see innovations with immune therapy changing how we've managed hepatocellular cancer in the last few years. And here, we're seeing an addition of a third agent to an already approved regimen of atezolizumab and bevacizumab. I was really curious to hear what your take-home message is from this study.   Dr. Shiraj Sen: Yeah, this was another very interesting abstract that was presented at ASCO this year. It's hard to believe that it was only 3 years ago that we first got the approval of atezo plus bev, and that it took more than a decade to really have us as a field improve on outcomes for patients with liver cancer above and beyond giving sorafenib. And here we are just 3 years later, already launching new phase 3 studies from these sorts of early-phase adaptive signal-seeking studies. The investigators as a whole should be commended for the speed at which new drug development has really progressed in liver cancers after, again, quite a lull we had in the pre-I/O days.   It's encouraging to see that in just 3 years that there's another phase 3 study now being launched in HCC on the heels of this data combining the atezo-bev backbone to the anti-TIGIT molecule tiragolumab. Now, I know there was a lot of discussion and some criticism of this study and what the real effects of adding tiragolumab to atezo-bev might be because of the underperformance of the control arm. In this study, the atezo-bev control arm, it should be noted that was only 18 patients, had a response rate of only 11%. And of course, with longer-term follow-up of the IMbrave150 study, we know that with the atezo-bev, we expect a response rate of about 30%. And so how a real-world population of individuals receiving atezo-bev would compare to those receiving tiro-atezo-bev has been discussed. But I think the only real way to answer that question would be with a large, randomized phase III study. And it's encouraging to see that one is being launched to ask that question.    Dr. Shaalan Beg: Absolutely. Let's change gears and talk about pancreatic cancer. LBA4005 explored short-course neoadjuvant FOLFIRINOX versus upfront surgery for people with resectable pancreatic head adenocarcinoma in the NORPACT-1 study. This is a multicenter randomized phase 2 trial and we're starting to see the reporting of clinical trials evaluating the sequencing of systemic therapies for resectable disease. We've heard studies for neoadjuvant therapy for borderline resectable as well as resectable trials in previous meetings. But there's a lot of discussion around the NORPACT-1 trial which may be causing some people to pause on our current understanding of treatment sequencing for resectable disease. I'm curious to hear what your take homes are.   Dr. Shiraj Sen: Thanks. Yes, I thought this was a very interesting study as well. Depending on which institution one practices in, in recent years, many have shifted their practice for individuals with resectable pancreatic cancer from administering full FOLFIRINOX or adjuvant therapy only after surgery to giving it in the neoadjuvant setting based on, again, a number of smaller studies, some that are single institution. This is one of the first studies that in a randomized fashion has asked the question in just resectable pancreatic cancer. So we're not talking about borderline resectable or other patients.    But in resectable pancreatic cancer, whether there are differences now comes if patients receive surgery first, followed by FOLFIRINOX-only adjuvant setting or essentially getting perioperative FOLFIRINOX and so neoadjuvant, followed by surgery, followed by, as tolerated, four cycles of adjuvant FOLFIRINOX. And I was a little surprised by some of the results and to me some of these data were a little intriguing.  Specifically, I think if we take a deeper look like the discussant had after the presentation, there are, I think, some unanswered questions. Specifically, half the patients were randomized to receive neoadjuvant FOLFIRINOX and half of them received upfront surgery. But in the group of individuals who received neoadjuvant FOLFIRINOX, it looked like only half of them completed neoadjuvant chemotherapy. And some answers into kind of why that was, and what it was about those patients then who were in the neoadjuvant arm, is one thing that comes to mind.    Secondly, what I thought was interesting was this study was that it was designed very well to try to take out as much heterogeneity as possible. However, in both arms, there was actually quite a substantial number of individuals who ended up receiving gemcitabine-based chemotherapy. And that's even in the patients who received neoadjuvant FOLFIRINOX, and individuals who received neoadjuvant FOLFIRINOX, only 25% post-op went on to receive adjuvant FOLFIRINOX. And 75% almost received gemcitabine-based therapy. And again, why so many patients received off-protocol adjuvant therapy is something that kind of struck me.  I think the third and final thing that really struck me was, in the patients that received neoadjuvant FOLFIRINOX, there was a higher rate of R0 resections. 56% of patients had an R0 resection compared to those who got upfront surgery, where there was only a 39% rate and similarly kind of higher levels of N0 resection. And yet, despite all of this, again, the authors did show quite clearly that there were not any significant improvements in outcomes for patients that received neoadjuvant therapy, but kind of how improved surgical endpoints do not translate to overall survival and overall endpoints; I think there are still some questions there.    However, I do agree overall that despite these limitations with the conclusions of the author, that at this time at least, it's not clear; the results don't support the widespread use of neoadjuvant FOLFIRINOX as a standard of care for resectable pancreatic cancer. Fortunately, there are studies ongoing, like the Alliance [for Clinical Trials in Oncology] study and the PREOPANC-3 study that hopefully will kind of help settle this verdict.    Dr. Shaalan Beg: Yeah, it's a stark reminder that we need better treatments. I think we've been shifting the sequencing of these treatments and slicing them in as many ways as we can. And the core challenge is in finding better systemic therapies that have been found to be effective in advanced stage as well as in curative stages like this. And one of the points that bothered me about this trial was the drop-off that they saw at the beginning when the biliary system was being drained, or they were getting biopsies because folks who went for surgery upfront didn't always require those procedures. They didn't require histologic diagnosis either. But as is standard practice, before we give systemic therapy, we require psychologic confirmation. And that may have introduced a delay of a couple of days or a couple of weeks, which could have resulted in some imbalances in how survival is measured and how folks were doing. Because, as you know, a lot of times people diagnosed with this disease can be fairly sick, and a matter of a couple of days or weeks can make a big difference in terms of treatment with those.  I'm really excited to wait and hear how the Alliance study and the PREOPANC follow-up trials pan out and as a very important cautionary note for everyone, both the folks who have adopted neoadjuvant therapy and those that have not followed the data. And kudos to the investigators for completing that trial.  Dr. Shiraj Sen: Yeah, I fully agree. I'm glad to see that these trials are being run. I think we should not take anything away from the fact that these are very challenging trials to run. I think we certainly owe a big kudos to the patients who enroll in these studies who have resectable disease, but they're still willing to go through the process of an extra consent form, an extra kind of screening process, additional testing required to go into a clinical trial. And it's only because of them that we're able to run these studies and, as a field, get some answers on how to best take care of our patients.   Dr. Shaalan Beg: Shiraj, thank you so much for coming to the podcast today and sharing your valuable insights on the ASCO Daily News Podcast.   Dr. Shiraj Sen: Thank you so much for having me, and to all of the ASCO staff for having this podcast.  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. 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 podcasts.    Disclaimer:   The purpose of this podcast is to educate and 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. Shaalan Beg  @ShaalanBeg  Dr. Shiraj Sen  @ShirajSenMDPhD     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. Shiraj Sen:   Employment: Roche/Genentech  Stock and Other Ownership Interests: Roche/Genentech  Research Funding (Institution): ABM Therapeutics, Zentalis Pharmaceuticals, Parthenon Therapeutics, Pyxis Oncology, Georgiamune Inc.      

