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Listen to ASCO's JCO Oncology Practice, Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last” by Dr. David Johnson, who is a clinical oncologist at University of Texas Southwestern Medical School. The article is followed by an interview with Johnson and host Dr. Mikkael Sekeres. Through humor and irony, Johnson critiques how overspecialization and poor presentation practices have eroded what was once internal medicine's premier educational forum. Transcript Narrator: An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last, by David H. Johnson, MD, MACP, FASCO   Over the past five decades, I have attended hundreds of medical conferences—some insightful and illuminating, others tedious and forgettable. Among these countless gatherings, Medical Grand Rounds (MGRs) has always held a special place. Originally conceived as a forum for discussing complex clinical cases, emerging research, and best practices in patient care, MGRs served as a unifying platform for clinicians across all specialties, along with medical students, residents, and other health care professionals. Expert speakers—whether esteemed faculty or distinguished guests—would discuss challenging cases, using them as a springboard to explore the latest advances in diagnosis and treatment. During my early years as a medical student, resident, and junior faculty member, Grand Rounds consistently attracted large, engaged audiences. However, as medicine became increasingly subspecialized, attendance began to wane. Lectures grew more technically intricate, often straying from broad clinical relevance. The patient-centered discussions that once brought together diverse medical professionals gradually gave way to hyperspecialized presentations. Subspecialists, once eager to share their insights with the wider medical community, increasingly withdrew to their own specialty-specific conferences, further fragmenting the exchange of knowledge across disciplines. As a former Chair of Internal Medicine and a veteran of numerous MGRs, I observed firsthand how these sessions shifted from dynamic educational exchanges to highly specialized, often impenetrable discussions. One of the most striking trends in recent years has been the decline in presentation quality at MGR—even among local and visiting world-renowned experts. While these speakers are often brilliant clinicians and investigators, they can also be remarkably poor lecturers, delivering some of the most uninspiring talks I have encountered. Their presentations are so consistently lackluster that one might suspect an underlying strategy at play—an unspoken method to ensure that they are never invited back. Having observed this pattern repeatedly, I am convinced that these speakers must be adhering to a set of unwritten rules to avoid future MGR presentations. To assist those unfamiliar with this apparent strategy, I have distilled the key principles that, when followed correctly, all but guarantee that a presenter will not be asked to give another MGR lecture—thus sparing them the burden of preparing one in the future. Drawing on my experience as an oncologist, I illustrate these principles using an oncology-based example although I suspect similar rules apply across other subspecialties. It will be up to my colleagues in cardiology, endocrinology, rheumatology, and beyond to identify and document their own versions—tasks for which I claim no expertise. What follows are the seven “Rules for Presenting a Bad Medical Oncology Medical Grand Rounds.” 1.  Microscopic Mayhem: Always begin with an excruciatingly detailed breakdown of the tumor's histology and molecular markers, emphasizing how these have evolved over the years (eg, PAP v prostate-specific antigen)—except, of course, when they have not (eg, estrogen receptor, progesterone receptor, etc). These nuances, while of limited relevance to general internists or most subspecialists (aside from oncologists), are guaranteed to induce eye-glazing boredom and quiet despair among your audience. 2. TNM Torture: Next, cover every nuance of the newest staging system … this is always a real crowd pleaser. For illustrative purposes, show a TNM chart in the smallest possible font. It is particularly helpful if you provide a lengthy review of previous versions of the staging system and painstakingly cover each and every change in the system. Importantly, this activity will allow you to disavow the relevance of all previous literature studies to which you will subsequently refer during the course of your presentation … to wit—“these data are based on the OLD staging system and therefore may not pertain …” This phrase is pure gold—use it often if you can. NB: You will know you have “captured” your audience if you observe audience members “shifting in their seats” … it occurs almost every time … but if you have failed to “move” the audience … by all means, continue reading … there is more! 3. Mechanism of Action Meltdown: Discuss in detail every drug ever used to treat the cancer under discussion; this works best if you also give a detailed description of each drug's mechanism of action (MOA). General internists and subspecialists just LOVE hearing a detailed discussion of the drug's MOA … especially if it is not at all relevant to the objectives of your talk. At this point, if you observe a wave of slack-jawed faces slowly slumping toward their desktops, you will know you are on your way to successfully crushing your audience's collective spirit. Keep going—you are almost there. 4. Dosage Deadlock: One must discuss “dose response” … there is absolutely nothing like a dose response presentation to a group of internists to induce cries of anguish. A wonderful example of how one might weave this into a lecture to generalists or a mixed audience of subspecialists is to discuss details that ONLY an oncologist would care about—such as the need to dose escalate imatinib in GIST patients with exon 9 mutations as compared with those with exon 11 mutations. This is a definite winner! 5. Criteria Catatonia: Do not forget to discuss the newest computed tomography or positron emission tomography criteria for determining response … especially if you plan to discuss an obscure malignancy that even oncologists rarely encounter (eg, esthesioneuroblastoma). Should you plan to discuss a common disease you can ensure ennui only if you will spend extra time discussing RECIST criteria. Now if you do this well, some audience members may begin fashioning their breakfast burritos into projectiles—each one aimed squarely at YOU. Be brave … soldier on! 6. Kaplan-Meier Killer: Make sure to discuss the arcane details of multiple negative phase II and III trials pertaining to the cancer under discussion. It is best to show several inconsequential and hard-to-read Kaplan-Meier plots. To make sure that you do a bad job, divide this portion of your presentation into two sections … one focused on adjuvant treatment; the second part should consist of a long boring soliloquy on the management of metastatic disease. Provide detailed information of little interest even to the most ardent fan of the disease you are discussing. This alone will almost certainly ensure that you will never, ever be asked to give Medicine Grand Rounds again. 7. Lymph Node Lobotomy: For the coup de grâce, be sure to include an exhaustive discussion of the latest surgical techniques, down to the precise number of lymph nodes required for an “adequate dissection.” To be fair, such details can be invaluable in specialized settings like a tumor board, where they send subspecialists into rapturous delight. But in the context of MGR—where the audience spans multiple disciplines—it will almost certainly induce a stultifying torpor. If dullness were an art, this would be its masterpiece—capable of lulling even the most caffeinated minds into a stupor. If you have carefully followed the above set of rules, at this point, some members of the audience should be banging their heads against the nearest hard surface. If you then hear a loud THUD … and you're still standing … you will know you have succeeded in giving the world's worst Medical Grand Rounds!   Final Thoughts I hope that these rules shed light on what makes for a truly dreadful oncology MGR presentation—which, by inverse reasoning, might just serve as a blueprint for an excellent one. At its best, an outstanding lecture defies expectations. One of the most memorable MGRs I have attended, for instance, was on prostaglandin function—not a subject typically associated with edge-of-your-seat suspense. Given by a biochemist and physician from another subspecialty, it could have easily devolved into a labyrinth of enzymatic pathways and chemical structures. Instead, the speaker took a different approach: rather than focusing on biochemical minutiae, he illustrated how prostaglandins influence nearly every major physiologic system—modulating inflammation, regulating cardiovascular function, protecting the gut, aiding reproduction, supporting renal function, and even influencing the nervous system—without a single slide depicting the prostaglandin structure. The result? A room full of clinicians—not biochemists—walked away with a far richer understanding of how prostaglandins affect their daily practice. What is even more remarkable is that the talk's clarity did not just inform—it sparked new collaborations that shaped years of NIH-funded research. Now that was an MGR masterpiece. At its core, effective scientific communication boils down to three deceptively simple principles: understanding your audience, focusing on relevance, and making complex information accessible.2 The best MGRs do not drown the audience in details, but rather illuminate why those details matter. A great lecture is not about showing how much you know, but about ensuring your audience leaves knowing something they didn't before. For those who prefer the structured wisdom of a written guide over the ramblings of a curmudgeon, an excellent review of these principles—complete with a handy checklist—is available.2 But fair warning: if you follow these principles, you may find yourself invited back to present another stellar MGRs. Perish the thought! Dr. Mikkael SekeresHello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami.  What a pleasure it is today to be joined by Dr. David Johnson, clinical oncologist at the University of Texas Southwestern Medical School. In this episode, we will be discussing his Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last."  Our guest's disclosures will be linked in the transcript.  David, welcome to our podcast and thanks so much for joining us. Dr. David JohnsonGreat to be here, Mikkael. Thanks for inviting me. Dr. Mikkael SekeresI was wondering if we could start with just- give us a sense about you. Can you tell us about yourself? Where are you from? And walk us through your career. Dr. David JohnsonSure. I grew up in a small rural community in Northwest Georgia about 30 miles south of Chattanooga, Tennessee, in the Appalachian Mountains. I met my wife in kindergarten. Dr. Mikkael SekeresOh my. Dr. David JohnsonThere are laws in Georgia. We didn't get married till the third grade. But we dated in high school and got married after college. And so we've literally been with one another my entire life, our entire lives. Dr. Mikkael SekeresMy word. Dr. David JohnsonI went to medical school in Georgia. I did my training in multiple sites, including my oncology training at Vanderbilt, where I completed my training. I spent the next 30 years there, where I had a wonderful career. Got an opportunity to be a Division Chief and a Deputy Director of, and the founder of, a cancer center there. And in 2010, I was recruited to UT Southwestern as the Chairman of Medicine. Not a position I had particularly aspired to, but I was interested in taking on that challenge, and it proved to be quite a challenge for me. I had to relearn internal medicine, and really all the subspecialties of medicine really became quite challenging to me. So my career has spanned sort of the entire spectrum, I suppose, as a clinical investigator, as an administrator, and now as a near end-of-my-career guy who writes ridiculous articles about grand rounds. Dr. Mikkael SekeresNot ridiculous at all. It was terrific. What was that like, having to retool? And this is a theme you cover a little bit in your essay, also, from something that's super specialized. I mean, you have had this storied career with the focus on lung cancer, and then having to expand not only to all of hematology oncology, but all of medicine. Dr. David JohnsonIt was a challenge, but it was also incredibly fun. My first few days in the chair's office, I met with a number of individuals, but perhaps the most important individuals I met with were the incoming chief residents who were, and are, brilliant men and women. And we made a pact. I promised to teach them as much as I could about oncology if they would teach me as much as they could about internal medicine. And so I spent that first year literally trying to relearn medicine. And I had great teachers. Several of those chiefs are now on the faculty here or elsewhere. And that continued on for the next several years. Every group of chief residents imparted their wisdom to me, and I gave them what little bit I could provide back to them in the oncology world. It was a lot of fun. And I have to say, I don't necessarily recommend everybody go into administration. It's not necessarily the most fun thing in the world to do. But the opportunity to deal one-on-one closely with really brilliant men and women like the chief residents was probably the highlight of my time as Chair of Medicine. Dr. Mikkael SekeresThat sounds incredible. I can imagine, just reflecting over the two decades that I've been in hematology oncology and thinking about the changes in how we diagnose and care for people over that time period, I can only imagine what the changes had been in internal medicine since I was last immersed in that, which would be my residency. Dr. David JohnsonWell, I trained in the 70s in internal medicine, and what transpired in the 70s was kind of ‘monkey see, monkey do'. We didn't really have a lot of understanding of pathophysiology except at the most basic level. Things have changed enormously, as you well know, certainly in the field of oncology and hematology, but in all the other fields as well. And so I came in with what I thought was a pretty good foundation of knowledge, and I realized it was completely worthless, what I had learned as an intern and resident. And when I say I had to relearn medicine, I mean, I had to relearn medicine. It was like being an intern. Actually, it was like being a medical student all over again. Dr. Mikkael SekeresOh, wow. Dr. David JohnsonSo it's quite challenging.  Dr. Mikkael SekeresWell, and it's just so interesting. You're so deliberate in your writing and thinking through something like grand rounds. It's not a surprise, David, that you were also deliberate in how you were going to approach relearning medicine. So I wonder if we could pivot to talking about grand rounds, because part of being a Chair of Medicine, of course, is having Department of Medicine grand rounds. And whether those are in a cancer center or a department of medicine, it's an honor to be invited to give a grand rounds talk. How do you think grand rounds have changed over the past few decades? Can you give an example of what grand rounds looked like in the 1990s compared to what they look like now? Dr. David JohnsonWell, I should all go back to the 70s and and talk about grand rounds in the 70s. And I referenced an article in my essay written by Dr. Ingelfinger, who many people remember Dr. Ingelfinger as the Ingelfinger Rule, which the New England Journal used to apply. You couldn't publish in the New England Journal if you had published or publicly presented your data prior to its presentation in the New England Journal. Anyway, Dr. Ingelfinger wrote an article which, as I say, I referenced in my essay, about the graying of grand rounds, when he talked about what grand rounds used to be like. It was a very almost sacred event where patients were presented, and then experts in the field would discuss the case and impart to the audience their wisdom and knowledge garnered over years of caring for patients with that particular problem, might- a disease like AML, or lung cancer, or adrenal insufficiency, and talk about it not just from a pathophysiologic standpoint, but from a clinician standpoint. How do these patients present? What do you do? How do you go about diagnosing and what can you do to take care of those kinds of patients? It was very patient-centric. And often times the patient, him or herself, was presented at the grand rounds. And then experts sitting in the front row would often query the speaker and put him or her under a lot of stress to answer very specific questions about the case or about the disease itself.  Over time, that evolved, and some would say devolved, but evolved into more specialized and nuanced presentations, generally without a patient present, or maybe even not even referred to, but very specifically about the molecular biology of disease, which is marvelous and wonderful to talk about, but not necessarily in a grand round setting where you've got cardiologists sitting next to endocrinologists, seated next to nephrologists, seated next to primary care physicians and, you know, an MS1 and an MS2 and et cetera. So it was very evident to me that what I had witnessed in my early years in medicine had really become more and more subspecialized. As a result, grand rounds, which used to be packed and standing room only, became echo chambers. It was like a C-SPAN presentation, you know, where local representative got up and gave a talk and the chambers were completely empty. And so we had to go to do things like force people to attend grand rounds like a Soviet Union-style rally or something, you know. You have to pay them to go. But it was really that observation that got me to thinking about it.  And by the way, I love oncology and I'm, I think there's so much exciting progress that's being made that I want the presentations to be exciting to everybody, not just to the oncologist or the hematologist, for example. And what I was witnessing was kind of a formula that, almost like a pancake formula, that everybody followed the same rules. You know, “This disease is the third most common cancer and it presents in this way and that way.” And it was very, very formulaic. It wasn't energizing and exciting as it had been when we were discussing individual patients. So, you know, it just is what it is. I mean, progress is progress and you can't stop it. And I'm not trying to make America great again, you know, by going back to the 70s, but I do think sometimes we overthink what medical grand rounds ought to be as compared to a presentation at ASH or ASCO where you're talking to subspecialists who understand the nuances and you don't have to explain the abbreviations, you know, that type of thing. Dr. Mikkael SekeresSo I wonder, you talk about the echo chamber of the grand rounds nowadays, right? It's not as well attended. It used to be a packed event, and it used to be almost a who's who of, of who's in the department. You'd see some very famous people who would attend every grand rounds and some up-and-comers, and it was a chance for the chief residents to shine as well. How do you think COVID and the use of Zoom has changed the personality and energy of grand rounds? Is it better because, frankly, more people attend—they just attend virtually. Last time I attended, I mean, I attend our Department of Medicine grand rounds weekly, and I'll often see 150, 200 people on the Zoom. Or is it worse because the interaction's limited? Dr. David JohnsonYeah, I don't want to be one of those old curmudgeons that says, you know, the way it used to be is always better. But there's no question that the convenience of Zoom or similar media, virtual events, is remarkable. I do like being able to sit in my office where I am right now and watch a conference across campus that I don't have to walk 30 minutes to get to. I like that, although I need the exercise. But at the same time, I think one of the most important aspects of coming together is lost with virtual meetings, and that's the casual conversation that takes place. I mentioned in my essay an example of the grand rounds that I attended given by someone in a different specialty who was both a physician and a PhD in biochemistry, and he was talking about prostaglandin metabolism. And talk about a yawner of a title; you almost have to prop your eyelids open with toothpicks. But it turned out to be one of the most fascinating, engaging conversations I've ever encountered. And moreover, it completely opened my eyes to an area of research that I had not been exposed to at all. And it became immediately obvious to me that it was relevant to the area of my interest, which was lung cancer. This individual happened to be just studying colon cancer. He's not an oncologist, but he was studying colon cancer. But it was really interesting what he was talking about. And he made it very relevant to every subspecialist and generalist in the audience because he talked about how prostaglandin has made a difference in various aspects of human physiology.  The other grand rounds which always sticks in my mind was presented by a long standing program director at my former institution of Vanderbilt. He's passed away many years ago, but he gave a fascinating grand rounds where he presented the case of a homeless person. I can't remember the title of his grand rounds exactly, but I think it was “Care of the Homeless” or something like that. So again, not something that necessarily had people rushing to the audience. What he did is he presented this case as a mysterious case, you know, “what is it?” And he slowly built up the presentation of this individual who repeatedly came to the emergency department for various and sundry complaints. And to make a long story short, he presented a case that turned out to be lead poisoning. Everybody was on the edge of their seat trying to figure out what it was. And he was challenging members of the audience and senior members of the audience, including the Cair, and saying, “What do you think?” And it turned out that the patient became intoxicated not by eating paint chips or drinking lead infused liquids. He was burning car batteries to stay alive and inhaling lead fumes, which itself was fascinating, you know, so it was a fabulous grand rounds. And I mean, everybody learned something about the disease that they might otherwise have ignored, you know, if it'd been a title “Lead Poisoning”, I'm not sure a lot of people would have shown up. Dr. Mikkael Sekeres That story, David, reminds me of Tracy Kidder, who's a master of the nonfiction narrative, will choose a subject and kind of just go into great depth about it, and that subject could be a person. And he wrote a book called Rough Sleepers about Jim O'Connell - and Jim O'Connell was one of my attendings when I did my residency at Mass General - and about his life and what he learned about the homeless. And it's this same kind of engaging, “Wow, I never thought about that.” And it takes you in a different direction.  And you know, in your essay, you make a really interesting comment. You reflect that subspecialists, once eager to share their insight with the wider medical community, increasingly withdraw to their own specialty specific conferences, further fragmenting the exchange of knowledge across disciplines. How do you think this affects their ability to gain new insights into their research when they hear from a broader audience and get questions that they usually don't face, as opposed to being sucked into the groupthink of other subspecialists who are similarly isolated? Dr. David Johnson That's one of the reasons I chose to illustrate that prostaglandin presentation, because again, that was not something that I specifically knew much about. And as I said, I went to the grand rounds more out of a sense of obligation than a sense of engagement. Moreover, our Chair at that institution forced us to go, so I was there, not by choice, but I'm so glad I was, because like you say, I got insight into an area that I had not really thought about and that cross pollination and fertilization is really a critical aspect. I think that you can gain at a broad conference like Medical Grand Rounds as opposed to a niche conference where you're talking about APL. You know, everybody's an APL expert, but they never thought about diabetes and how that might impact on their research. So it's not like there's an ‘aha' moment at every Grand Rounds, but I do think that those kinds of broad based audiences can sometimes bring a different perspective that even the speaker, him or herself had not thought of. Dr. Mikkael SekeresI think that's a great place to end and to thank David Johnson, who's a clinical oncologist at the University of Texas Southwestern Medical School and just penned the essay in JCO Art of Oncology Practice entitled "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last."  Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts.  David, once again, I want to thank you for joining me today. Dr. David JohnsonThank you very much for having me. 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.    Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr David Johnson is a clinical oncologist at the University of Texas Southwestern Medical School.