Iwan and Ben hear from Dr Ayush Sharma, Surgeon Scientist from Ambedkar Central Railway Hospital in India, on his trials exploring a role for Cerebrolysin (https://www.cerebrolysin.com) to help boost recovery after surgery for Degenerative Cervical Myelopathy. This is a recognised research priority.

Drs. Vamsi Velcheti and Jack West discuss key abstracts in advanced SCLC and NSCLC, along with highlighting the largest known data set correlating ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial, in advance of the 2023 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I am Dr. Vamsidhar Velcheti, your guest host of the ASCO Daily News Podcast today. I am a professor of medicine at NYU Grossman School of Medicine and the director of thoracic oncology at Perlmutter Cancer Center at NYU Langone Health. I am delighted to welcome Dr. Jack West, a thoracic oncologist and associate professor in medicine at the City of Hope Comprehensive Cancer Center.                                  Today, we'll be discussing key posters and oral abstracts in lung cancer that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Jack, it's great to have you on the podcast today. Dr. Jack West: Well, thank you so much, it's my pleasure to be here.  Dr. Vamsidhar Velcheti: Let's begin with Abstract 8512. This is the follow-up of the Gronberg trial, the Danish trial of BID thoracic radiation for limited-stage small cell lung cancer. What are your key takeaways from this trial? Dr. Jack West: Well, as you noted, this has been presented before a few years ago. It's a trial for limited-stage small cell lung cancer and it directly compared chemotherapy with either 45 Gray or 60 Gray of chest radiation delivered twice daily. It's not an enormous study, it's 170 eligible patients. And years ago, we saw that the efficacy endpoints looked very promising for the patients who received a higher dose of 60 Gray on a BID schedule, which is above our standard. We generally either give 45 Gray BID or probably more commonly in the US and I think globally give maybe 60 Gray on a once-a-day schedule. But the efficacy looked quite promising and without any clear increase in the toxicity of it. And really, despite the impressive results, this hasn't changed practice. It is not a large study and I think that I would say that most of the radiation oncology world has been reserving judgment until potentially seeing a larger study.  But what's being presented at ASCO are the longer-term results that continue to look excellent. You have a progression-free survival median of 18.6 months versus 10.9 months. That's not statistically significant but has a hazard ratio of 0.76 associated with it. And the median overall survival is even more pronounced of 43.5 months favoring the 60 Gray arm compared to 22.6 months in 45 Gray on a BID schedule that has a hazard ratio of 0.69. And this is statistically significant. The authors note that they will be presenting five-year overall survival as well. And there's also just passing mention that, as was seen previously, there was no increase in toxicity, no prohibitive toxicity. So I don't think it's necessarily going to change practice because the numbers of patients, which I think are really the leading concern, hasn't changed. But these very promising results still hold up over time and I think should compel us to carefully assess this as an option to potentially increase outcomes for this challenging setting where progress is slow to come. Dr. Vamsidhar Velcheti: Yeah, I completely agree, Jack. And I think one of the things that we have seen, at least in the non-small cell setting, like the higher dose of conventional radiation is not superior to the 45 Gray, BID dosing. I think there were some studies with CALGB and the Gronberg trial, but I think at the end of the day, it comes down to patient conveniencer. It's not often feasible for patients to come in twice a day for radiation. That might be something that might limit utilization here.  Dr. Jack West: I think that's a very good point. It's just difficult when you have the potential for higher cure rates, but it is at least challenging, if not completely infeasible. But I really agree with you that that's a big part of why it's underutilized relative to the strength of the data for BID. But we have to be able to actually administer these. Dr. Vamsidhar Velcheti: So let's move on to another trial. And again, we've seen the data before. This is Abstract 8521, the CheckMate-816 trial. They reported the three-year results of the neoadjuvant nivolumab chemotherapy versus chemotherapy by definitive surgery in patients with resected non-smoker lung cancer. What is the data that's being presented at ASCO this year? Dr. Jack West: So yes, as you mentioned, we've seen data on CheckMate-816 for a few years now. It's been published in the New England Journal of Medicine and it's FDA-approved and has become a standard of care, if not the standard of care, but there are many dimensions to this. And one of the questions has been what happens to the patients who did not undergo surgery, which was about 17% of patients on the chemoimmunotherapy arm, a full quarter of patients on the chemo arm. What happened to these folks? And that's what is being presented by Dr. Jonathan Spicer, a thoracic surgeon in Montreal who's been heavily involved with this trial. And I think that's going to be the overwhelming focus of this.  And what is reported in the abstract, and I'm sure we'll see more interesting results, is that the outcomes are superior in the patients who received chemoimmunotherapy with nivolumab, in the patients who did not undergo surgery as well as those who did. Specifically, they report on the median time before death or distant metastases, and that was 24.8 months as a median for the chemoimmunotherapy arm versus 15.6 months for the patients who receive neoadjuvant chemo alone. The hazard ratio for that's 0.63. There was also a striking difference in the three-year survival rates, 36% versus 13% also favoring chemo and nivolumab.  They also talked about the actual treatments that patients received when they didn't have surgery, and about 60% in both of those arms received radiation instead of surgery, and about half the patients also received additional systemic therapy. So we will see more. But I think it helps to address one lingering question of what happens to the patients who did not end up pursuing surgery and showing that the results were more favorable for the recipients of chemo nivolumab, even in that subset. Dr. Vamsidhar Velcheti: It's simply fascinating how the field is evolving in the perioperative space, Jack. And there are more unanswered questions here and up for debate for years with the recent agent trials we had seen at AACR. We've seen the same kind of trend even with the agent, I think it was 20%, who did not make it to surgery. A lot of them are like stage 3 patients. So it begs the question, are we kind of just being more aggressive with induction therapy? Maybe some of these patients are biologically or anatomically not bound to have surgery. I mean, it's hard to really tell. Dr. Jack West: It really is important for us to still select appropriate patients for this, rather than become overly ambitious and try to shoehorn patients who are really not ideal or appropriate candidates for surgery and anticipate or have kind of aspirational resectability if they aren't de novo great candidates for surgery. We, of course, need to remember that chemoradiation followed by consolidation durvalumab on the PACIFIC trial is not some terrible consolation prize. We've done remarkably better with this over the years, and it's a very strong option.  Dr. Vamsidhar Velcheti: Exactly. The other open question, but of course this abstract doesn't really address is, what do you do with all the patients who perhaps have major pathologic responses and what do you do after surgery? That's kind of an open question, and we probably need a better way to determine who might need adjuvant therapy or surgery. I don't know if you have any thoughts on that.  Dr. Jack West: As you say, I think that's a big question, a gaping hole in our knowledge base, but it's not addressed here. I think we are going to be struggling with that in the coming years.   Dr. Vamsidhar Velcheti: Right. So let's move on to Abstract 9002. This is a report of the first pivotal study results of DZD9008 sunvozertinib in patients with exon 20 EGFR mutation. What are your key takeaways from the study? Dr. Jack West: So I would say obviously we have a couple of agents that target EGFR exon 20 mutations, but unfortunately, neither of the agents that are commercially available is especially active. And they certainly have toxicity challenges, whether it's amivantinab or mobocertinib,  they both share some challenges and they're not as efficacious as some of the other targeted therapies we use in different molecular settings. So I would say there's still some unmet need here. And these results with sunvozertinib DZD9008 selective irreversible EGFRexon20 insertion inhibitor really got my attention as very impressive. These are patients who were heavily pretreated. The median was two prior lines of therapy. This is not de novo first line, and that's a setting where it's pretty hard to see response rates that are over 30 or 40%, but what they actually report is about 60.8% response rate and nearly 100 patients assessed. They also looked at patients who had brain metastases and 31 patients in their sample had de novo metastases and the intracranial response rate was 48.5%, so nearly half.  