N Engl J Med 2001;344:1879-1887Background: Acute coronary syndrome is broadly categorized into unstable angina, non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). In unstable angina, there is no rise in cardiac biomarkers, although some challenge this clinical entity in the current era of high sensitivity troponins. In NSTEMI, there is elevation of cardiac biomarkers but no ST segment elevation on the electrocardiogram. In STEMI, there is an ST segment elevation on the electrocardiogram as well as a rise in cardiac biomarkers.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.In patients with STEMI, percutaneous coronary intervention (PCI) significantly improves outcomes. However, its role in acute coronary syndrome without ST-segment elevation is less clear for several reasons. Patients with NSTEMI tend to be older and have more comorbidities, increasing procedural risks. This also means that they have competing risks for mortality, potentially reducing the benefit of PCI. Another key challenge is that NSTEMI patients frequently have multivessel disease, making it more difficult to identify the culprit lesion; since there is usually only partial occlusion of the culprit coronary artery. In contrast, there is usually complete occlusion of a coronary artery in STEMI and ST-segment elevation on the electrocardiogram helps localize the infarcted area, making it relatively easy to identify the culprit artery.The findings from previous randomized trials of revascularization in unstable angina and NSTEMI, have been inconsistent. The TACTICS–Thrombolysis in Myocardial Infarction 18 trial sought to compare early invasive vs conservative strategy in patients with unstable angina or NSTEMI.Patients: Eligible patients had angina within 24 hours that was: >20 minutes in duration, accelerating angina, or recurrent episodes at rest or with minimal effort. Patients also had to have one of the following: ST-segment depression of at least 0.05 mV, transient ( 2.5 mg/dL.Baseline characteristics: The trial randomized 2,220 patients – 1,114 randomized to early invasive strategy and 1,106 randomized to conservative strategy.The average age of patients was 62 years and 66% were men. Approximately 28% had diabetes and 39% had prior myocardial infarction.Troponin T levels were elevated (>0.01 ng/ml) in 54% of the patients.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo early invasive vs conservative strategy.Patients received aspirin 325 mg daily, intravenous unfractionated heparin (5000U bolus, followed by an infusion at 1000U/ hour for 48 hours), and intravenous tirofiban (0.4 μg/kg/minute for 30 minutes followed by an infusion of 0.1 μg/kg/minute for 48 hours or until revascularization with tirofiban administered for at least 12 hours after PCI).Patients in the early invasive arm underwent coronary angiogram between 4 and 48 hours after randomization and underwent PCI as appropriate. Patients in the conservative arm were treated medically. If stable, they underwent an exercise-tolerance test before discharged (83% of these tests were with nuclear perfusion or echocardiography imaging). Patients in the conservative arm underwent coronary angiography with PCI if they had angina at rest associated with ischemic EKG changes or elevation in cardiac biomarkers, had clinical instability or had ischemia on their stress test.Endpoints: The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome, at six months.The estimated sample size to provide 80% power was 1,720 patients. This assumed that 22% of the patients in the conservative arm would experience the primary outcome and that the early invasive strategy would result in 25% relative risk reduction in the primary outcome. The sample size was later increased to 2,220 patients.Results: In the early invasive strategy, 97% of the patients underwent coronary angiogram after a medium of 22 hours after randomization, and 60% underwent PCI or CABG. In the conservative arm, 51% underwent coronary angiogram and 36% underwent revascularization during the index hospitalization.The primary composite endpoint was lower with the early invasive strategy (15.9% vs 19.4%, odds ratio: 0.78, 95% CI: 0.62 - 0.97; p= 0.025). The Kaplan-Meier curves started to separate at approximately one week. This benefit was driven by lower myocardial infarction and lower rehospitalization for an acute coronary syndrome with the early invasive strategy; (4.8% vs 6.9%) and (11.0% vs 13.7%), respectively. There was no difference in all-cause death (3.3% vs 3.5%).There were 3 important subgroup interactions. First is based on ST changes where patients with ST changes at presentation had all the benefit with an early invasive strategy (16.4% vs 26.3% [for patients with ST changes] and 15.6% vs 15.3% [for patients without ST changes]). Second is based on Troponin T levels where patients with troponin T> 0.1 ng/mL had significantly more benefit with an early invasive strategy (16.4% vs 24.5% and 15.1% vs 16.6%). The third is based on TIMI score where patients with higher TIMI score had more benefit with an early invasive approach. For a high TIMI score of 5-7, the event rate was 19.5% with early invasive vs 30.6% with conservative approach. Patients with TIMI score of 0-2 had no benefit with an early invasive strategy (12.8% with early invasive vs 11.8% with conservative strategy).Note to readers: TIMI score is a risk stratification tool used to predict 14-day adverse outcomes in patients with unstable angina or NSTEMI. The score ranges from 0 to 7 with higher scores indicating worse prognosis.Conclusion: In patients with unstable angina or NSTEMI, an early invasive strategy reduced the composite endpoint of death from any cause, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months with a number needed to treat of approximately 29 patients.The subgroup analysis of this trial is particularly important and biologically plausible, as the presence of ST changes and level of cardiac biomarkers elevation indicate more significant myocardial ischemia or necrosis. Patients without ST changes comprised 62% of the study participants, while those with negative cardiac biomarkers made up 59%, and the study results should not be generalized to these subgroups.Another key consideration is the lack of detailed criteria for what was deemed ‘appropriate' revascularization. Only 60% of patients in the early invasive strategy group underwent revascularization, underscoring that not all patients with unstable angina or NSTEMI benefit from coronary angiography and that further risk stratification is necessary.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

In this JCO Article Insights episode, Peter Li summarizes “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al. published on December 13, 2024. TRANSCRIPT Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al.  For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy.  They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver.   Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm.   Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials.  The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach.  In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone.   This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.   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.  

Lancet 2016;388:2743-52Background: PCI was commonly used for the management of patients with left main coronary artery disease and favorable pathology (i.e., absence of complex lesions). This was recommended by the guidelines at the time and based mainly on the prespecified subgroup of 705 patients with left main disease in the SYNTAX trial. The NOBLE trial sought to more rigorously test the hypothesis that PCI with drug eluting stents was non-inferior to CABG in patients with unprotected left main coronary artery stenosis.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients: Inclusion criteria for study enrollment were stable angina pectoris, unstable angina, or acute coronary syndrome with a left main lesion with visually assessed stenosis diameter >/= 50% or fractional flow reserve I. The number of target lesions was 2 in both groups. The average SYNTAX score was 22.5 (for reference, it was 28.7 in the SYNTAX trial). The percentage of patients with stable angina was 82% and acute coronary syndrome was 18%. Patients were enrolled from 36 different centers but 5 centers contributed 42% of them. A screening log from these 5 centers was presented in the main paper. For these centers, the enrolled/screened ratio was 52%. The most common reasons for exclusion were unsuitable coronary anatomy for PCI.Procedures: Patients were assigned 1:1 to undergo PCI with drug eluting stents or CABG. After treatment of 73 patients with PCI, the Biolimus-eluting stent became the recommended study stent. Randomization was stratified by sex, the presence of a distal left main bifurcation lesion, and diabetes.The intent was to achieve complete revascularization of all vessels with significant lesions. The techniques for CABG and PCI as well as post-treatment medicines were chosen based on local practice but included 75-150 mg of aspirin lifelong. In both groups, patients with acute coronary syndrome received 75 mg of clopidogrel daily for 12 months. All patients in the PCI group also received 75 mg clopidogrel daily for 12 months and prasugrel or ticagrelor could be substituted at the discretion of the PCI operator.Endpoints: The primary endpoint was a composite of death from any cause, non-procedural myocardial infarction, repeat revascularization, or stroke.Analysis was performed based on the intention-to-treat principle. The primary analysis was a non-inferiority analysis. The main hypothesis tested was non-inferiority of PCI to CABG, assessed as the upper limit of the 95% CI of the hazard ratio (HR) of PCI to CABG, not exceeding 1.35 at median 3 years of follow-up. It should be noted that the sample size calculation for NOBLE was based on 1 year event estimates from the SYNTAX trial that were extrapolated to 2 years. The sample size of 1,200 patients came from the original hypothesis test of non-inferiority corresponding to a total of 275 events at median 2 years of follow-up. However, due to slow accrual of events, assessment of the primary endpoint could not be reached within the limit of the study and so the primary endpoint assessment was pushed back to 3 years of follow-up. Despite this, the prespecified event total (275 events) was not reached.Results: 1,201 patients were enrolled, which included 598 in the PCI group and 603 in the CABG group; however, only 592 patients in each group were entered into the final intention-to-treat analysis. Compared to CABG, PCI increased the primary composite endpoint (28% vs 18%; HR 1.51; 95% CI 1.13-2.00). Since the upper bound of the 95% CI was >1.35, PCI did not pass the test for non-inferiority. The primary outcome was driven mainly by differences in non-procedural MI (6% vs 2%; HR 2.87; 1.40-5.89) and repeat revascularization (15% vs 10%; HR 1.50; 1.04-2.17), which favored the CABG group. There was no difference in all-cause mortality (11% vs 9%; HR 1.08; 0.67-1.74) or its sub-component of cardiovascular mortality (3% vs 3%; HR 0.92; 0.44-1.90). The outcome of stroke was numerically higher with PCI but the difference was not statistically significant (5% vs 2%; HR 2.20; 0.91-5.36). When examining the Kaplan-Meier curves for the primary outcome, the curves start to diverge at 1 year.PCI was associated with significantly lower 30 day morbidity compared to CABG exemplified by 3 outcomes: duration of index treatment admission (2 vs 9 days; p