This is, of course, something that we hope to see as a pattern when we have a targeted therapy that's very effective for the right target, not just overall extracranial, but intracranial efficacy. And we're going to need to see the details on the tolerability because, as I mentioned, the available agents now have the dual challenge of just modest efficacy and really quite challenging, particularly GI toxicities and amivantamab has issues also with infusion reactions. So some work there and I think there's room to improve on that. This looks to me very promising and I would welcome having the opportunity to use it in my patients who have an exon20 mutation.  Dr. Vamsidhar Velcheti: Yeah, I think certainly the brain intracranial activity is perhaps going to be the differentiator here. Given that mobocertinib has limited intracranial activity, I think that's very encouraging to see. So let's move on to the next abstract, the SCARLET trial, Abstract 9006. So this is a clinical trial of sotorasib plus chemotherapy in KRAS G12C-positive patients. Can you tell us a little bit more about this study, Dr. West? Dr. Jack West: Sure. So this was a single-arm phase II trial. It's not large, it's 30 patients, but we really have yet to see results that would compel me to move sotorasib into the first-line setting. I was a little underwhelmed with the CodeBreaK 200 results that didn't beat docetaxel for survival in the second-line setting. But here it's a combination of carboplatin pemetrexed with sodorasib in the first-line setting in patients, of course, with a KRAS G12C mutation and nonsquamous histology. And the reported response rate by independent review is 88.9%, which is quite impressive. The median PFS is not reached yet. The PFS at six months is 61.2%. So I think we'll need to see the full data set, but that really impresses me as a very relevant finding. So I would love to learn more about this. And I think that if it is anything close to holding up with these response rates, close to 90%, I mean, even if it's 70 or 80%, I think that is compelling enough to really want to study this further in the first line setting and maybe a path to getting KRAS inhibitors used in the front line. Dr. Vamsidhar Velcheti: Yeah, I completely agree. And I think with all the issues around the combination with checkpoint inhibitors, especially with sotorasib high liver toxicity, so I think the only way this could move into the frontline is with combination with chemotherapy, especially in certain subsets like KEAP1 CUL drug patients, STK11/KEAP1 patients where immunotherapy historically underperforms. So it'll be interesting to see how this can evolve.  So, moving on to Abstract 9012, this is a clinical trial evaluating a often very neglected patient population. This is a retrospective study of chemo without immunotherapy in the elderly population of patients with PD-L1-positive tumors. So what is your takeaway from this study? Dr. Jack West: I would say that it really complements in my mind the presentation by Dr. Akinboro and colleagues from the FDA last year at ASCO, which was looking at the data for the trials of immunotherapy or chemoimmunotherapy in patients with high PD-L1 50% or higher. And what they found was that there was an improvement in response rate and progression-free survival and a trend, but not a significant difference in overall survival favoring chemoimmunotherapy in those patients. But they also noted that patients who were 75 or older did not seem to benefit from chemoimmunotherapy relative to immunotherapy alone. Now, that is in patients with high tumor PD-L1. This is looking specifically at patients who are 75 and older in Japan, 58 centers, and we're talking about over 1,200 patients, 1,245. And they looked at patients with any PD-L1. So the full spectrum, about 22% had PD-L1 less than 1%,31%, one to 49%, and just over a third, 34% with PD-L1 over 50%. I would presume the balance, that missing 13%, was not tested. But these are real-world data and they have strengths and limitations relative to controlled clinical trials.  But I think that there is some power in numbers and real-world data. And what they saw was that the patients who received chemoimmunotherapy had a median overall survival of 20 months. It was 19.8 months with a checkpoint inhibitor alone. And those data for both of those conditions are far better than a platinum doublet alone with a median overall survival of 12.8 months. Single-agent chemo just median overall survival of 9.5 months. And then when they looked at toxicities, saw that the grade three or higher immune-related adverse events was clearly higher in the patients who had chemoimmunotherapy, they had a greater need for steroids and a greater probability of pneumonitis than the patients over 75 who received a checkpoint inhibitor alone.  And so I would say it's not randomized data. You can only take this so far, but the fact is that it, I think, complements what we saw from the FDA. And that would help me in a situation where we need to make a nuanced decision, there's competing potential standards of care. I think this is informative along with the IPSOS trial that has been presented in some other settings and shows a benefit for in that setting was atezolizumab, I believe, first as the immunotherapy for older patients and PS2. So I think that we're seeing converging evidence to support this concept. Dr. Vamsidhar Velcheti: Yeah, and I completely agree. And I think sometimes the clinical nuances at the individual patient level, I think there are so many other factors that we can actually look at the real-world data, like, for example, tumor burden and medical tomographies. There's so many things that we need to factor into while making those decisions.  Let's move on to the next abstract. This is Abstract 9022. This is an abstract looking at correlations of ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial. What are your key takeaways from this study? Dr. Jack West: I would love to use ctDNA for clinical decision-making in a few years. I think it could be as pivotal as PET scans, but we don't have the data yet to show that you can use the results to improve outcomes. But this is looking at ctDNA in a different setting, as you mentioned, it's looking at the EMPOWER-Lung 1 trial, which was cemiplimab versus chemotherapy in patients with PD-L1 over 50% and did not have a driver mutation. They had ctDNA samples available from 175 patients who were pretty evenly split between chemo and checkpoint inhibitor cemiplimab. What they found was that molecular response, or particularly complete molecular response, if it was seen as in complete eradication of ctDNA at week nine, so after three cycles, was highly correlated with imaging-based response for patients who got cemiplimab. It was not correlated for the patients who got chemotherapy and, perhaps not surprisingly, the patients who had a complete molecular response that was associated with the best overall survival, an immediate overall survival of 29 months compared to the rather dismal results for patients who had no drop in their ctDNA, where the median overall survival was just eight months.  So, I think that it would be wonderful to be able to use this as a help. We know that sometimes patients have ambiguous imaging. There is the possibility of pseudoprogression and just potentially pneumonitis, making it difficult to interpret. I think that ctDNA could be helpful in that situation, but also for early feedback on who might benefit from intensification and adding chemotherapy, who we should cut our losses and switch to something else other than cemiplimab. And in the best-case scenarios, we do have a subset of patients who are doing extraordinarily well, potentially one or a couple of years later, and we just don't know if or whether to stop it and whether patients can do just as well after stopping after a prolonged period on treatment compared to staying on it. And we don't want to give this for years longer at the expense of cumulative toxicities and requiring a patient to come in for ongoing treatments month after month, year after year, for any longer than they would need.  I think that there's great potential utility for this as a concept. But again, at some point, what we'll really need is not to just apply this retrospectively, but prospectively to guide therapeutic decisions, to see if we can have patients do better by intensifying for those patients who need it or de-intensifying for patients who don't. Dr. Vamsidhar Velcheti: It's great, Jack. And I completely agree. I think those kinds of de-escalation trials are very much needed. I'm hoping that we'll get there very soon.   Thank you so much, Dr. West, for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate your time. Thank you so much. Look forward to seeing you in Chicago. Dr. Jack West: Awesome. Great.  Dr. Vamsidhar Velcheti: And I'd like to thank all the listeners for joining us today. 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. Thank you so much.  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.   Follow today's speakers: Dr. Vamsidhar Velcheti @VamsiVelcheti Dr. H. Jack West @JackWestMD  Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Jack West: Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics Speakers' Bureau: Takeda, Merck, AstraZeneca

This month on Episode 47 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the March 31 issue of Circulation Research. We'll also provide an overview of the Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease published in the April 14 issue. Finally, this episode features an interview with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   Article highlights:   Shi, et al. LncRNAs Regulate SMC Phenotypic Transition   Chen, et al. Bilirubin Stabilizes Atherosclerotic Plaque   Subramaniam, et al. Mapping Non-Obvious cAMP Nanodomains by Proteomics   Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease   Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to share three articles selected from our March 31st issue of Circulation Research and give you a quick summary of our April 14th Compendium. I'm also excited to speak with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   So first the highlights. The first article we're going to discuss is Discovery of Transacting Long Noncoding RNAs that Regulates Smooth Muscle Cell Phenotype. This article's coming from Stanford University and the laboratory of Dr Thomas Quertermous. Smooth muscle cells are the major cell type contributing to atherosclerotic plaques. And in plaque pathogenesis, the cells can undergo a phenotypic transition whereby a contractile smooth muscle cell can trans differentiate into other cell types found within the plaque, such as macrophage-like cells, osteoblast-like cells and fibroblast-like cells. These transitions are regulated by a network of genetic and epigenetic mechanisms, and these mechanisms govern the risk of disease.   The involvement of long non-coding RNAs, or Lnc RNAs as they're called, has been increasingly identified in cardiovascular disease. However, smooth muscle cell Lnc RNAs have not been comprehensively characterized and the regulatory role in the smooth muscle cell state transition is not thoroughly understood. To address this gap, Shi and colleagues created a discovery pipeline and applied it to deeply strand-specific RNA sequencing from human coronary artery smooth muscle cells that were stressed with different disease related stimuli. Subsequently, the functional relevancy of a few novel Lnc RNAs was verified in vitro.   From this pipeline, they identified over 4,500 known and over 13,000 unknown or previously unknown Lnc RNAs in human coronary artery smooth muscle cells. The genomic location of these long noncoding RNAs was enriched near coronary artery disease related transcription factor and genetic loci. They were also found to be gene regulators of smooth muscle cell identity. Two novel Lnc RNAs, ZEB-interacting suppressor or ZIPPOR and TNS1-antisense or TNS1-AS2, were identified by the screen, and this group discovered that the coronary artery disease gene, ZEB2, which is a transcription factor in the TGF beta signaling pathway, is a target for these Lnc RNAs. These data suggest a critical role for long noncoding RNAs in smooth muscle cell phenotypic transition and in human atherosclerotic disease.   Cindy St. Hilaire:              The second article I want to share is titled Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency. This article is coming from the Heart Research Institute and the corresponding author is Roland Stocker. The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin, a byproduct of heme catabolism, is inversely associated with risk of cardiovascular disease, but the link between bilirubin and atherosclerosis is unknown.   Chen et el addressed this gap by crossing a bilirubin knockout mice to a atherosclerosis prone APOe knockout mouse. Chen et el addressed this gap by crossing the bilirubin knockout mouse to the atherosclerosis-prone APOE knockout mouse, and used the tandem stenosis model of plaque instability to address this question. Compared with their litter mate controls, bilirubin-APOE double knockouts showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia. And they had higher atherosclerotic plaque burden.   Hemeatabolism was increased in unstable plaques compared with stable plaques in both of these groups as well as in human coronary arteries. In mice, the bilirubin deletion selectively destabilized unstable plaques and this was characterized by positive arterial remodeling and increased cap thinning, intra plaque hemorrhage, infiltration of neutrophils and MPO activity. Subsequent proteomics analysis confirmed bilirubin deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils and associated oxidative stress in the unstable plaque. Thus, bilirubin deficiency generates a pro atherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaques, thereby providing a link between bilirubin and cardiovascular disease risk.   Cindy St. Hilaire:              The third article I want to share is titled Integrated Proteomics Unveils Regulation of Cardiac Monocyte Hypertrophic Growth by a Nuclear Cyclic AMP Nano Domain under the Control of PDE3A. This study is coming from the University of Oxford in the lab of Manuela Zaccolo. Cyclic AMP is a critically important secondary messenger downstream from a myriad of signaling receptors on the cell surface. Signaling by cyclic AMP is organized in multiple distinct subcellular nano domains, regulated by cyclic AMP hydrolyzing phosphodiesterases or PDEs.   The cardiac beta adrenergic signaling has served as the prototypical system to elucidate this very complex cyclic AMP compartmentalization. Although studies in cardiac monocytes have provided an understanding of the location and the properties of a handful of these subcellular domains, an overview of the cellular landscape of the cyclic AMP nano domains is missing.   To understand the nanodynamics, Subramanian et al combined an integrated phospho proteomics approach that took advantage of the unique role that individual phosphodiesterases play in the control of local cyclic AMP. They combined this with network analysis to identify previously unrecognized cyclic AMP nano domains associated with beta adrenergic stimulation. They found that indeed this integrated phospho proteomics approach could successfully pinpoint the location of these signaling domains and it provided crucial cues to determine the function of previously unknown cyclic AMP nano domains.   The group characterized one such cellular compartment in detail and they showed that the phosphodiesterase PDE3A2 isoform operates in a nuclear nano domain that involves SMAD4 and HDAC1. Inhibition of PDE3 resulted in an increased HDAC1 phosphorylation, which led to an inhibition of its deacetylase activity, and thus derepression of gene transcription and cardiac monocyte hypertrophic growth. These findings reveal a very unique mechanism that explains the negative long-term consequences observed in patients with heart failure treated with PDE3 inhibitors.   Cindy St. Hilaire:              The April 14th issue is our compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease. Dr Heidi Noels from the University of Aachen is our guest editor of the 11 articles in this issue. Chronic kidney disease is defined by kidney damage or a reduced kidney filtration function. Chronic kidney disease is a highly prevalent condition affecting over 13% of the population worldwide and its progressive nature has devastating effects on patient health. At the end stage of kidney disease, patients depend on dialysis or kidney transplantation for survival. However, less than 1% of CKD patients will reach this end stage of chronic kidney disease. Instead, most of them with moderate to advanced chronic kidney disease will prematurely die and most often they die from cardiovascular disease. And this highlights the extreme cardiovascular burden patients with CKD have.   The titles of the articles in this compendium are the Cardio Kidney Patient Epidemiology, Clinical Characteristics, and Therapy by Nicholas Marx, the Innate Immunity System in Patients with Cardiovascular and Kidney Disease by Carmine Zoccali et al. NETs Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney disease by Yvonne Doering et al. Accelerated Vascular Aging and Chronic Kidney Disease, The Potential for Novel Therapies by Peter Stenvinkel et al. Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients with Chronic Kidney Disease by Heidi Noels et al. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease by Claudia Goettsch et al. Fibrosis in Pathobiology of Heart and Kidney From Deep RNA Sequencing to Novel Molecular Targets by Raphael Kramann et al. Cardiac Metabolism and Heart Failure and Implications for Uremic Cardiomyopathy by P. Christian Schulze et al. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease by Michael Burnier et al. Role of the Microbiome in Gut, Heart, Kidney crosstalk by Griet Glorieux et al, and Use of Computation Ecosystems to Analyze the Kidney Heart Crosstalk by Joachim Jankowski et al.   These reviews were written by leading investigators in the field, and the editors of Circulation Research hope that this comprehensive undertaking stimulates further research into the path flow of physiological kidney-heart crosstalk, and on comorbidities and intra organ crosstalk in general.   Cindy St. Hilaire:              So for our interview portion of the episode I have with me Dr Elizabeth Tarling and Dr Bethan Clifford. And Dr Tarling is an associate professor in the Department of Medicine in cardiology at UCLA, and Dr Clifford is a postdoctoral fellow with the Tarling lab. And today we're going to be discussing their manuscript that's titled, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels. So thank you both so much for joining me today.   Elizabeth Tarling:             Thank you for having us.   Bethan Clifford:               Yeah, thanks for having us. This is exciting.   Cindy St. Hilaire:              I guess first, Liz, how did you get into this line of research? I guess, before we get into that, I should disclose. Liz, we are friends and we've worked together in the ATVB Women's Leadership Committee. So full disclosure here, that being said, the editorial board votes on these articles, so it's not just me picking my friends. But it is great to have you here. So how did you enter this field, I guess, briefly?   Elizabeth Tarling:             Yeah, well briefly, I mean my training right from doing my PhD in the United Kingdom in the University of Nottingham has always been on lipid metabolism, lipoprotein biology with an interest in liver and cardiovascular disease. So broadly we've always been interested in this area and this line of research. And my postdoctoral research was on atherosclerosis and lipoprotein metabolism. And this project came about through a number of different unique avenues, but really because we were looking for regulators of LDL biology and plasma LDL cholesterol, that's sort of where the interest of the lab lies.   Cindy St. Hilaire:              Excellent. And Bethan, you came to UCLA from the UK. Was this a topic you were kind of dabbling in before or was it all new for you?   Bethan Clifford:               It was actually all completely new for me. So yeah, I did my PhD at the same university as Liz and when I started looking for postdocs, I was honestly pretty adamant that I wanted to stay clear away from lipids and lipid strategy. And then it wasn't until I started interviewing and meeting people and I spoke to Liz and she really sort of convinced me of the excitement and that the interest and all the possibilities of working with lipids and well now I won't go back, to be honest.   Cindy St. Hilaire:              And now here you are. Well-   Bethan Clifford:               Exactly.   Cindy St. Hilaire:              ... congrats on a wonderful study. So LDLR, so low density lipoprotein receptor, it's a major determinant of plasmid LDL cholesterol levels. And hopefully most of us know and appreciate that that is really a major contributor and a major risk for the development of atherosclerosis and coronary artery disease. And I think one thing people may not really appreciate, which your study kind of introduces and talks about nicely, is the role of the liver, right? And the role of receptor mediated endocytosis in regulating plasma cholesterol levels. And so before we kind of chat about the nitty-gritty of your study, could you just give us a brief summary of these key parts between plasma LDL, the LDL receptor and where it goes in your body?   Elizabeth Tarling:             Yeah. So the liver expresses 70% to 80% of the body's LDL receptor. So it's the major determinant of plasma lipoprotein plasma LDL cholesterol levels. And through groundbreaking work by Mike Brown and Joe Goldstein at the University of Texas, they really define this receptor mediated endocytosis by the liver and the LDL receptor by looking at patients with familial hypercholesterolemia. So those patients have mutations in the LDL receptor and they either express one functional copy or no functional copies of the LDL receptor and they have very, very large changes in plasma LDL cholesterol. And they have severe increases in cardiovascular disease risk and occurrence and diseases associated with elevated levels of cholesterol within the blood and within different tissues. And so that's sort of how the liver really controls plasma LDL cholesterol is through this receptor mediated endocytosis of the lipoprotein particle.   Cindy St. Hilaire:              There's several drugs now that can help regulate our cholesterol levels. So there's statins which block that rate limiting step of cholesterol biosynthesis, but there's this new generation of therapies, the PCSK9 inhibitors. And can you just give us a summary or a quick rundown of what are those key differences really? What is the key mechanism of action that these therapies are going after and is there room for more improvement?   Bethan Clifford:               Yeah, sure. So I mean I think you've touched on something that's really key about the LDR receptor is that it's regulated at so many different levels. So we have medications available that target the production of cholesterol and then as you mentioned this newer generation of things like PCSK9 inhibitors that sort of try and target LDL at the point of clearance from the plasma.   And in response to your question of is there room for more regulation, I would say that given the sort of continual rate of increased cholesterol in the general population and the huge risks associated with elevated cholesterol, there's always capacity for more to improve that and sort of generally improve the health of the population. And what we sort of found particularly exciting about RNF130 is that it's a distinct pathway from any of these regulatory mechanisms. So it doesn't regulate the level of transcription, it doesn't regulate PCSK9. Or in response to PCSK9, it's a completely independent pathway that could sort of improve or add to changes in cholesterol.   Cindy St. Hilaire:              So your study, it's focusing on the E3 ligase, RNF130. What is an E3 ligase, and why was this particular one of interest to you? How did you come across it?   Elizabeth Tarling:             is predTates Bethan joining the lab. This is, I think, again for the listeners and those people in training, I think it's really important to note this project has been going in the lab for a number of years and has really... Bethan was the one who came in and really took charge and helped us round it out. But it wasn't a quick find or a quick story. It had a lot of nuances to it. But we were interested in looking for new regulators of LDL cholesterol and actually through completely independent pathways we had found the RNF130 locus as being associated with LDL cholesterol in animals. And then it came out in a very specific genome-wide association study in the African American care study, the NHLBI care study. And so really what we started looking at, we didn't even know what it was.   Elizabeth Tarling:             So we asked ourselves, well what is this gene? What is this protein? And it's RNF, so that's ring finger containing protein 130 and ring stands for really interesting new gene. Somebody came up with the glorious name. But proteins that contain this ring domain are very characteristic and they are E3 ubiquitin ligases. And so they conjugate the addition of ubiquitin to a target protein and that signals for that protein to either be internalized and/or degraded through different decorative pathways within the cell. And so we didn't land on it because we were looking at E3 ligases, we really came at it from an LDL cholesterol perspective. And it was something that we hadn't worked on before and the study sort of blossomed from there.   Cindy St. Hilaire:              That's amazing and a beautiful, but also, I'm sure, heartbreaking story because these long projects are just... They're bears. So what does this RNF130 do to LDLR? What'd you guys find?   Bethan Clifford:               As Liz said, this is a long process, but one of the key factors of RNF130 is it's structurally characteristically looked like E3 ligase. So the first thing that Liz did and then I followed up with in the lab is to see is this E3 ligase ubiquitinating in vitro. And if it is going to ubiquitinate, what's it likely to regulate that might cause changes in plasma cholesterol that would explain these human genetic links that we saw published at the same time.   And so because the LDL cholesterol is predominantly regulated by the LDL receptor and the levels of it at the surface of the parasites in the liver, the first question we wanted to see is does RNF130 interact in any way with that pathway? And I'm giving you the brief view here of the LDL receptor. We obviously tested lots of different receptors. We tested lots of different endocytose receptors and lipid regulators, but the LDL receptor is the one that we saw could be ubiquitinated by RNF130 in vitro. And so then we wanted to sort of go on from there and establish, okay, if this E3 ubiquitin ligase, is it regulating LDL receptor? What does that mean in an animal context in terms of regulating LDL cholesterol?   