N Engl J Med 2012;367:2375-2384Background: The first large trial to compare PCI vs CABG was SYNTAX. In the subgroup of patients with diabetes, which made up approximately 25% of the trial population, PCI was associated with a higher rate of adverse events compared to CABG, primarily driven by higher rates of repeat revascularization in the PCI group.The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial sought to assess the optimal revascularization strategy for patients with diabetes and multivessel coronary artery disease.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients: Eligible patients had diabetes and multivessel coronary artery disease defined as a stenosis of 70% or more in two or more major coronary arteries supplying at least two separate territories.Patients with left main stenosis of 50% or more were excluded as well as patients with severe congestive heart failure, prior CABG or valve surgery, stroke within 6 months, significant bleeding within 6 months, 2 or more chronic total occlusions in major coronary territories that are targets for revascularization, and patients with STEMI within 72 hours.Baseline characteristics: The trial randomized 1,900 patients – 953 randomized to PCI and 947 to CABG.The average age of patients was 63 years and 71% were men. The average HbA1c was 7.8 and 32% were using insulin. Approximately 26% had prior myocardial infarction and 16% were current smokers. The average left ventricular ejection fraction was 66%.Approximately 83% had three vessel disease and 6% of the lesions were classified as chronic total occlusions. The SYNTAX score was low (22 or less) in 35% of the patients, intermediate (23 - 32) in 45% and high (33 or more) in 20%.Procedures: Patients were randomized in a 1:1 ratio to undergo CABG or PCI using drug-eluting stents. The use of arterial conduits was encouraged for patients undergoing CABG.Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least 12 months following PCI.Endpoints: The primary endpoint was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke. Secondary analysis was performed based on the SYNTAX score and study center location; north America vs not.Analysis was performed based on the intention-to-treat principle. The estimated sample size was 1,900 patients to be followed up for at least 2 years. This sample size would provide 80% power to detect a 27% relative risk reduction in one treatment group based on an estimated event rate of 21.5% in the arm with higher event rate.It's important to note that the initial sample size was 2,400 patients but this was amended twice due to slow recruitment.Authors performed 3 interim analyses and therefore, the p value to indicate statistical significance for the primary outcome was adjusted to be 0.044.Results: Among 32,966 patients who were screened for inclusion, 3,309 (10%) were found eligible. Among eligible patients, 1,900 consented to the trial and were randomized. The breakdown for excluding patients was not provided. The median follow up time was 3.8 years (interquartile range: 2.5 - 4.9). In the PCI arm, the average number of lesions stented per patient was 3.5 and 34% underwent a staged procedure. In the CABG arm, the average number of vessels grafted was 2.9 and 94% had a left internal mammary artery graft.At 5-years, the primary outcome was lower in the CABG arm (18.7% vs 26.6%, absolute difference 7.9%, 95% CI: 3.3 – 12.5; p= 0.005). All-cause death was lower with CABG (10.9% vs 16.3%; p= 0.049) as well as myocardial infarction (6.0% vs 13.9%; p< 0.001). When examining the Kaplan-Meier curves for the primary endpoint as well as death (figure 1 of the manuscript), the curves start to diverge, in favor of surgery, at approximately 2-years of follow up.Stroke was higher with CABG (5.2% vs 2.4%; p= 0.03). Excess stroke in the CABG arm was largely within 30-days after the procedure (1.8% vs 0.3%).Major bleeding within 30-days after revascularization was not significantly different between both treatment groups (3.6% with CABG vs 2.4% with PCI; p= 0.13). Acute renal failure requiring dialysis within 30-days after revascularization was higher with CABG (0.8% vs 0.1%; p= 0.02).There were no significant subgroup interactions that included the SYNTAX score, sex, 2- or 3-vessel disease and study center location; north America vs not.Conclusion: In patients with diabetes and multi-vessel stable coronary artery disease, CABG was superior to PCI in reducing the primary endpoint that consisted of death from any cause, nonfatal myocardial infarction, and nonfatal stroke with a number need to treat (NNT) of approximately 13 patients over an average follow-up period of 3.8 years. All-cause death and myocardial infraction were significantly lower with CABG with a NNT of approximately 19 and 13, respectively. Stroke was higher with CABG with a number needed to harm (NNH) of 36 patients. CABG also increased the risk of acute renal failure requiring dialysis within 30-days after revascularization with a NNH of approximately 143.A key difference between this trial and the early CABG trials is the frequent use of internal mammary grafts in FREEDOM (94% vs 10%). Internal mammary grafts are resistant to atherosclerosis and have high patency rates. One possible explanation for the divergent results between this trial and SYNTAX, which also used arterial grafts frequently, is the follow up time. In SYNTAX, patients were followed for 1 year while FREEDOM followed patients up to 5 years and the curves for the primary outcome and death favoring CABG started to diverge at approximately 2 years.When deciding between CABG and PCI for patients meeting the trial's eligibility criteria, it's important to consider the early risks associated with surgery, with the benefits of CABG becoming more apparent after 2 years. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Listen to ASCO's Journal of Clinical Oncology essay, “The Road Less Traveled: Perspective From an Australian Oncologist” by Stephanie Hui-Su Lim, Medical Oncologist at Macarthur Cancer Therapy center in New South Wales, Australia. The essay is followed by an interview with Lim and host Dr. Lidia Schapira. Lim shares her thoughts as an oncologist dealing with a patient that has decided not to continue with treatment.  TRANSCRIPT Narrator: “The Road Less Traveled: Perspective From an Australian Oncologist” by Stephanie Hui-Su Lim  He had been diagnosed with metastatic colorectal cancer in his late 30s and was responding well to first-line treatment. Physically fit, with a good tolerance to therapy, there was no stigma of sickness or telltale signs of cancer lurking around him. His partner usually attends with him, offers polite nods, few questions asked, but you could sense her underlying nervousness and fear of the unknown. Between the short phrases of broken English and the interpreter talking, consultations were usually pleasant, the right questions were asked, and I would end the consultation by asking how his family was doing back in Vietnam. Born to Chinese-Vietnamese parents in a city on the outskirts of the capital, he migrated to Australia 10 years ago. He worked hard, exercised, ate a healthy blend of an Asian and Western diet, and check-boxed all the requisites to build a good life. On this occasion, his cancer was slowly progressing although remained largely asymptomatic. His optimism stayed stable, and he kept his full-time job. I discussed switching treatment. “Do you have any questions?” As I shuffled the consent form, information sheets in Vietnamese, pathology form, imaging request, and follow-up bookings, I waited for the interpreter on the other end of the phone to speak. COVID-19 was still lingering, and our face-to-face interpreter service had largely been replaced by phone calls. My now 40-year-old patient, alone today in the clinic room, looked at me and the care coordinator, then spoke something to the phone. The voice on the other end said he has no questions, he is “keen to get on with it.” “Ok then, we'll get him to sign here, and I'll need your healthcare interpreter number too.” An exchange of words ensued, perhaps some things were repeated over. Then my patient smiled, and waited. “He says thank you doctor but he doesn't want any treatment.” It was not the answer I was expecting. I had explained his slow disease progression, multiple lines available, and good tolerability of treatment, maintaining his quality of life and maximizing survival. I had gone through the projected life expectancy at this point, which was still measured in the order of short years if we pursued all standard therapies. “Can you ask him again? That he does not want any treatment?” Perhaps the interpreter had not relayed what I said. Perhaps I had not emphasized the benefits of continuing treatment. Perhaps there were misplaced reasons for declining evidence-based treatment, the clues of which I had learned to pick up quickly, gleaned from conversations over family dinners from my own family of migrants. When my patients decline treatment in a context where the clinical benefits clearly outweigh potential harm, I often feel I have not done enough. If I spent more time talking them through their decision making, guiding them through hypothetical what-if scenarios, then would we have gotten to the same page? Was I sure they were compos mentis? Should I call the other listed relatives and have the same conversation with them? In his case, he had made a capable and informed decision. We are used to the well-trodden path of exhausting appropriate standard treatment before transitioning to a best supportive care approach. However, when patients choose the less traveled path where their cancer journey and life expectancy are truncated by choice, we may struggle to understand their decision. I felt a sense of frustration at his polite declining of potential years of life and unfairness when the next patient, unfit and exhausted of all therapies, begged for more treatment options or anything that could give them another extra day. I sought to try to better understand the reasoning behind his decision. I have encountered many culturally and linguistically diverse (CALD) patients throughout my journey as an oncologist and personal experiences in my own migrant family. Our health district has one of the most diverse populations in the state, with one in 10 having limited English proficiency. Almost half the population speak a language other than English.1 We often see as many interpreters as patients in the waiting room, multiple extended family members crowding into small consult rooms, and multitude of language translations of patient booklets being the only recognizable information to new patients in an otherwise foreign cancer center. I understood the importance of cultural awareness, and that cultural differences feed into decision making. But what were the beliefs, concepts, and cultural norms that shape what they do and value? An Australian study investigating the attitudes of Chinese migrant patients toward cancer identified several key areas including the nondisclosure of a poor prognosis, importance of family in mediating between health professionals and patients, incorporation of Chinese culture–specific treatment, importance of interpreters, and psychological and spiritual support.2 Chinese patients use combat strategies on the basis of traditional Chinese medicine, Chinese beliefs of food to maintain health, exercise with Qigong, Feng Shui/spatial organization, and ancestor worship.3 Chinese illness conceptualization includes concepts of karma, fate, and retribution.4 There are recurring themes that arise, with another study highlighting the importance of the Chinese beliefs in fate and luck, ying and yang, stoicism as a coping mechanism, importance of family, fear of losing face, and denial of diagnosis as a means of protecting the family. A common thread of family playing an essential role, rather than a patient autonomy approach, was evident. There is a need to incorporate these beliefs into culturally appropriate programs.5 Sadly, not much is known about the cultural impacts on patient decision making. Research into race, culture, and ethnicity is thought to be too restrictive.6 Research investigating interventions to improve patient-centered care and participation in the treatment process in CALD has found positive effects of culturally tailored video and patient navigator interventions.7 A recent review also found patient navigation as an effective strategy in improving patient care, from screening through to diagnosis, treatment initiation, and likely also in the active treatment and survivorship phase.8 Importantly, cultural barriers were evident. An Australian study looking at CALD needs in outpatient cancer clinics highlighted the importance of recognizing language-related needs and care teams adapting practices and available resources to make it work for CALD communities.9 Work in other CALD groups has also focused on the triadic relationship between the patient, the patient's family, and physicians.10 Latin American women who were less acculturated deferred to their families or friends to make treatment decisions, highlighting the importance of familism as one of the most culturally specific values for Latinas. Loyalty and solidarity among members of the family are integral to decision making. Asian and Latino patients are seen to have a higher rate of patient passivity because of cultural norms that respect physician authority.11 A systemic review of cancer beliefs in minority populations, the majority based in United Kingdom and United States, found low health literacy, fatalism, and stoicism as common themes.12 Decision making in a systematic review, with a predominant African American minority group, found the themes of spirituality, fatalism, and acculturation to be important in the treatment decision process.13  Ultimately, all these cultural beliefs and concepts feed into how patients decide which treatment road they wish to take. Shared decision making models in ethnic minorities have taken into account human values recognized across different countries and the relation between these.14,15 As clinicians, we often focus on the disease, with the goal being to get rid of as many cancer cells as we humanly can and prolong our patient's life expectancy while maintaining quality of life. I often feel we require tangible goals which can be measured in time and percentages, hazard ratios, and survival odds at 2 or 3 years. For the patient sitting on the opposite side of the desk, who are only single points on a Kaplan-Meier curve, goals may be very different, shaped by their own cultural values and beliefs. What numerical value can we place on traveling overseas back home, enjoying conversations over family dinners, rather than going to the cancer center for the next cycle of treatment? My patient had decided his goal was to return home to his family in Vietnam. I saw him in clinic several times, each time gaining more of an understanding of his decision. I spoke to his partner, we obtained a face-to-face interpreter. We discussed culturally appropriate support groups. He was active in local community groups who provided spiritual and existential support. I enquired about herbal remedies, which he had been on preceding his cancer diagnosis and continued with our pharmacist's approval. We turned to discussing where he was going to be living in Vietnam, potential complications during the flight home, provision of a medical letter, and copies of his tests. He remained uncertain about the prospect of further treatment, that it was hard to access good medical care and did not offer any answers about whether he planned to seek out treatment in the big city hospitals back home. He reassured me he would be fine. Every time I see a CALD patient, I remember my patient who politely said no, thank you. I wondered if he ever accessed any treatment, how quickly his disease progressed, when and how he died. My initial frustration has evolved into the understanding of how important it was for him to be surrounded by family. I found solace knowing he died with family by his side. The treatment he wanted could not be offered through an intravenous drip or medication. It could only be found in the safe familiarity of family. Every time I see a CALD patient, I try to create a culturally familiar place for them to be treated and place their decision making amid their cultural beliefs, norms, and values. The theme of last year's World Cancer Day is “Close The Care Gap.” Language, literacy, ethnicity, race, income, education, socioeconomic status, and geographical location are just a few of the factors that contribute to the cancer care gap. We need to have cultural sensitivity in mainstream health care and respect the differences that feed into the decision to accept or decline treatment in ethnic minority groups. Ethnic minorities are defined as nondominant groups, connected by a shared cultural heritage, values, and often language. It is important to note that this is also a relative definition, and my patient in Australia falls into the CALD group, but would be the dominant group back in his home country of Vietnam. Health and illness are not only visceral but also a social and cultural phenomenon. Sometimes, it is recognizing that closing the care gap does not bring us to the same destination, but to walk the road less traveled with them. As the years pass and I reflect on my patient's cancer journey, I have come to understand that as his doctor, it was my job to ensure he understood his disease and treatment options. However, perhaps even more importantly as his doctor, it was my honor to support him down the path he had chosen. Dr. Lidia Schapira: Hello and welcome to JCO's Cancer stories, the Art of Oncology, which features essays and personal reflections from authors exploring their experience in the field of oncology. I'm your host, Dr. Lidia Schapira. I'm a Professor of Medicine at Stanford University. With me today is Dr. Stephanie Lim, a Medical Oncologist at Macarthur Cancer Therapy center in New South Wales, Australia. In this episode, we will be discussing her Art of Global Oncology article, “The Road Less Traveled: Perspective from an Australian Oncologist”.   At the time of this recording, our guest has no disclosures.  Steph, welcome to our podcast, and thank you for joining us. Dr. Stephanie Lim: Thank you very much for having me. Dr. Lidia Schapira: Let's start by talking a little bit about the role of writing and reflection for us in oncology practice. Tell us a little bit about what led you to write this case up and then to decide to share it with your colleagues.  Dr. Stephanie Lim: Yeah, so writing is definitely a creative outlet for me. I also love to paint, and I think there's so much art in the oncology space. There's so much storytelling, the rich and diverse stories that our patients live out in their cancer journey. So I think for me, writing definitely is an avenue for me to process the patient scenarios, to distill what I've experienced emotionally with the patient in front of me, and really to put it down on paper. It's almost a debriefing exercise as well for me sometimes. It's quite cathartic to write and to paint, and I find it's also a way to remember a patient. So if there's something I really don't want to forget, I think writing is a way to almost memorialize that patient's scenario and that patient experience. Dr. Lidia Schapira: Very beautifully said. So with that, let's go to the case in the particular patient that you chose to write about. And in my reading of your essay, I think you have a message. What is that message for the reader?  Dr. Stephanie Lim: So I think let's take a step back and just go through some of the themes that really resonated with me, that took me quite a few years to go through and think through before I actually wrote it down in this essay. In fact, this essay is an amalgamation of quite a few cultural and linguistically diverse, or CALD patients that I've met and looked after over the years, and those themes just kept recurring.  The first is patients when they said no to treatment. As a clinician, I struggle. I struggle with that when patients flatly refuse what I sincerely feel is the best treatment option for them. I feel frustration, disappointment, even anger and sadness, almost grieving that lost opportunity for potential life lengthening years that the patients may otherwise have. In fact, I was listening to one of your other podcasts the other day, “Knuckleheads”, which, again, resonated with me because it was, again about another story of patient refusal and a different story, but the same theme. And I think when you add the CALD population into it, which is really the theme, the message of this essay, you add another layer of complexity, another layer of cultural diversity and differences to an already complex decision making process. So those two things really sort of challenged me over the years.  And I think the other pervasive theme is that human side. We always talk about the art of oncology, the humanistic aspect, but it's true. So I think the importance of the patient's story and really just paying attention to the background and that lived experience. Someone once told me, medicine, it's a humanistic enterprise, it's not just about numbers and medians. In fact, in the essay I mentioned that the patient in front of me is really just one point on a Kaplan–Meier curve. Medians to them don't really mean very much. There's really no value that we can place on time spent with family. Or in this case, when I tell a patient they've got progression, or try and outline and map out the next treatment plan, and then they turn around and ask me, “Okay, doc. So can I hop on a plane, fly across to the other side of the world and spend three months with my family? Because that's what I want to do.” So I think there's that struggle of trying to really do what's best for the patient in terms of medians and survival and quality of life, but also trying to balance those things that are really hard to put a value on.  I hope the message of this essay is that we can try and understand, identify these things, pay attention to patients, listen to their stories, and really help appreciate those choices. So it's certainly by listening to them and really trying to understand more about CALD and the concepts and values behind their decision making. I've grown to appreciate the choices they make and really helped to support them down what I called the path less traveled, a very unfamiliar path that I otherwise wouldn't have chosen for them.  Dr. Lidia Schapira: So let's unpack all of these wisdoms that you've just told us about. The motivation is clear, the intentions are clear. Let's talk a little bit about your discomfort as an oncologist, because I'm sure our readers and our listeners have experienced that when a patient gives you an informed decision to refuse treatment, why do you think it makes us so uncomfortable? And why did it make you so uncomfortable to have your patient say, “Thank you very much, I understand you, but no thanks”? Dr. Stephanie Lim: Yeah, I think as clinicians we want the best for our patients. And I think a lot of the time that is what's best in terms of survival, what the evidence says we should be doing, weighing up the pros and cons of treatment. And we map out the lines of treatment for our patients while trying to maintain a quality of life and take into account all their wishes, of course. But I think sometimes we might get carried away with what we want for them or what we feel is best for them. But listening, if you really spend time asking what they really want, it might be something as simple as I just want to spend more time with my family rather than coming to the chemo suite for another infusion. I think as time goes on I'm doing a lot more listening, a lot less talking.  When I started out I was telling patients medians and this is what we're going to expect, this is the 50% survival rates, and a lot of time patients look at me and it means not very much to them. So I think for us there is a root that in our minds we've mapped out for them which we sincerely feel is the best for them. And I think when they refuse that it can be quite frustrating, but also I think, challenging because as I said, it's a path that's unfamiliar. When patients go from diagnosis to, “Well, I actually don't want any treatment,” really they shorten their- as I think I put in the essay, intentionally shortening their survival and choosing best supportive care when they're not there yet is something that I still struggle with, especially in my younger patients. Dr. Lidia Schapira: So let's talk a little bit about that. And I'm just challenging you in the best possible collegial way here when we talk about honoring our patients autonomy and providing sufficient information for them to really give us informed consent based on being aware of their choices and trade offs. And yet when those decisions don't conform to what we think we would choose or what we've recommended, there's disquiet. And yes, we know that the patient ultimately is the main decider on what gives their life value and meaning, but it's difficult for us. Can you talk a little bit about how you resolve this tension in your practice? Even if a patient is very fluent in your primary language, that's almost a detail. It complicates things here. But it's not the only thing that really, I think, is so challenging and feels so difficult sometimes for the oncologist.  Dr. Stephanie Lim: Yes, I think in the CALD population, there's several other layers of complexity. So yes, the patient is ultimately the person receiving treatment and yes, they are the ones who should be deciding what they want. I think in the CALD population it's more complex because we talk about patient and clinician shared decision making, but there is this triad of family physician and patient relationship that exists in a lot of CALD populations, not only in Southeast Asian or South Asian, but perhaps even in the Latin American population, and that importance of families. So there is not just a patient and a physician, but there is also the whole family that is making that decision.  To complicate things in Asian culture, there is also this autonomy that's given to the doctor. So that belief that the decision making in some ways should be delegated to the health professional because they're the ones who know what they're doing. And a lot of my Asian patients might say, “Well, you're the doctor. You should be telling me what to do.” So I think it's a balance between respecting that, if that is their belief, respecting that doctor autonomy, but also taking into account that triad of decision making with patients, family, and even the wider community. So I think certainly in a CALD population, my approach would be to really understand why they've made that decision, to involve the family in that decision making, perhaps to see the patient over time, over multiple consultations, which we've done with this particular patient in the essay, and really just to understand what the barriers are or what their reasons are for going down a different path to what I've recommended. And I think once that's all unpacked, I think it becomes quite clear and it gets us to the same page. Dr. Lidia Schapira: So, Steph, if this patient had been 65 or older, do you think it would have been easier for you to accept his decision to say ‘no' to treatment and go home to be with family, whether or not access to any treatment is available to him there? Dr. Stephanie Lim: That's a good point. I think I personally do struggle more in my younger patients, patients closer in age to me at a similar stage of life, they have young children, and I think a lot of it is because they are so fit. We feel that they can tolerate so many lines of treatment. I'm almost grieving that lost opportunity, lost time that they may have with their children or their family. So I think definitely in the younger patients, it resonates with me more. I struggle more with that. Having said that, it's still a struggle when older patients who are fit for treatment say ‘no'. But definitely, I agree with you. I think the younger patients definitely are harder to manage.  Dr. Lidia Schapira: I was very impressed in reading your essay with the fact that you remained curious about the person who was your patient. You were curious and engaged and wanted to learn what he was thinking. And you not only wanted to make sure that he understood his options medically, but you wanted to understand the context, as you say, who else was influencing the decision, and still wanted to preserve the relationship. Tell us a little bit about how that evolved over time and what you learned and how you brought yourself to a place where you could accept this, at least not be distressed by his refusal of treatment.  Dr. Stephanie Lim: So I think, again, a lot of it was listening to his stories. Over time, that conversation shifted from me trying to tell him that if you have this treatment, this is what we expect, this is what we could gain. These are the survival years that you potentially could benefit from. So I think the conversation, over time, shifted from that to a focus on his values, other support systems, whether it's the support communities that were in place, the importance of even complementary or Chinese medicines that he was also pursuing, basically trying to unpack all that. And I think our conversations shifted from a lot less talk about treating the cancer to treating him as a person and what he needed.  So I think over time, I basically sat back and listened to him and what he wished to do. And over time, that conversation then evolved into, “Okay, you're going to leave, so how can I best support you?” And even then, I was trying to see if he was going to seek treatment overseas. I was ready to call someone at the other end of the world to say, “Here are the medical records. This is what can be done for him.” But I think over time, I've come to realize that definitely was not his priority. He needed to be with family. He wanted to go home. And as a clinician, as his treating clinician, I think my job was to support him through that and try and understand. So I think over time, just spending that time listening to them, I did understand. I did struggle with it. But I think ultimately, I was at peace with his decision.  Dr. Lidia Schapira: In the essay, you mentioned that your family also migrated to Australia. Do you think that their experience in some way has shaped your attitude towards understanding cultural and linguistic differences? And if so, how?  Dr. Stephanie Lim: Yeah, thanks for asking that, Lidia. So I was born in Southeast Asia. In fact, I grew up in Brunei, on Borneo island, which is in the heart of Southeast Asia. My dad is Bruneian. My mom is Malaysian. I did finish off my high school in Australia and did all my medical training in Australia. So this is through an Australian lens. In fact, the reviewers wanted me to include that, to point out that CALD is a very relative definition. But I think I class myself as a 1.5 generation Australian. So I hope that I do have some insights from my background and my upbringing to understand a little bit more about the nuances, to be able to pick out some of the subtleties when I see patients, when I talk to patients, that complex cultural belief that underpins all their decision making. So I think that definitely, I hope, has enabled me to be more sensitive and to be able to pick out some of those nuances that helps me better understand and frame a patient's decision making. Dr. Lidia Schapira: And ultimately, did you feel all right with your decision and your patient's decision? Dr. Stephanie Lim: Yes, I did. So I think ultimately, the goal is to create this culturally safe and appropriate place for patients where they're comfortable, where the clinicians are also comfortable with that final decision that we reached. And I think we got there. But my hope is that with all future patients, that we can create this with the help of patient care navigators, patient translators. It comes from a systems level, a team level, and definitely an individual level to understand, identify these concepts, as I pointed out in the essay, to reach a point where we feel that the patients have had a culturally safe and language appropriate care, that we've explored all the avenues, all their concepts, all their beliefs, and we've reached the decision that we're both comfortable with. Dr. Lidia Schapira: Well, Steph, it's been a pleasure to chat with you today, and I know that I did, and I know my colleagues have learned a lot from reading your story and wish you all the best. And thank you for sending your work to JGO. Dr. Stephanie Lim: Thank you, Lidia, it was a pleasure chatting to you. Dr. Lidia Schapira: And until next time, thank you for listening to JCO's Cancer Stories, The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO shows asco.org/podcasts. 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.  

Drs. Shaalan Beg and Aparna Parikh discuss the role of ctDNA as a powerful prognostic biomarker for GI cancers, along with its impact on risk stratification and the detection of recurrence. They highlight key studies in ctDNA that were featured at the 2024 ASCO GI Cancers Symposium, including COBRA, GALAXY, and BESPOKE in CRC, as well as the promise of ctDNA testing in the preoperative detection of iCCA. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host for the ASCO Daily News Podcast today. I am an adjunct associate professor at UT Southwestern's Harold Simmons Comprehensive Cancer Center in Dallas. On today's episode, we will be discussing the emergence of circulating tumor DNA (ctDNA) technology in GI cancers. I am delighted to be joined by Dr. Aparna Parikh, an assistant professor of medicine at Harvard University and the director for colorectal medical oncology at the Massachusetts General Hospital Cancer Center, where she also serves as the medical director of the Young Adult Colorectal Cancer Center. Dr. Parikh will share her insights on key research on this hot topic in GI oncology that was featured at the recent ASCO Gastrointestinal Cancers Symposium.  Our full disclosures are available in the transcripts of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Parikh, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much, Dr. Beg.  Dr. Shaalan Beg: In recent years, it has become evident that liquid biopsy and other emerging ctDNA technologies are changing how we treat GI cancers, and colorectal cancer (CRC) is in the forefront of this space. Before we dive into key studies, can you briefly highlight for our listeners how ctDNA is advancing the field and how it can influence the care that we deliver to our patients in the future? Dr. Aparna Parikh: Absolutely, ctDNA is certainly a hot topic. What we have learned over the years is that ctDNA has emerged across many solid tumor types as one of the most powerful, if not the most powerful, prognostic biomarker we have to date. ctDNA has improved risk stratification. We have learned a lot about the role in what is called minimal or molecular residual disease in patients with early-stage disease, and ctDNA being a biomarker of recurrence for those patients, with ctDNA, we have a better understanding of tumoral heterogeneity, both spatially and temporally, getting a better glimpse of what is happening in a given patient with multiple metastases, as well as genomic evolution of tumors over time. So certainly many, many roles and areas where ctDNA is emerging. Dr. Shaalan Beg: This was a hot topic at the 2024 ASCO GI Cancers Symposium, and we're going to take a deep dive into some of the abstracts that were presented. Let's start with the COBRA study, which is the NRG-GI005. That was Abstract 5 at the ASCO GI Cancers Symposium, and the GALAXY study, which was Abstract 6 at the symposium. So, the COBRA study reported results of ctDNA as a predictive biomarker in adjuvant chemotherapy for people with colon cancer. At a high level, it was a negative study, but there are some important lessons for us to learn. Similarly, in the GALAXY study, investigators from Japan presented an updated analysis on the correlation of ctDNA dynamics with outcomes in colorectal cancer with minimal residual disease. How do you synthesize all this information and help the listeners understand our current state for ctDNA applications in colorectal cancer? Dr. Aparna Parikh: Yeah. Let's take the COBRA study first. Let's talk a little bit about the design of COBRA. COBRA was intended to look at patients that were resected, stage 2 colorectal cancer patients, or colon cancer patients who were 2A. These are patients where the treating physician would, at the outset, decide that there was no adjuvant chemotherapy indicated. These are patients where active surveillance would be entirely appropriate as the standard of care. Patients were randomized to arm 1, which was active surveillance, or randomized to arm 2, which was assay-directed therapy. If there were ctDNA positive in arm 2, then they were given chemotherapy, FOLFOX or CAPOX. And if they were “ctDNA not detected,” then they would also go on to active surveillance.   And so, the plan was that nearly 1,500 patients are to be recruited, and at the time of this data cut, they had around 630-some patients. The primary objective was to look at the clearance rates of ctDNA between the ctDNA-positive cohorts, remember, the chemotherapy and the active surveillance cohorts at 6 months. They had around a 5% detection rate of ctDNA patients. Ultimately, that was around 16 patients. The reason that the study shut down was that what they found was that in the surveillance arm, the arm that was not getting any treatment, they had a ctDNA clearance of 43% versus 11% in the chemotherapy arm. They had an interim analysis to look at the clearance rate between the 2 arms, and what was surprising to the investigators and the community was what was happening in terms of clearance. Why do we have a 43% clearance rate in patients that were not getting anything? And so, because of that, the study was shut down as it did not meet its prespecified interim look at clearance in those 2 arms.   Many things came up in terms of learnings from COBRA. Number one was the characteristics of the assay. And so, you take an assay in a low-risk patient population that has a fixed specificity, and when your baseline prevalence of recurrence is so low, for example, in low-risk stage 2 patients, your composite predictive value is very susceptible to small changes in that specificity. And so, your PPV is going to be a lot lower in a low-risk patient population than a higher-risk patient population. The COBRA study used an older version of a tumor-uninformed assay, so it definitely called into question some characteristics of the assay. Is one-time-point clearance sufficient, and is that the right endpoint? We have seen now, including the GALAXY study that we'll talk about here, previously reported just spontaneous clearance happening in 5%, 10% of patients. The question with that spontaneous clearance is: Was it actually clearance, or was chemotherapy just perhaps in a low ctDNA shedding state? Are you just suppressing the ctDNA below the level of limited detection?  And then in this study, the clearance draw was actually done in the chemotherapy arm right before the last cycle of chemotherapy, again to that point of, are you just suppressing the ctDNA with chemotherapy? There is also stochastic sampling error that can happen in patients with very low residual tumor volume. So, I think this is a disappointing study in the sense that it is still a really important question. There are still 2A patients that recur, but maybe [this was] not the right test, or maybe single-time-point testing wasn't enough. And so, lots of lessons to be learned from this study in terms of test and design, but hopefully more to come. I think certainly stage 2 patients remain an area where I think, hopefully, ctDNA still plays a factor for those patients.  Dr. Shaalan Beg: And how was the patient population for the GALAXY study? That was Abstract 6, compared to the COBRA study. Could you summarize those findings for us?  Dr. Aparna Parikh: Yeah, so GALAXY was part of a large study in Japan that includes an observational cohort plus therapeutic cohorts as well. And so, GALAXY was just further reporting of the observational cohort. So unlike COBRA, which is a low-risk, stage 2 study that was actually asking that interventional question: Can you use it to guide therapy? The GALAXY and the updated GALAXY just continues to show more clinical validity data rather than clinical utility data. And it was nearly 3,000 patients, pan stages. Again, the lion's share were stage 2 and 3 patients, but there were also stage 1 and stage 4 patients as well. And what they showed was that ctDNA is undoubtedly prognostic. They showed very consistent Kaplan-Meier curves, which we've seen time and time again, where if you're ctDNA-positive, you don't do as well.  What they showed was, not surprisingly, with longer-term follow-up – this is 24-month follow up, so longer-term follow up than was published in their paper last year – was that when you test at one time point, so landmark testing, the sensitivity of detecting recurrence was around 48%, and that fell from the publication last year which was around 58%, 59%, which is not surprising as you follow more people. I think single time point testing soon after surgery may miss those late recurrences, but it's still prognostic and showed a specificity of around 94%.   They also continued to show that if you continued to test with serial testing, your sensitivity improves, but what was really interesting and new, what they presented this time, was a clearance analysis. And showing, again, comparable to COBRA, in many ways, in the sense that clearance can be a little bit finicky, especially at one time point, is what they showed is that patients who had sustained clearance, and these are patients that had at least two time points with their ctDNA remained to be negative, they did very well. But if you had transient clearance, and again, the definition was a little bit broad, at least having one negative and then one positive, those patients ultimately, at 24 months, the curves came together with the no clearance curve. So initially, they did better than the people that didn't have any clearance. But if you transiently cleared at two years, the curves came back together.   And what was interesting is that in those patients that sort of transiently clear by 9 to 12 months, 80% of those are actually having a rapid return of ctDNA. And so this begs the question of was chemotherapy just suppressing that ctDNA or maybe if you have a better test you could have actually improved it.  These were some of the updated, interesting learnings from GALAXY, which remains incredibly prognostic. And then the concept of clearance, which I think we have to look into a little bit more as a field, and understanding that maybe just one time point clearance isn't sufficient.  Dr. Shaalan Beg: Yeah, and one of the most important applications for ctDNA can be its ability to inform adjuvant chemotherapy. Its ability to not only identify more people who may benefit from chemotherapy, but maybe even identify people who don't need chemotherapy. And along those lines, Abstract 9, the BESPOKE study, looked to understand the role of ctDNA-based detection of molecular residual disease to inform adjuvant therapy for stage 2 and 3 colorectal cancer. And they presented interim data at the GI ASCO this year. What were your takeaways from this study? Dr. Aparna Parikh: Exactly. Beyond the prognostic implications, I think what was really interesting was that there was the initial data looking at the benefit of adjuvant chemotherapy. So, what they did was they said, “Okay. We're going to take the MRD-positive patients and look at the benefit of adjuvant chemotherapy and then the benefit of adjuvant chemotherapy in the MRD-negative patients.” And again, remember, this is a prospective observational study, so it's not looking at negative and positive to guide therapy, but it's just looking prospectively and observationally at how those patients are doing. But what they showed again is that indeed, in the adjuvant chemotherapy group, the benefit of adjuvant chemotherapy again with the follow-up to date on the study was different in the MRD-positive patients.  First of all, I guess taking a step back, the DFS in the ctDNA-negative patients at 2 years was very good. So negative patients had over 98% 2-year DFS in both the adjuvant chemotherapy and observational group. And there was no real difference between adjuvant or not. But in the positive patients, not surprisingly, the DFS was worse. But what was reassuring to see is that you can make an impact with adjuvant chemotherapy in the positive patients. And the difference in DFS between the positive and negative patients, with adjuvant or not, was 42% versus 12.5%, in the observational patients. So, it is benefitting the patients who are positive so it does give us more data that, again, at least in the positive patients, you may be able to reverse the recurrences there with adjuvant chemotherapy. And maybe if you're negative, eventually, we'll get to a point of de-escalation of care. Again, keeping in mind the kinds of sensitivity limitations as well.  Dr. Shaalan Beg: Wonderful. And one of the other malignancies in the GI space where precision therapies and molecular biomarkers are making a huge difference are intrahepatic cholangiocarcinoma. Genomic profiling using ctDNA is increasingly being used in this population to inform precision oncology approaches and determine mechanisms of resistance to targeted therapies as well. In Abstract 528, investigators looked at the role of preoperative ctDNA testing for resectable intrahepatic cholangiocarcinoma. What are your thoughts on that study?  Dr. Aparna Parikh: Yeah, it's such an important area, as you mentioned, in the metastatic space – FGFR, IDH1, all these alterations that are emerging in intrahepatic cholangios. This was a very small study, it was preoperative, and so the tumor was intact, and around 14 patients. They used a tumor-informed approach just for detection and quantification of ctDNA. So this was not a study that was looking at a next-generation sequencing approach where you're going to actually be able to detect the alterations, but it's actually looking for the detection and quantification of ctDNA rather than genomic characterizations. And patients had about a month or so where they had their baseline blood detected. And I think what was reassuring to say was that ctDNA was actually detected in all the patients with the primary tumor intact, except for one patient who was a very low-risk stage 1A patient. There was some correlation, against a small number of patients, between the concentration of ctDNA in patients that had the lower stage and then the higher stage groups. Small numbers were actually hard to characterize and correlate with recurrence or mortality, but at least, some correlation with pathologic tumor size, they were able to because it was a bespoke panel and you're sampling the tissue and then looking in the blood, IDH1 and 2 were mutations that were tracked based on the genomic profiling and a couple of the patients were able to have their IDH mutations tracked.  So it gives us a sense, a little bit, that ctDNA, we know has a lot of variable shedding across disease states and tumor locations, but gives us some promise that it is reliably detected with the tumor-informed approach, at least preoperatively in cholangios. So may again open some more opportunities for MRD testing in cholangiocarcinoma as well.  Dr. Shaalan Beg: Thank you. That's a wonderful review of ctDNA applications in gastrointestinal cancers from the 2024 ASCO GI Cancers Symposium. Thank you, Dr. Parikh, for sharing your valuable insights with us on the podcast today. Dr. Aparna Parikh: Thank you so much for having me. Dr. Shaalan Beg: 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 ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Aparna Parikh @aparna1024   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Aparna Parikh: Consulting or Advisory Role (An Immediate Family Member): PMV Consulting or Advisory Role: Checkmate Pharmaceuticals, Guardant Health, Foundation Medicine, Abbvie, Value Analytics Labs, Bayer, Taiho Oncology, Delcath, Seagen, CVS, SAGA Diagnostics, Scarce, Illumina, UpToDate, Takeda, AstraZeneca, Takeda, Pfizer, Kahr, Xilio Therapeutics, Sirtex Research Funding: PMV Pharma, Erasca, Inc, Syndax Research Funding (Institution): Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo, Karkinos Other Relationship: C2i Genomics, Xgenomes, Parithera, Cadex