Cindy St. Hilaire:              Yeah, and I guess we should also explain, ubiquitination, in terms of this receptor, and I guess related to Goldstein and Brown and receptor mediated endocytosis, like what does that actually mean for the liver cell and the cholesterol in the LDLR that is binding the receptor?   Bethan Clifford:               So yes, ubiquitination is a really common regulatory mechanism actually across all sorts of different cells, all sorts of different receptors and proteins. And basically what it does is it signals for degradation of a protein. So a ubiquitin molecule is conjugated to its target such as in our case the LDL receptor and that ubiquitin tells the cell that this protein is ready for proteasomal degradation. And that's just one of the many things ubiquitination can do. It can also signal for a trafficking event, it can signal for a protein to protein interaction, but it's most commonly associated with the proteasomal degradation.     Cindy St. Hilaire:              So in terms of... I guess I'm thinking in terms of PCSK9, right? So those drugs are stemming from observations in humans, right? There were humans with gain and loss of function mutations, which caused either more or less of this LDLR receptor internalization. How is this RNF130 pathway different from the PCSK9 activities?   Elizabeth Tarling:             Yeah, so PCSK9 is a secreted protein, so it's made by hepatocyte and actually other cells in the body and it's secreted and it binds to the LDL particle, LDL receptor complex, and signals for its internalization and degradation in the proteasome. So this is not ubiquitination event, this is a completely different trafficking event. And so the RNF130, actually what Bethan showed, is it directly ubiquitinates the LDL receptor itself, signaling for an internalization event and then ultimately degradation of the LDR receptor through a decorative pathway, which we also define in the study.   So these are two unique mechanisms and actually some key studies that we did in the paper were to modulate RNF130 in animals that do not have PCSK9. And so in that system where in the absence of PCSK9 you have a lot of LDR receptor in the liver that's internalizing cholesterol. What happens when you overexpress RNF130? Do you still regulate at the LDL receptor? And you absolutely do. And so that again suggests that they're two distinct mechanisms and two distinct pathways.   Cindy St. Hilaire:              That was one thing I really loved about your paper is every kind of figure or section, the question that would pop up in my head, even ones that didn't pop in my head were beautifully answered with some of these really nice animal models, which is never an easy thing, right? And so one of the things that you brought up was difficulty in making one of the animal models. And so I'm wondering if you could share a little bit for that challenge. I think one thing that we always tend to hide is just science is hard and a lot of what we do doesn't work. And I really think especially for the trainees and really everyone out there, if we kind of share these things more, it's better. So what was one of the most challenging things in this study? And I guess I'm thinking about that floxed animal.   Elizabeth Tarling:             Yeah, so I'll speak a bit about that and then I'll let Bethan address because she was really the one on the ground doing a lot of the struggles. But again, we actually weren't going to include this information in the paper. And upon discussion and actually prompted by the reviewers of the paper and some of the questions that they asked us, we realized, you know what? It's actually really important to show this and show that this happens and that there are ways around it.   And so the first story is before Bethan even arrived in the lab, we had purchased embryonic stem cells that were knockout first condition already. And so this is a knockout strategy in which the exon of interest is flanked with lots of P sites so that you can create a flox animal, but also so you can create a whole body knockout just by the insertion of this knockout first cassette.   Elizabeth Tarling:             And so we got those mice actually in the first year of Bethan joining the lab. We finally got the chimeric mice and we were able to stop reading those mice. And at the same time we tried to generate our flox animals so that we could move on to do tissue-specific studies. And Bethan can talk about the pain associated with this. But over two years of breeding, we never got the right genotypes from the different crosses that you need to do to generate the flox animal.   And it was actually in discussions with Bethan where we decided we need to go back. We need to go back to those ESLs that we purchased five years ago and we need to figure out if all of the elements that the quality control step had told us were in place are actually present. And so Bethan went back and sequenced the whole locus and the cassette to figure out what pieces were present and we found that one of the essential locks P sites that's required for every single cross from the initial animal was absent and therefore we could actually never make the mouse we wanted to make.   And so that's sort of just a lesson for people going down that route and making these tools that we need in the lab to answer these questions is that despite paying extra money and getting all of the sort of QCs that you can get before you receive the ESLs, we should have gone back and done our own housekeeping and sort of a long journey told us when we went back that we didn't have what we thought we had at the beginning. And that was a real sticking point as Bethan can-   Cindy St. Hilaire:              Yeah. And so you know you're not alone. My very first postdoc that I did, I went with a mouse that they had also bought and were guaranteed that it was a knockout and it was not. And it is a painful lesson, but it is critical to... You get over it.   So Bethan, maybe you can also tell us a little bit about what are the other kind of next things you tried? You pivoted and you pivoted beautifully because all the models you used I thought were quite elegant in terms of exactly asking the question you wanted to ask in the right cells. So can you maybe explain some of the in vivo models you used for this study?   Bethan Clifford:               Sure, there are definitely a lot. So I mean I think Liz sort of encapsulated the trouble we have with the knockout really succinctly, but actually I want to just take this moment to sort of shout out to another postdoc in the Tarling lab, Kelsey Jarrett, who was really instrumental in the pivoting to a different model. So for the knockouts when we sort of established we didn't have exactly what we thought we did and then to compound that we also weren't getting the DeLiAn ratios breeding this whole body knockout.   We wanted to sort of look at a more transient knockout model. And that's where Kelsey really stepped in and sort of led the way and she generated AAV-CRISPR for us to target RNF130 specifically in the liver. And that had the added beauty of, one, not requiring breeding to get over this hurdle of the knockout being somewhat detrimental to breeding. But it also allowed us to ask the question of what RNF130 is doing specifically in the liver where the liver regulates LDL receptor and LDL cholesterol.   And so that was one of the key models that really, really helped get this paper over the finish line. But we did a whole barrage of experiments, as you've seen. We wanted to make sure... One of the key facets of the Tarling lab is whenever you do anything, no matter what you show Liz, it will always be, "Okay, you showed it to me one way, now show it to me a different way." Can you get the same result coming at it from different ways? And if you can't, why is that? What is the regulation behind that? And so that's really what the paper is doing is asking the same question in as many ways as we can accurately and appropriately probe what RNF130 does to the LDR receptor.   So we tried gain of function studies without adenovirus overexpression. We tried transient knockdown with antisense oligonucleotides, and then we did, as I said, the AAV-CRISPR knockdown with the help of Kelsey and our whole body knockout. And then we also repeated some of these studies such as the adenovirus and the ASO in specific genetic backgrounds. So in the absence of PCSK9, can we still regulate the LDL receptor? And then we also, just to really confirm this, in the absence of the LDL receptor, do we see a difference? And the answer is no, because this effect was really dependent on that LDL receptor being present. So there was a big combination.   