Dr Gibson and Dr Nero discuss the oft maligned issue of medical statistics.  Their discussion covers the pros and cons of traditional Cox proportional hazards regression models and Kaplan-Meier curves and newer techniques including win ratios.  They then dip their toes into AI.  A great overview by one of our leading clinical trialists.

NEJM 1995;333:1670-6.Background Up to this point in history, a series of trials had been conducted using ACEi's in post-MI patients. A small to moderate short-term benefit had been shown when the drugs were started immediately (GISSI-3 and ISIS-4) and much greater long-term benefits were demonstrated when the drugs were started 5-11 days, on average, following AMI in patients with LV dysfunction and congestive heart failure (SAVE and AIRE).The SAVE and AIRE trials, however, were more selective and it was not clear how representative they were among all potentially eligible patients. Thus, TRACE authors sought to re-test the hypotheses tested in SAVE and AIRE with a focus on generalizability of trial procedures and results. Specifically, the Trandolapril Cardiac Evaluation Study (TRACE) sought to test the hypothesis that trandolapril would reduce all-cause mortality in post-MI patients with LV dysfunction when used in the majority of consecutively screened, potentially eligible patients.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Consecutive patients ≥18 years of age who were hospitalized with a confirmed AMI were screened between day 2 and 6 after the onset of symptoms. All screen eligible patients underwent echocardiography and those with a wall motion index of ≤1.2, which corresponds to an EF ≤35%, were considered for enrollment. The key exclusion criteria included an absolute or relative contraindication to an ACEi or a definite need for an ACEi, severe uncontrolled diabetes, a serum sodium 2.3 mg/dl.Baseline characteristics The average age of patients was 68 years and 72% were men. Approximately one third of patients had a prior MI, 13% had diabetes, 23% had hypertension and smoking status was not listed. The average wall motion index was 1.0. Two thirds of patients had a Q wave MI (anterior 47% and inferior 19%). The mean time to randomization was 4.5 days. Forty-five percent of patients received thrombolysis. The average blood pressure and heart rate were 120/70 mmHg and 76 beats per minute, respectively. At the time of randomization 16% of patients were receiving a beta blocker and 28% digoxin. Before randomization, 60% of patients had been classified as Killip class ≥2 and at the time of randomization it was 21%.A total of 6,676 consecutive patients experienced an AMI of whom 2,606 had a wall motion index of ≤1.2. There was an inverse relationship between wall motion index and mortality. In patients with scores ≥1.3, 40% had signs of CHF and the 1-year mortality rate was 12%. Among patients with scores ≤1.2, 74% had signs of CHF and the 1-year mortality was 34%.Of the 2,606 eligible patients, 859 (33%) were excluded. The most common reasons for exclusion included need for mandatory ACE inhibition [6%], cardiogenic shock [4%], death during screening [3%], renal failure or a single kidney [2%], intolerance of the test dose of trandolapril [1%], lack of consent [8%], or other reasons [8%].Altogether, 1,749 (67%) of patients with a wall motion index score ≤1.2 were enrolled.Procedures Eligible patients were given a test dose of 0.5 mg of trandolapril, which led to the exclusion of 1% of patients. These patients were not included in the ITT analysis. Double-blind medication was started between day 3 and day 7 after AMI. Patients were randomly assigned to receive 1 mg of trandolapril once daily or matching placebo. After two days, the dose was increased to 2 mg once daily. After four weeks, the dose was again increased, to 4 mg once daily. If the highest dose was not tolerated, patients could continue with a dose of 2 mg or 1 mg once daily, but the drug was withdrawn if a dose of 1 mg once daily was not tolerated.Outpatient visits were scheduled one and three months after the infarction, with subsequent visits every three months. Echocardiography was repeated after 3, 6, and 12 months.The original protocol specified that treatment would continue for at least 12 months. When the results of the SAVE study were published in 1992, showing no survival benefit until after almost one year of treatment with ACE inhibitors, the steering committee decided (without any knowledge of the results of the study) to extend the closing date to 24 months after the last random assignment.Endpoints The primary study endpoint was all-cause mortality. Secondary endpoints were death from a cardiovascular cause, sudden death, progression to severe heart failure, recurrent MI, and change in wall motion index.The investigators estimated they would need a sample size of 1,500 patients to detect a 25% relative reduction in the risk of death with 80% power and 1-sided alpha of 2.5%. This was based on an estimated death rate of 30% at 12 months in the placebo group; however, the steering committee increased the sample size to 1,860 patients to allow for the possibility of a lower-than-expected placebo mortality rate.In the spring of 1992 the overall mortality of randomized patients followed for 1 year was 24%. Inclusion of patients was therefore terminated at the end of June 1992 at the point where 1,749 patients had been randomized.Results The final analysis included 1,749 patients; 876 in the trandolapril group and 873 in the placebo group.Information on the percentage of patients discharged on various doses of the study drug are not provided.Compared to placebo, trandolapril significantly reduced all cause death by 22% [(35% vs 42%; 95 percent confidence interval, 0.67 to 0.91 p = 0.001)}. The mortality curves diverged early (Kaplan–Meier estimate of mortality at one month 9% vs 11%) and continued to diverge throughout the follow-up period. Trandolapril also significantly reduced secondary endpoints, including death from CV causes, sudden death, and progression to severe heart failure but it did not significantly reduce reinfarction.Examination of subgroups showed no evidence of treatment effect heterogeneity for all cause mortality, but again, similar to the SAVE and AIRE trials, the size of TRACE limits subgroup testing.Premature withdrawals from study drug, not including death, occurred in 37% of patients in the trandolapril group compared to 36% in the placebo group. The most common reason for withdrawal was need for treatment with an open-label ACEi and this occurred more in the placebo group. Withdrawal due to cough, hypotension and reduction in kidney function were rare in both groups but slightly more common in patients on trandolapril compared to placebo.Conclusions In the majority (67%) of consecutively screened patients with AMI complicated by left ventricular dysfunction, trandolapril significantly reduced death over at least 2 years of follow-up with a number needed to treat of approximately 14 patients. Results from TRACE strengthen support for ACEi in post-MI patients, and the trial has high external validity. It not only tested the intervention in two-thirds of potentially eligible patients but was highly transparent about why patients were excluded. A clinician looking to apply the procedures used in TRACE to the management of patients in clinical practice would not have to guess whether or not their patient would have been included. This is rare in clinical research and the investigators should be applauded for their efforts.Investigators studying ACEi in post-MI patients have triangulated the population of patients who benefit from this therapy. In our opinion, TRACE provides the final piece to the puzzle. There is no doubt about the clinical efficacy of these drugs in the overwhelming majority of post-MI patients and higher risk patients stand to benefit the most.Thank you for reading Cardiology Trial's Substack. This post is public so feel free to share it. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