Cindy St. Hilaire:              It was really nice, really a beautiful step-wise progression of how to solidly answer this question. But a lot of, I think, almost all you did was in mice. And so what is the genetic evidence for relevancy in humans? Can you discuss a little bit about those databases that you then went to to investigate, is this relevant in humans?   Bethan Clifford:               I think Liz might be better off answering that question.   Elizabeth Tarling:             And I think this sort of pivots on what Bethan was saying. So when we had struggles in the lab, it was a team environment and a collaboration between people in the lab that allowed us to make that leap and make those next experiments possible to then really answer that question. And to be able to include the antisense oligonucleotides required a collaboration with industry. We were very lucky to have a longstanding collaboration with Ionis, who provided the antisense oligonucleotides.   And for the human genetics side of things, that also was a collaboration with Marcus Seldin, who was a former postdoc with Jake Lusis and is now our PI at UC Irvine. And what he helped us do is dive into those summary level databases and ask from that initial study in the NHLBI care population, do we see associations of RNF130 expression in humans with LDL cholesterol with cardiovascular outcomes. And so one database which I would recommend everybody use, it's publicly available, is the StarNet database. And it's in the paper and the website is there. And that allowed us to search for RNF130.   Elizabeth Tarling:             And what it does is it asks how RNF130 expression in different tissues is associated with cardiometabolic outcomes and actual in CAD cases and controls, so people with and without heart disease. And we found that expression of RNF130 in the liver was extremely strongly correlated with the occurrence of cardiovascular disease in people with CAD. So in cases versus controls. And then we were also able to find many other polymorphisms in the RNF130 locus that were associated with LDL cholesterol in multiple different studies.   And I think the other message from this paper is this, unlike PCSK9 and unlike LDR receptor itself, which are single gene mutations that cause cardiovascular disease, there are many sub genome-wide significant loci that contribute to this multifactorial disease, which is extremely complex. And I think RNF130 falls within that bracket that those sort of just on the borderline of being genome-wide significant still play significant biological roles in regulating these processes. And they don't come up as a single gene hit for a disease, but combinatorialy they are associated with increased risk of disease and they have a molecular mechanism that's associated with the disease. And so that's what Marcus helped us do in terms of the human genetics is really understand that and get down to that level of data.   Cindy St. Hilaire:              Yeah. Yeah, it really makes you want to go back and look at those. Everyone always focuses on that really high peak and those analyses, but what are all those other ones above the noise, right? So it's really important.   Elizabeth Tarling:             I think it's really hard to do that. I think that's one where people... Again, it comes down to team science and the group of people that we brought together allowed us to ask that molecular question about how that signal was associated with the phenotype. I think by ourselves we wouldn't have been able to do it.   Cindy St. Hilaire:              Yeah. So your antisense oligonucleotide experiments, they were really nice. They showed, I think it was a four-week therapy, they showed that when you injected them expression of RNF130 went down by 90%. I think cholesterol in the animals was lowered by 50 points or so. Is this kind of a next viable option? And I guess related to that, cholesterol's extremely important for everything, right? Cell membrane integrity, our neurons, all sorts of things. Is it possible with something that is perhaps really as powerful as this to make cholesterol too low?   Elizabeth Tarling:             I think that what we know from PCSK9 gain and loss of function mutations is that you can drop your plasma cholesterol to very low levels and still be okay because there are people walking around with mutations that do that. I think RNF130 is a little different in that it's clearly regulatory in a homeostatic function in that it's ubiquitously expressed and it has this role in the liver to regulate LDL receptor availability, but there are no homozygous loss of function mutants people walking around, which tells us something else about how important it is in potentially other tissues and in other pathways. And we've only just begun to uncover what those roles might be.   So I think that as a therapy, it has great potential. We need to do a lot more studies to sort of move from rodent models into more preclinical models. But I do think that the human data tell us that it's really important in other places too. And so yeah, we need to think about how best it might work as a therapy. If it's combinatorial, if it's dosed. Those are the types of things that we need to think about.   Cindy St. Hilaire:              Yeah, it's really exciting. Do you know, are there other protein targets of RNF130? Is that related to my next question of what is next?   Elizabeth Tarling:             I mean, so I should point out, so Bethan unfortunately left the lab last year for a position at Amgen where she's working on obesity and metabolic disease. But before she left, she did two very, very cool experiments searching for new targets or additional targets of RNF130. Starting in the liver, but hopefully we'll move those into other tissues. And so she did gain of function RNF130 versus what loss of function we have of RNF130, and she did specific mass spec analysis of proteins that are ubiquitinated in those different conditions. And by overlaying those data sets, we're hoping to carve out new additional targets of RNF130. And there are some, and they're in interesting pathways, which we have yet to completely test, but definitely there are additional pathways, at least when you overexpress and reduce expression. Now, whether they turn out to be, again, bonafide in vivo, actual targets that are biologically meaningful is sort of the next step.   Cindy St. Hilaire:              Yeah. Well, I'm sure with your very rigorous approach, you are going to find out and hopefully we'll see it here in the future. Dr Elizabeth Tarling and Dr Bethan Clifford, thank you so much for joining me today. I really enjoyed this paper. It's a beautiful study. I think it's a beautiful example, especially for trainees about kind of thoroughly and rigorously going through and trying to test your hypothesis. So thanks again.   Elizabeth Tarling:             Thank you.   Bethan Clifford:               Thank you very much.   Cindy St. Hilaire:              That's it for the highlights from the March 31st and April 14th issues of Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes, and #DiscoverCircRes. Thank you to our guests, Dr Liz Tarling and Dr Bethan Clifford.   This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.   This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.  

Guideline-orientated management of immunoglobulin A nephropathy (IgAN) includes enrolling patients who remain proteinuric despite optimized standard of care in clinical trials. Credit available for this activity expires: 3/22/24 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/989932?ecd=bdc_podcast_libsyn_mscpedu

In this episode of the IJGC podcast, Editor-in-Chief, Dr. Pedro Ramirez, is joined by Drs. Ainhoa Madariaga and Robert Coleman, two of the Guest Editors for this month's special issue entitled “Novel Therapies Leading to a New Landscape in Gynecologic Tumors”. Dr. Madariaga is a Medical Oncologist in the Gynecologic Cancer Unit at 12 de Octubre University Hospital in Madrid, Spain. She is the chair of the Young and Early Career Investigator - EORTC Gynecological Cancer Group. Her research interests include patient reported outcomes and drug development. Dr. Coleman is a Gynecologic Oncologist and Chief Medical Officer at Sarah Cannon Research Institute (SCRI) in Nashville, TN. His research interests include drug development, clinical trial design and global medical education in gynecologic oncology. Highlights: - The alignment of cancer biology and novel treatment approaches are significantly extending the lives of patients with gynecologic malignancies, particularly with agents such as antibody drug conjugates, immunotherapy, and targeted agents. - The evolving therapeutic landscape is escalating the need for a clearer understanding of how precision medicine can most efficiently be implemented. - Emergence of drug resistance provides new challenges and opportunities through creative and strategic investigation of novel treatment and combinations. - Advances in testing platforms in bringing genomic testing to the global audience. - Clinical trial interpretation requires critical evaluation of analytical primary and hypothesis-generating secondary endpoints – strategies to make appropriate inference is key to clinical trial design.

This episode features Rebecca Maniago, PharmD, BCOP, Associate Director of Clinical Oncology at Flatiron Health. Here, she discusses the top barriers in uptake of new cancer therapies and the role technology plays in ensuring clinicians have easy access to information on these novel therapies.This episode is sponsored by Flatiron.

Your skin barrier is your body's first line of defense against diseases, germs, and injury. But what happens when your skin barrier is damaged? Join me today as I discuss with my colleague, physician-scientist Dr. Jack Arbiser, the skin barrier and how we can protect and maintain it. Dr. Arbiser is known for his clinical acumen and research skills and shares with us today how he uses some common, and even old remedies, to help restore the integrity of our skin barrier. Proof that sometimes the best treatments, are the simplest! Want to connect with Dr. Jack Arbiser: arbiser@hotmail.com Twitter: arbisermd

Featuring perspectives from Drs Jesús Berdeja, Rafael Fonseca, Sagar Lonial, Robert Orlowski and Noopur Raje, including the following topics: Front-Line Treatment of Multiple Myeloma (MM)  Introduction (0:00) Case: A woman in her early 50s with newly diagnosed MM (NDMM) and 1q gain who presents with a pathologic fracture and receives daratumumab/RVd — Bhavana (Tina) Bhatnagar, DO (2:49) Cases: An otherwise healthy man in his late 80s with NDMM who is disinclined to undergo aggressive therapy and a transplant-ineligible woman in her late 70s with NDMM — Erik Rupard, MD and Hans Lee, MD (10:05) Dr Orlowski presentation (15:45) Integration of Novel Therapies into the Management of Relapsed/Refractory MM  Cases: A transplant-eligible man in his late 60s with well-controlled HIV-1 and standard-risk NDMM and a man in his late 60s with high-risk, t(4;14) multiregimen-refractory MM with travel limitations who receives belantamab mafodotin — Neil Morganstein, MD and Syed Farhan Zafar, MD (29:19) Cases: A woman in her early 70s who receives daratumumab, bortezomib and dexamethasone for relapsed MM 6 years after RVd followed by autologous stem cell transplant and maintenance bortezomib, and a man in his mid 50s with NDMM who received RVd followed by maintenance lenalidomide, which was discontinued by the patient after 1 year — Henna Malik, MD and Dr Rupard (35:50) Dr Fonseca presentation (41:57) Current Role of Chimeric Antigen Receptor (CAR) T-Cell Therapy for MM  Case: A man in his early 70s with NDMM who receives induction daratumumab/RVd — Spencer H Bachow, MD (52:27) Cases: A woman in her early 60s with relapsed MM and pathologic fractures who received induction daratumumab/Rd and palliative radiation therapy for bone disease, and a woman in her mid 70s with refractory MM 6 months after induction daratumumab/RVd lite — Dr Bhatnagar and Kimberly Ku, MD (57:00) Dr Raje presentation (1:01:12) Bispecific Antibodies in the Treatment of MM  Case: A man in his early 70s with t(4;14) NDMM who initiates RVd, which is put on hold to treat severe depression — Warren S Brenner, MD (1:14:38) Case: A woman in her mid 70s with multiregimen-refractory del(17p) MM who is considered for BCMA-directed therapy — Dr Bachow (1:16:28) Dr Berdeja presentation (1:22:18) Other Investigational Novel Agents for MM  Case: A woman in her mid 80s with congestive heart failure and t(4;14), t(11;14) and t(14;16) MM who receives dose-reduced RVd and develops chalazion eye toxicity — Jennifer L Dallas, MD (1:36:23) Dr Lonial presentation (1:39:34) CME information and select publications

In 2022 we covered many live events and conferences both on the subject of anesthesia and perioperative medicine; we produced audio versions of some of the most interesting speakers in the field of perioperative medicine and provided you with exclusive interviews and behind the scenes access to some of the key opinion leaders and thinkers in medicine. That's not to mention occasional exclusive news releases, hard hitting debates and the friendly charm of your favorite presenters; Desiree, Monty, Sol, Mike and the rest of the team. Do ensure you've taken advantage of the current offers available now on the Evidence Based Perioperative Medicine (EBPOM) website: www.ebpom.org In this podcast: A preview of "The National Institute for Health and Care Research | EBPOM London" https://topmedtalk.libsyn.com/the-national-institute-for-health-and-care-research-ebpom-london - this link will be active upon release. We also look back at: "I know nothing..." Hugh Montgomery https://topmedtalk.libsyn.com/i-know-nothing-hugh-montgomery-ernest-henry-starling-plenary-lecture-ebpom-2022 The Great Fluid Debate | EBPOM 2022 https://topmedtalk.libsyn.com/the-great-fluid-debate-ebpom-2022 Novel Therapies for Perioperative Care. This from EBPOM Dingle 2022 https://www.topmedtalk.com/novel-therapies-for-perioperative-care-ebpom-dingle/ Efficient trial design, ‘evidence' in the era of ‘Big Data' | Dingle 2022 https://www.topmedtalk.com/efficient-trial-design-evidence-in-the-era-of-big-data-dingle-2022/ Enhanced Recovery After Cardiac Surgery (ERAS) - Is it really that different? | Dingle 2022 https://www.topmedtalk.com/enhanced-recovery-after-cardiac-surgery-eras-is-it-really-that-different-dingle-2022/ ASA Global Scholars - Part 1: https://www.topmedtalk.com/the-asa-global-scholars-program-part-1-anesthesiology-2022/ Part 2: https://www.topmedtalk.com/the-asa-global-scholars-program-part-2-anesthesiology-2022/

Dr Jeffrey Zonder from Karmanos Cancer Institute in Detroit, Michigan discusses the biology, presentation and current management of AL amyloidosis and emerging data with novel therapies. CME information and select publications here (http://www.researchtopractice.com/OncologyTodayALAmyloidosis22).

The words "prevent not stent" are the highest goal of care at the Kahn Center and can be confirmed by the "test not guess" philosophy of using CIMT and CT imaging for plaque detection. In many, plaque is already present and needs attempts at reversal. This week Dr. Kahn discusses two supplements he has used for years for disease reversal based on a rich medical science literature. He then describes two new approaches that are novel, natural, and new but supported by amazing science. Thanks to memoryhealth.com and the discount code Kahn15.

Coeliac disease is an autoimmune disorder stimulated by the ingestion of gluten, a protein found naturally in wheat, barley and rye. The condition affects approximately 1% of the Western world. However, currently the only approved treatment for coeliac disease is adherence to a gluten-free diet for life. Therefore there is much research underway to develop alternative treatment options that may help these patients. One novel antigen-focused therapy that has been hypothesised is the use of plant bioactives. Specifially, in vitro work by Dr. Charlene Van Buiten has looked as whether there is a mechanism by which polyphenols from green tea could be of benefit. Her work shows that these polyphenols can mitigate gliadin-mediated inflammation and intestinal permeability in vitro. Click here for show notes. Click here to subscribe to Premium.