BUFFALO, NY- February 7, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 2, entitled, “PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance.” The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings. In this new study, researchers Shiue-Wei Lai, Yi-Chiao Cheng, Kee-Thai Kiu, Min-Hsuan Yen, Ying-Wei Chen, Vijesh Kumar Yadav, Chi-Tai Yeh, Kuang-Tai Kuo, and Tung-Cheng Chang from Taipei's National Defense Medical Center, Taipei Medical University, Taipei Medical University Shuang-Ho Hospital, and National Taitung University used the ULCAN portal and noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Their assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations. “Our study emphasized the connection between PROX1 and α-SMA in CAFs.” Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship. PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition. “As we advance in this field, the development and clinical validation of small-molecule inhibitors targeting PROX1/α-SMA become imperative, paving the way to refine and optimize CRC therapeutic interventions.” DOI - https://doi.org/10.18632/aging.205447 Corresponding author - Tung-Cheng Chang - 09432@s.tmu.edu.tw About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Visit our website at https://www.Aging-US.com​​. MEDIA@IMPACTJOURNALS.COM

In this episode Matt and Hailey discuss Chapter 22 of the 4th edition of Modern Epidemiology. This is a chapter focused on time to event analyses including core concepts related to time scales, censoring, and understanding rates. We discuss the issues and challenges related to time to event analyses and analytic approaches in this setting including Kaplan Meier, Cox Proportional Hazards, and other types of fancy models that are frequently taught in advanced epi courses (e.g., Weibull, Accelerated Failure Time) but infrequently used in the real-world. The chapter ends with a brief discussion of competing risks. It's clear that Matt and Hailey need to brush up on concepts related to competing risks and semi-competing risks, and fortunately next month we'll have an expert join us to answer all of our questions!

    Drs. Diwakar Davar and Jason Luke discuss KEYNOTE-716, KEYNOTE-942, RELATIVITY-047, and other key advances in melanoma, including the promise of mRNA vaccines in melanoma and potentially other cancers, as well exciting advances in neoadjuvant therapies across malignancies featured at the 2023 ASCO Annual Meeting. TRANSCRIPT  Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh Hillman Cancer Center. I'm delighted to have my colleague and good friend Dr. Jason Luke on the podcast today to discuss some practice-changing studies and other advances in immunotherapy that were featured at the 2023 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapy Center, as well as the associate director of clinical research at the University of Pittsburgh's Hillman Cancer Center.     You can find both of our disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Jason, there was a lot of exciting data in the immunotherapy space highlighted at the Annual Meeting, and it's great to have you back on the podcast to discuss some of this work.   Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: So, the abstracts that we had selected have several key themes. We'll be covering some of the early advances in melanoma in the stage 2 and stage 2B/C space with KEYNOTE-716. I think this is a study that you know a little bit about seeing you are the presenting author and the principal investigator for the study, as well as the pivotal KEYNOTE-942 trial. And then going on to themes with using third-generation checkpoints, neoadjuvant therapy in non-small-cell lung cancer, and cutaneous squamous cell carcinoma.    But we'll start with KEYNOTE-716. So, this is LBA9505, the study which evaluated pembrolizumab versus placebo as adjuvant therapy in stage 2B and stage 2C melanoma patient population for which historically there was no real effective therapy other than remotely interferon. And these are the final results of the DMFS analysis from this phase 3 trial. So, Jason, what are your thoughts about this, and can you contextualize the results relative to the recent publication?   Dr. Jason Luke: Thanks. I think the important point to level set on this was just a few years ago; this was a population of patients that we didn't treat in clinic. In fact, sometimes they weren't even referred to medical oncology for evaluation. And that was despite the fact that we knew from historical data that the risk of melanoma-specific survival, death from melanoma, was just as high for this population of patients as it was for the patients with stage 3 melanoma, where obviously adjuvant immunotherapy has been a standard for quite some time. And so we launched this clinical trial, KEYNOTE-716. It was a global, randomized phase 3 study of almost 1,000 patients, randomizing patients to either get pembrolizumab or placebo. Importantly, these patients being those with deep primary lesions, stage 2B and 2C with negative sentinel lymph node evaluation.    People will recall that this study hit its primary endpoint on the first protocol-specified analysis at a year. And what we updated at ASCO this year was the final analysis of distant metastasis-free survival. Obviously, an important secondary endpoint because if patients eventually going to develop metastatic disease and pass away, it's the distant metastasis that we worry about. And what we saw in this trial with a landmark 36-month follow-up median of 39 months was that the benefit was increasing. In other words, the magnitude of the hazard ratio change was increasing over time as would be expected, such that at this analysis there was a 41% reduction in the risk of distant metastasis for patients treated with pembrolizumab versus placebo. And we saw a consistent benefit in the recurrence-free survival also out through that same period of time and importantly no change in the safety summary with of course the adverse event profile of pembrolizumab being what it is and well understood across oncology.    So I think these are very important data because they really kind of set the stage for the field. It is now the case that at least discussing adjuvant therapy for patients with stage 2B and 2C is the standard of care; it should be offered to all the patients. Of course, it's always a risk-benefit about whether or not patients want to pursue adjuvant therapy versus consideration of treatment at the time of recurrence. But in my clinic at least, many patients do prefer to try to eliminate the possibility of recurrence and distant metastasis as much as possible.    So I think these are very important data because they really level set the field for what to expect in this population of patients and then they also start to set the table for what's going to come after this. And that's going to be sort of the next step in our conversation here because the next generation of adjuvant studies in melanoma are now going to think about all of melanoma in the adjuvant setting as really one entity, starting from stage 2B going all the way through stage 4 resected. And that'll be relevant actually as we talk about the next abstract that will come in this discussion.   Dr. Diwakar Davar: Just to underscore, positive RFS data, positive DMFS data, and now this therapy has currently got regulatory approval in this investigation and is approved in the United States and certainly in Europe and Australia. One interesting point that we will probably have to contend with, and some of the listeners may be thinking about, is overall survival. So the last adjuvant study that demonstrated overall survival benefit was actually ipilimumab, and increasingly, the Illuminati in melanoma do not believe that we will ever see OS benefit in this disease going forward, even though it has to be an endpoint in all registration phase 3 trials. So, Jason, what are your thoughts about whether or not we'll have a positive OS readout, and even if we don't, why this is still a very important advance in this disease at this time?   Dr. Jason Luke: Your points are well taken. I think it's unclear, probably trending towards unlikely, that we would see an overall survival advantage in this trial given that we have not seen that in the stage 3 adjuvant studies. Now people can debate if, whether or not overall survival is the only meaningful endpoint for patients. I personally do not believe that's true. And to me, preventing recurrence has a value in and of itself, whether or not that's connected to overall survival. And part of the reason that I say that is that for an average patient, the median patient on a trial, of course, we can tell them treatment now, treatment later. It's a wash when you look at the overall study. And yet at the same time, for an individual person who's facing melanoma or cancer, generally they're not going to be the average patient; they're going to be one patient. And it's very possible they could end up with the type of recurrence that in fact is not highly treatable at that time.     So I think that's really the nuance that goes into those adjuvant discussions. The regulatory endpoints have been recurrence in melanoma for a long time. And I think it's important that patients understand the pros and the cons of each. The complexity in adjuvant therapy and neoadjuvant therapy is you don't necessarily know that you had to have it. You're only really going to know whether or not it didn't work if you recur later on. But to me and in my clinic, most patients are willing and interested to want to pursue those therapies in the perioperative setting to try to reduce the possibility of ever developing metastatic disease.    Dr. Diwakar Davar: Excellent. So I think key advance [is] positive DMFS data to add to the earlier reported RFS data and truly practice-changing.     So, moving on to the next study, LBA9503. This is the phase 2 trial of the Moderna vaccine. This is the trial that almost every medical oncologist knows intimately or has been called about by either the press or patients. So what is this study? This essentially is a phase 2 trial evaluating the personalized cancer vaccine PCV Moderna, made by Moderna, the mRNA vaccine, that is being studied in combination with anti-PD-1 pembrolizumab in the stage 3 BCD and stage 4 resected setting. And so there are really two very interesting results here because this is an update of the RFS data that was presented at AACR earlier this year, which was positive. What are your takes on the DMFS results, and maybe a quick blurb on how is this vaccine generated for those who may not be aware of this particular platform?    Dr. Jason Luke: Yeah, certainly. So this individualized neo-antigen therapy, as we're now calling it, is a technology platform that allows us to develop an individualized treatment for each patient based on their own cancer. So taking the actual tumor specimen, whole exome sequencing is performed to try to identify changes in the DNA, and then through a reasonably complex bioinformatic pipeline, those mutations that are likely to generate proteins that can be bound within class 1 MHC molecules are then identified in the computer and then synthesized with an mRNA, very similar to the way that the COVID vaccines were made. And then that becomes the actual drug.    So in the clinical trial, which was KEYNOTE-942, about 160 patients were randomized 2 to 1 to receive either pembrolizumab for a year as per standard adjuvant therapy but then with the addition of the individualized neoantigen therapy starting with dose 3 and throughout the rest of the year versus the control arm of pembrolizumab as the standard of care. As you mentioned, the recurrence-free survival were highly positive in this trial when it was first presented earlier this year, and at the updated ASCO we see the 18-month RFS in which the hazard ratio continues to be maintained. But I think most impressively is that distant metastasis-free survival, where we saw an even greater advantage for distant metastasis-free survival – hazard ratio here being 0.35. And so that's a huge advantage for distant metastasis-free survival in this population of patients.     And very interestingly in the clinical trial, when you follow the Kaplan-Meier plots, what you see over time is that they overlap almost the entire first year. And it's really at about a year, basically after the vaccine has had time to kick in and these neoantigens have been identified, that we then start to see the separation of the curve, which looks very flat over time. And so I think this is a very, very exciting kind of technology platform and very exciting results because there was minimal increase in toxicity – just at the site of the local injection – for the addition of the individualized neoantigen therapy.    And beyond that, hypothetically, this is not necessarily just a melanoma thing. So, of course, based on these phase 2 results, a phase 3 clinical trial called KEYNOTE-V940 is going to be launching later this year to compare pembrolizumab versus pembrolizumab plus this V940 individualized neoantigen therapy. And we're very, very excited in the field to see what those results will look like because the concept here is you could really, really enhance adjuvant therapy with this kind of an approach. Meanwhile, we're just about to talk in a little bit about all the exciting things happening in the neoadjuvant space as well. And with no increase in toxicity, obviously, that looks really good.    Suffice it to say that this technology is not specific to melanoma but rather could be applied almost to any cancer where we think about an adjuvant therapy platform. So I think the results are very, very exciting. It is a phase 2 study and it does have some caveats about not being the largest study and some other things, but you can't help but be impressed by the data that have been presented here so far.   Dr. Diwakar Davar: One important plug, I guess, in addition to that is that you mentioned that there's data using the platform in other diseases. And one really exciting paper that came out recently was Dr. Vinod Balachandran's paper; for those who haven't read it, it's in Nature, and really in a very provocative proof of concept study, they studied the platform, the vaccine plus checkpoint inhibitor therapy plus chemotherapy in a highly adverse tumor patient population. So these are patients with resectable pancreatic cancer who had the vaccine generated from pancreatic cancer that was resected after Whipple surgery. And extraordinarily, out of the 16 patients who had immune responses, 8 of them did not have relapse at a median follow-up of almost a year and a half, which is really quite extraordinary given the lack of really any effective drug outside of chemotherapy in that setting.     So, the point that you're making regarding the benefit of this therapy, suggesting that it could potentially be extended to not just melanoma, potentially other tumors such as highly immunogenic tumors, and potentially even nonimmunogenic tumors such as pancreatic cancer, really suggests that this is going to be a very exciting landscape. And potentially this area, adjuvant therapy and neoadjuvant therapy, like we'll talk about, is potentially an area in which other drugs and potentially combinations will be developed.    So next, we will be discussing 3 abstracts evaluating the theme of combinations, and these abstracts are 9501, 9502, and 4010. Abstract 9501 is an evaluation of the combination of fianlimab and cemiplimab anti-LAG-3 and anti-PD-1, respectively, in advanced melanoma, specifically focusing on the post-PD-1 experience in this disease by Dr. Omid Hamid. 9502 is the updated 2-year survival results from RELATIVITY-047, which evaluated nivolumab and relatlimab against nivolumab alone in frontline metastatic melanoma. And Abstract 4010 are the results from the MORPHEUS platform study, specifically looking at tiragolumab and atezolizumab in patients with advanced unresectable HCC.    But focusing on 9501 and 9502, Jason, what do you make of the combination of fianlimab and cemiplimab post-PD-1 setting?   Dr. Jason Luke: I think the data look very intriguing for this second combination of PD-1 and LAG-3 combination. When nivolumab and relatlimab, the approved LAG-3 inhibitor, kind of burst on the scene a couple of years ago, it was somewhat to the surprise of a lot of people in the community who had really come to think that while PD-1 and CTLA-4 were core molecules for therapeutics and cancer, that we just weren't ever really going to see something else come along in checkpoint blockade. And so nivo and rela got approved. We'll talk about them again in a second. But the data now coming forward for another PD-1 LAG-3 combination, again with cemiplimab PD-1 and fianlimab LAG-3, looks very, very promising.    So in Abstract 9501, they updated a phase 1 expansion cohort, phase 2 cohort looking at patients across the various different settings. And whereas in the treatment naive frontline metastatic setting they had previously described about a 63% response rate, they saw a similar level of response rate in patients who had previously gotten adjuvant anti-PD-1, had a period of time off treatment, and then were treated again. And that was reassuring because it suggested that this is still an active combination even with prior exposure to IO in the past.     Now, the thing that I found to be the most interesting about this combination was whereas with nivo and rela, at least from the RELATIVITY-047 phase 3 trial, it looked like there was less benefit in some of the high-risk population cohorts, at least for this combination in early testing for cemi and fian; like we talk about it sometimes, we saw there was a high response rate even in patients with liver metastases and some other high-risk features. And so I think this combination looks quite potent, and I'm very excited to see what the data will look like. I think it's very unlikely we'll ever actually get a randomized trial of two PD-1 LAG-3 combinations against each other. But suffice it to say that the data we've seen so far for fianlimab LAG-3 with cemiplimab PD-1 looks very intriguing. It certainly justifies the frontline metastatic phase 3 and the adjuvant phase 3 trials that are already in planning or ongoing.   Dr. Diwakar Davar: So one thing to consider is on the RELATIVITY-020 trial – the early trial that was led by Dr. Ascierto that really took a long time to read out – the response rate in patients with prior checkpoint inhibitor therapy was quite low. In fact, the data was quite surprising, as you'd mentioned that we had even seen this movement in the frontline setting because the response rate by BICR was only about 12%. So do you feel like the 2 LAG-3 inhibitors are fundamentally different? And if so, can you speculate as to why that might be? Again, with the caveat to the fact that these are very early data and we don't have enough information. And maybe we can also talk a little bit about the 2 pending trials that are ongoing in the advanced and adjuvant therapy landscapes perspective.   Dr. Jason Luke: I think we don't have enough data yet to truly understand whether or not they're really different. The trials that have been run so far are so different that it's hard to compare things back and forth. You can notice that the dose, the milligram dosage of fianlimab in terms of anti-LAG-3 is quite a bit higher, like a log fold higher almost than with relatlimab. And so there's some question of whether or not just merely more drug-blocking LAG-3 might in fact be more efficacious relative to the dose that's approved for relatlimab in melanoma. But beyond that, I think the data hold up very well for this new combination, again noting all the caveats about cross-trial comparison to, say, it looks to be at least as potent, possibly more potent than the relatlimab combination. But again, I think probably we need to see the data from randomized trials and how that fits into the landscape when the trials actually read out because there's a lot of things going on in melanoma that are likely to change between now and then.   Dr. Diwakar Davar: So just to draw people's attention, there are actually 2 ongoing pivotal phase 3 trials: fian plus cemi versus pembro in patients with advanced metastatic and locally advanced, previously untreated melanoma, as well as an adjuvant trial of the combination against pembrolizumab. Again, highly high-risk resected melanoma. These trials are ongoing. We don't have the results yet and we are looking forward to them.    Now, 9502, a 2-year RELATIVITY-047 result presented by Dr. Hussein Tawbi.    Dr. Jason Luke: So this is the study we were just alluding to before, the randomized phase 3 study of nivolumab versus nivolumab plus for relatlimab. To me, the most useful data sort of updating with this two-year survival follow-up is to show the maintenance of benefit between the 2 arms. And so, consistent with what we saw with nivolumab and ipilimumab, there seems to be a persistent delta between the arms for both progression-free and for overall survival out over that extended period of time, where we can see with that updated data now, at 2 years, that it's 52% of patients still alive on the relatlimab combo versus 42 with nivolumab. And it does seem like this is probably a higher-risk population of patients than participated in CheckMate-067.    So it's a little bit difficult to compare the landmarks except to notice that that difference between the control and experimental groups is consistent over a long period of time and that there were no new safety signals either, and so that was also reassuring. To me, the most interesting nugget of data in the abstract, though, is to look at what happened to patients after they were on the first-line treatment. So one of the big questions in our field is really “If patients get nivolumab and relatlimab upfront, what should they get after that?” Should they then get nivo plus ipi, or vice versa? And I think we don't have an answer clearly to that question just yet.    There was an important letter to the editor of the New England Journal now going on about a year ago by Alex Menzies and colleagues that suggested that the use of ipilimumab was attenuated, the utility of it, after a prior exposure to nivolumab plus relatlimab. They quoted a response rate on the order of only about 10% for patients who got an ipilimumab-containing regimen after initial LAG-3. In the data from Hussein Tawbi at ASCO, however, in a small number of patients, caveat, the response rate was more in sort of the low 20% range, 22% to 25%. And so that would be a much more meaningful and important sort of consideration. If we do have independent activity, then lining up sequential therapies and the toxicities associated with each will become increasingly important as we think about how to maximize these kinds of treatments for our patients, but important longer-term data to show that the benefit is holding up and it's safe, and some new insights into what to do after progression on one of these regimens.    Dr. Diwakar Davar: So, pivoting slightly to combinations, we are going to be discussing a combination of TIGIT plus checkpoints. So tiragolumab is the FC-active TIGIT inhibitor from Regeneron-Roche and this is currently in multiple pivotal phase 3 trials, several of which have been negative, including SKYSCRAPER-01 in non-small cell lung cancer and SKYSCRAPER-03 in small cell lung cancer. The MORPHEUS platform trial essentially is a platform study evaluating multiple different combinations, in this case in liver cancer. And so we have a very interesting Abstract 4010, which is giving us an early readout of the evaluation of tiragolumab plus atezolizumab along with bevacizumab in unresectable, locally advanced or metastatic hepatocellular carcinoma giving us a result that is a little different from what we had seen from the prior negative results of TIGIT. So Jason, what do you make of these early results in the advanced HCC setting?   Dr. Jason Luke: I think these are cautiously intriguing results to really highlight the point is the third checkpoint possibly being LAG-3, now a fourth checkpoint maybe with TIGIT, but with all the caveats that you talked about. In this study, the flow is that there's a continuously accruing control arm which in hepatocellular carcinoma is a combination of atezolizumab plus bevacizumab, and then other arms are added where you add in a third agent. In this case, it's the anti-TIGIT tiragolumab. And in an intriguing fashion, the response rate to the triplet was 42.5% compared to the doublet which was only 11%. So that's a pretty big difference in this population.     Now, it wasn't the largest study, only 58 patients, but it was a randomized clinical trial. And so I think those data really make people kind of open their eyes again. It's worth a little bit of a caveat here that HCC is an unusual cancer in that what is deemed to be unresectable and therefore amendable to systemic therapy is a moving target and that requires multidisciplinary evaluation of patients. And so I think a larger number of patients would really be needed to fully understand this. But certainly, a fourfold increase in the benefit or in terms of response rate looks quite intriguing.    I think the other piece of this is to be just cautious a little bit was when the initial data in non-small cell lung cancer in the CITYSCAPE study came forward, and they looked roughly sort of like this: There was more than a doubling in the PFS and the response rate, which is what triggered all of those phase 3 studies. So to me, this is enough to continue to be very interested in TIGIT as a therapeutic target. And there are many phase 3 trials already ongoing. And so I think, I'm cautiously optimistic that some of those actually will be positive and we could see more movement around TIGIT becoming a standard of care agent.    Dr. Diwakar Davar: To your point about TIGIT being an interesting target, recent data looking at the neoadjuvant landscape in melanoma from Merck, with Merck, also FC-active TIGIT and also some data from authors looking at that TIGIT also presented in this case at ASCO specifically from the ARC-7 study. So very interesting target. Several pivotal trials have been announced. Do you know of any trials that are ongoing in the adjuvant setting in other diseases?   Dr. Jason Luke: Well, as you alluded to, the vibostolimab data in melanoma for TIGIT in the neoadjuvant setting was interesting. And in fact, that has been enough to trigger a global, randomized phase 3 adjuvant study of pembrolizumab and vibostolimab versus pembrolizumab in melanoma. And that sort of takes us back to the beginning of our discussion here, building on the KEYNOTE-716 data. So, yes, TIGIT will be moving forward in the adjuvant space in melanoma and obviously at a static setting for several different tumor types with a PD-1 or PD-L1 backbone.   Dr. Diwakar Davar: So now pivoting towards neoadjuvant therapy and non-small cell lung cancer. The standard of care in this setting was established by the CheckMate-816 trial that essentially established nivolumab plus chemotherapy in the setting of resectable non-small cell lung carcinoma path. Response rate in this setting is approximately 21%. And we have several studies that are essentially looking at novel combinations or in this case, different PD-1 inhibitors in this setting. So Abstract 8500 essentially looked at nivolumab plus relatlimab from a NEOpredict-Lung trial. Jason, do you want to tell us a little bit about this?    Dr. Jason Luke: Yes, I think this is a very interesting study and that this is sort of our first peek at targeting LAG-3 in the context of lung cancer. So obviously we talked about LAG-3 for melanoma. Although the audience is probably aware that there have been neoadjuvant data for LAG-3 with relatlimab in melanoma that substantiated the phase 3 data for the metastatic setting. So one of the questions as we start to apply the LAG-3 in other diseases would be, “Do we see it hold up in both metastatic disease and in the neoadjuvant space?” But in this study, while there were no changes in the safety profile; it didn't impact on whether or not patients could have surgery. There really didn't look to be a big difference in this study between nivolumab and nivolumab plus relatlimab, with the major pathologic response as you alluded to right around 30% for both arms.    Now, it wasn't really the biggest study, but that's certainly quite a bit in contrast with what we've seen in melanoma, where with a PD-1 inhibitor you get again 25%-30%, but with adding on LAG-3, that pushes you up closer to 60%. So I think these were very interesting data that probably put a little bit of an eyebrow raise to say, “Well, let's see what happens in the metastatic setting in lung cancer with the addition of relatlimab LAG-3 on top of a PD-1.” I think it might not be quite so straightforward as what we saw in melanoma, but we'll look forward to those results because those phase 3 trials in metastatic lung cancer should be maturing sometime in the next year or two.   Dr. Diwakar Davar: The theme of neoadjuvant therapy non-small lung cancer, LBA100, which has again previously been discussed in an episode of this podcast by Dr. Jack West and Dr. Velcheti is KEYNOTE-671. And this is a study essentially that looked at pembrolizumab or placebo with platinum-based chemotherapy doublet and followed by resection. So again, a direct parallel to CheckMate-816. What do you make of the results that were reported by our colleagues in this setting, Jason?   Dr. Jason Luke: So not to rehash this, because our colleagues in the lung cancer group have already discussed this at length and obviously they're experts in that disease, but we'll just note that there was a threefold increase in major pathologic response, which turned into a major advantage for event-free survival. And so I think this is at least the third PD-1, PD-L1 combination regimen for neoadjuvant lung cancer that looks very, very promising. It certainly, to me, seems like neoadjuvant consideration really should be the standard of care already moving forward.   To me, what the big question that is left with is “Do we still need the adjuvant component after we give the neoadjuvant?” So, some of the trials are including neoadjuvant and adjuvant, some of them are only neoadjuvant. And I think that's going to be a really important question as we move into the future, both in terms of what is that contribution of the adjuvant component, and then again, going back to earlier in our discussion here, if there could be a major advantage to adding individualized neoantigen therapy, maybe it is important to have both. But I think that's one of the big questions we have to get teased out by the field over the next couple of years.   Dr. Diwakar Davar: And finally pivoting towards cutaneous squamous cell carcinoma. We have 2 abstracts discussing perioperative therapy. So cutaneous squamous cell carcinoma is a high-TMB tumor. The median tumor mutation burden in this disease is threefold that of melanoma. This is a disease in which checkpoint inhibitor therapy is approved as a single agent both with pembrolizumab and cemiplimab on the basis of nonrandomized phase 2 trials. And increasingly, there has been early development in the perioperative setting. The first data in this space came from our colleague Dr. Gross at MD Anderson, who reported in a small, nonrandomized phase 2 trial of 20 patients, a path CR rate with two cycles of cemiplimab at approximately 50%.    A larger multi-institutional phase 2 trial demonstrated that a longer duration of perioperative therapy of four cycles or 3 months of cemiplimab did not particularly improve the path response rates. The response rates were similar at approximately 50% as well. And what we have right now are 2 other trials. The first is the MATISSE trial, Abstract 9507 ,that evaluated nivolumab or nivolumab plus epilimumab in this disease. And the other one was the NEO-CESQ trial, or Abstract 9576, that evaluated neoadjuvant plus adjuvant therapy that's cemiplimab in the high-risk patient population. So we're starting with 9507. Jason, what do you make of the ipi and ipi-nivo data reported in this setting?   Dr. Jason Luke: So I think this is a really interesting study because I think part of the intent is the clinical aspect of how you manage patients with cutaneous squamous cell carcinoma. For those that don't do cutaneous oncology, many of these patients have the development of lesions, which can be actually quite difficult to resect in a way that's not otherwise mutilating or cosmetically quite problematic. And that was part of the impetus for this trial where, again, they looked at either monotherapy PD-1 or a PD-1 plus CTLA-4, and they saw great success. As was predicted based on the other data that you alluded to, response rates are more than 50% near 60%, with actually a substantial number of patients on the trial actually refusing to have surgery after they received their neoadjuvant therapy because they were so certain that they had had a good outcome.    So I think these data are quite reassuring in the context of all of this emerging data around cutaneous squamous cell carcinoma. We'll talk about this NEO-CESQ trial in just a second, but I think it really is emerging to be the standard of care very soon for the use of perioperative PD-1 for cutaneous squamous cell.   Dr. Diwakar Davar: What do you feel about the dose and schedule of checkpoint inhibitor therapy used here? So the dose of ipilimumab used was ipi-1 and not ipi-3, and they waited 4 weeks. So when patients only got two cycles of Q2 weekly nivo, and one cycle of ipilimumab, do you think the responses would have been deeper if they'd waited longer?   Dr. Jason Luke: I think it is possible that they might have been deeper, although I'm not totally sure about that. One of the other abstracts we're not directly mentioning here was a study in Merkel cell carcinoma which suggested that in fact, adding ipi and that also highly immuno-oncology-responsive tumor type did not add to the response rate. So I'm not totally sure about that. I think rather what would be most interesting here is sort of the sort of next generation of biomarker work.    As part of their presentation, the MATISSE trial team showed gene expression profiling that really strongly identified which patients were going to do well on the trial. And I think that's probably eventually going to be how we need to think about this. There are patients in the neoadjuvant setting who are going to do really well with anti-PD-1 alone. And then for those who aren't, that's where we probably really need to think about do we need combos, how long to give the treatment, etc. And I think we're really only on the cusp in the beginning of this, which is exciting as we think about moving into the future.    Dr. Diwakar Davar: Certainly, many combinations are being evaluated in this space and we are very excited for the data that it's about to hopefully come in the next couple of months to years.    So the NEO-CESQ – it's quite a puzzle as to how to pronounce this acronym – and this evaluated cemiplimab in the high-risk setting. So it's worthwhile noting that Dr. Gross's first trial looked at high-risk stage 2, 3, and 4 disease. So the context of cutaneous squamous cell carcinoma that's node-positive disease and distant metastatic disease that is in one location or patients with node-positive disease invention. And his multi-institutional cemiplimab trial of four cycles evaluated included patients with stage 2, 3, and 4 disease.    So here in a study just in stage 3 and 4 diseases, Dr. Ascierto reported the results of 2 cycles of cemiplimab and importantly, these patients had both the neoadjuvant and the adjuvant portion of cemiplimab. So, Jason, you mentioned earlier that one of the key aspects that we start thinking about neoadjuvant therapy is exactly how much do you need. Do you need both the pre-surgical therapy and the post-surgical therapy? Is the presurgical therapy enough? After all, neoadjuvant response equals cure. How much benefit are you getting from post-surgical portions? So what do you make of the results that they've seen here and what is the impact? How do you think we'll be disentangling the impact of the neoadjuvant and the adjuvant portion of the immunotherapy upon response and survival?    Dr. Jason Luke: So just to leverage those comments, I think these data are reassuring because in this higher-risk group of patients, they saw excellent outcomes very similar to what Gross et al had previously reported. So that's good. To your question about how we are going to disentangle this adjuvant versus non-adjuvant question, there's a trial in melanoma called the NADINA trial which is ongoing now in which the use of the adjuvant therapy is actually risk-adapted. So after patients have an initial neoadjuvant treatment they're evaluated, and if they have had a pathologic complete response, they're actually going to stop that treatment and they're not going to give the neoadjuvant therapy. And so I think obviously it's a slightly different disease, but those kinds of data, I think, will be very meaningful to help us sort this out.    And I'm not sure whether or not in cutaneous squamous we would need a different trial than in melanoma, although I think in a different tumor, maybe like, say, lung cancer, you probably would need a dedicated study to try to look at that because I think just the responsiveness to checkpoint blockade is going to vary quite a bit once you get outside of cutaneous oncology. But to summarize, reassuring that a similar pathologic response rate, and I think this question of adjuvant or nonadjuvant, I think that's the next question we've got to answer in the field.    Dr. Diwakar Davar: We have now come to the end of our back-and-forth discussion on these very, very exciting abstracts. So Jason, thank you for highlighting these advances and for engaging in a robust discussion.    Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: And thank you to our listeners today for taking the time to listen to this podcast. You will find the links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear in the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, 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. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:      Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy    Dr. Jason Luke:      Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio        

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there's been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we're now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Thank you for your attention. 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. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

A new research paper was published in Oncotarget's Volume 14 on May 4, 2023, entitled, “Human LY6 gene family: potential tumor-associated antigens and biomarkers of prognosis in uterine corpus endometrial carcinoma.” The human Lymphocyte antigen-6 (LY6) gene family has recently gained interest for its possible role in tumor progression. In this new study, researchers Luke A. Rathbun, Anthony M. Magliocco and Anil K. Bamezai from Villanova University carried out in silico analyses of all known LY6 gene expression and amplification in different cancers using TNMplot and cBioportal. In addition, the team analyzed patient survival by Kaplan-Meier plotter after mining the TCGA database. “We report that upregulated expression of many LY6 genes is associated with poor survival in uterine corpus endometrial carcinoma (UCEC) cancer patients.” Importantly, the expression of several LY6 genes is elevated in UCEC when compared to the expression in normal uterine tissue. For example, LY6K expression is 8.25× higher in UCEC compared to normal uterine tissue, and this high expression is associated with poor survival with a hazard ratio of 2.42 (p-value = 0.0032). Therefore, some LY6 gene products may serve as tumor-associated antigens in UCEC, biomarkers for UCEC detection, and possibly targets for directing UCEC patient therapy. “Further analysis of tumor-specific expression of LY6 gene family members and LY6-triggered signaling pathways is needed to uncover the function of LY6 proteins and their ability to endow tumor survival and poor prognosis in UCEC patients.” DOI - https://doi.org/10.18632/oncotarget.28409 Correspondence to - Anil K. Bamezai - anil.bamezai@villanova.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28409 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - LY6 gene family, uterine cancer, tumor-associated antigen, patient survival, biomarker About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

A new research paper was published in Oncotarget's Volume 14 on April 15, 2023, entitled, “Importance of carbohydrate antigen (CA 19-9) and carcinoembrionic antigen (CEA) in the prognosis of patients with duodenal adenocarcinoma: a retrospective single-institution cohort study.” Duodenal adenocarcinoma (DA) is a rare malignancy without validated tumor markers. In practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) are often used in the management of DA, though their prognostic value is unknown. In this new study, researchers Ellery Altshuler, Raymond Richhart, William King, Mahmoud Aryan, Akash Mathavan, Akshay Mathavan, Keegan Hones, Daniel Leech, Logan Pucci, Joshua Riklan, Pat Haley, Ilyas Sahin, Brian Ramnaraign, Sherise Rogers, Ibrahim Nassour, Steven Hughes, Thomas J. George, and Jesus Fabregas from the University of Florida, University of Florida Health Cancer Center and University of Alabama at Birmingham conducted a single-institution retrospective review including patients diagnosed with biopsy-confirmed adenocarcinoma of the duodenum between 2006 and 2021. “To our knowledge, this is the first study to evaluate the role of tumor markers in patients with DA. In fact, this is the largest single institution study in the US evaluating this disease.” Peri-ampullary tumors were excluded. Levels of CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal Ca 19-9

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages. So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly. So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings. For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that. Dr. Greg Hundley: Very nice. Well, thank you so much, Amil. And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper? Dr. Ntobeko Ntusi: Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle. And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms. We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex. And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution. The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease. And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations. So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg. Dr. Greg Hundley: Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research? Dr. Amil Shah: So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life. And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in. I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients. Dr. Greg Hundley: Very nice. Ntobeko, do you have anything to add? Dr. Ntobeko Ntusi: Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward. The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease. Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time. And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events. Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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, please visit ahajournals.org.

A new research paper was published in Oncotarget's Volume 14 on January 31, 2023, entitled, “Novel inflammation-combined prognostic index to predict survival outcomes in patients with gastric cancer.” In vivo inflammatory responses are involved in cancer growth, invasion and metastasis, and the involvement of systemic inflammatory responses and the surrounding microenvironment is intricately intertwined. In this recent study, researchers Noriyuki Hirahara, Takeshi Matsubara, Shunsuke Kaji, Hikota Hayashi, Yohei Sasaki, Koki Kawakami, Ryoji Hyakudomi, Tetsu Yamamoto, and Yoshitsugu Tajima from Shimane University Faculty of Medicine and Matsue Red Cross Hospital in Japan focused on the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and devised an inflammation-combined prognostic index (ICPI) as a prognostic marker of cancer-specific survival (CSS). “We reviewed the clinicopathological data of 480 patients with gastric cancer undergoing curative laparoscopic gastrectomy between 2009 and 2019. This study examined the significance of LMR, NLR, PLR, and ICPI as cancer-specific prognostic markers.” In univariate analysis, tumor diameter, histological differentiation, pathological tumor-node-metastasis (pTNM) stage, LMR, NLR, PLR, C-reactive protein (CRP) level, carcinoembryonic antigen (CEA), and postoperative chemotherapy were significantly associated with CSS. In multivariate analysis, pTNM stage and CEA were the independent risk factors for CSS, although LMR, NLR, and PLR were not the independent risk factors for CSS. The ICPI formula was constructed using hazard ratios for three inflammation-based biomarkers with worse prognosis identified in the univariate analysis: LMR

A new research paper was published in Oncotarget's Volume 13 on December 6, 2022, entitled, “Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.” Hepatocellular carcinoma (HCC) has limited systemic therapy options when discovered at an advanced stage. Thus, there is a need for accessible and minimally invasive biomarkers of response to guide the selection of patients for treatment. In this new study, researchers Yehia I. Mohamed, Dan G. Duda, Muhammad O. Awiwi, Sunyoung S. Lee, Lina Altameemi, Lianchun Xiao, Jeffrey S. Morris, Robert A. Wolff, Khaled M. Elsayes, Rikita I. Hatia, Aliya Qayyum, Shadi M. Chamseddine, Asif Rashid, James C. Yao, Armeen Mahvash, Manal M. Hassan, Hesham M. Amin, and Ahmed Omar Kaseb from MD Anderson Cancer Center, Massachusetts General Hospital, Harvard Medical School, Michigan State University, University of Pennsylvania, and Perelman School of Medicine investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev). “The present study was designed to investigate the association between GH levels and overall survivals (OS) and progression free survival (PFS) in HCC patients treated with current standard, atezolizumab plus bevacizumab.” The study included unresectable HCC patients scheduled to receive Atezo/Bev. Patients were followed to determine progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups (the cutoff normal GH levels in women and men are ≤3.7 μg/L and ≤0.9 μg/L, respectively). The Kaplan-Meier method was used to calculate median OS and PFS and Log rank test was used to compare survival outcomes between GH-high and -low groups. Thirty-seven patients were included in this analysis, of whom 31 were males and 6 females, with a median age of 67 years (range: 37–80). At the time of the analysis, the one-year survival rate was 70% (95% CI: 0.51, 0.96) among GH low patients and 33% (95% CI: 0.16, 0.67) among GH high patients. OS was significantly superior in GH-low compared to GH-high patients (median OS: 18.9 vs. 9.3 months; p = 0.014). PFS showed a non-significant trend in favor of GH-low patients compared to the GH-high group (median PFS: 6.6 vs. 2.9 months; p = 0.053). “Plasma GH is a biomarker candidate for predicting treatment outcomes in advanced HCC patients treated with Atezo/Bev. This finding should be further validated in larger randomized clinical trials in advanced HCC patients.” DOI: https://doi.org/10.18632/oncotarget.28322 Correspondence to: Ahmed Omar Kaseb - akaseb@mdanderson.org Keywords: growth hormone, hepatocellular carcinoma, immunotherapy, atezolizumab, bevacizumab About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com.

"In part two this ASCO Education Oncology, Etc. podcast, healthcare policy expert, pulmonary physician, epidemiologist, and writer Dr. Peter Bach shares what it was like to face his wife Ruth's cancer and eventual passing − as a husband and as a doctor. The episode also explores delivering difficult news to patients. If you liked this episode, please subscribe. Learn more at https://education.asco.org, or email us at education@asco.org. Resources: Cancer Topics - Delivering Serious News" The Day I Started Lying to Ruth by Peter Bach, MD After a Cancer Diagnosis, Wishing for a Magic Number - The New York Times   TRANSCRIPT Pat Loehrer: Hi, I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University. I'm here with Dave Johnson, a Medical Oncologist at The University of Texas Southwestern in Dallas, Texas. This is the second half of our Oncology, Etc. conversation with health policy and payment expert, pulmonary physician, epidemiologist, and writer, Peter Bach. In part one, we chatted with Dr. Bach about his upbringing, the trajectory of his career from English Literature to Medicine, and from academia to industry. We also explored his seminal work on drug pricing and improving health equity. Today, we're going to continue our conversation with Dr. Bach by asking about something deeply personal: his wife, Ruth, who sadly passed away from cancer at the age of 46. Probably about seven or eight years ago, you wrote a wonderful article in The New York Times, and there was another article you wrote, but the one that I liked reading was called, “The Day I Started Lying to Ruth”, and this is where cancer stabbed you very personally. Can you tell us a little bit about that, and tell us a little bit about your wife, Ruth? Peter Bach: So, it was in New York Magazine, just to give credit where it's due, I'm very grateful to them for running it. I wrote that after she died, and it followed on a series I had in The New York Times called, The Doctor's Wife, which I wrote while she was getting her initial treatment for breast cancer, and then I walked through the steps of adjuvant therapy that she received, in my experience. And then the piece in The New York Magazine talks about her last months basically, and my experiences then. The story goes that she was tragically taken from us and tragically taken from my son when he was very young, and my experience being at her side-- and I think I was a good husband, I was present -- was an alarmingly dissociative experience along every dimension. You know, I'd go to her appointment, I would swipe in with my badge. You know, this was my place, and the doctor who took care of her is and was a dear friend, and so were the other doctors in most cases. And the visits, you know, I had nurses and people in the hall would say "Hi" to me. And then I was going through this absolutely devastating experience, you know, tearing apart the sort of prevailing narrative and experience and structure of my life and our family. And so, for whatever reason, it was this out-of-body experience where I could see stuff very, very clearly. Not only clinical realities, like I knew what was happening, but also the mechanics of healthcare, the interactions, and I felt like I should journal it, if you will. And then when I journaled it, I thought I should publish it, and so I wrote about what it was like to stand there when my friend, Chip Cody, the surgeon said, "This is cancer, I can feel axillary lymph nodes, you've got cancer." And what that morning was like between the-- look, most people have a lump, what's the big deal? We'll go, we'll deal with it. She's young. She had just had a mammogram actually, to that. And then the experience of, you know, and I was in Biostat at MSK. So, I'd sat for a gazillion protocol reviews, I'd read a gazillion informed consent forms, and then there was one in front of her for a randomized trial for adjuvant therapy. I mean, it was Avastin versus placebo versus a longer period of Avastin, if I remember correctly, and ultimately a negative trial I saw at ASCO. But sitting there and actually thinking about like, "What is this like for somebody who doesn't know all of this stuff?" And my wife was way smarter than me, that you guys know me, that is the least surprising fact ever. But it was still dizzying for her. And so, I wrote about that, like, hawt was our conversation like that night after that whole, like, “Do you want to join this trial?" And her peppering me with questions, like, essentially, “What the hell is wrong with you guys? Why don't you know these answers?" And it was sort of like, "Okay, this is why we do randomized trials, this is why we have placebo. This is–” And she's smart, not irate. She was much more relaxed and philosophical through the whole thing up until the day she died, or a few days before, than I ever was. So, I wrote about that. Like, what was that conversation like? What was she being asked to do, and how important was it that she did it? And I remember sitting in the room when that trial was presented, and The Kaplan-Meier overall survival curves, and I was pretty sure I saw the step in that curve. I'm pretty sure I saw her on that graph. And it made me-- obviously, I'm desperately sad that she's gone - but it made me proud that she had contributed to it, even though, you know negative studies are important, too. So, I wrote about those things, and I wrote about prognosis and what it was like to have a conversation when she asked about prognosis, and in an article called ‘Waiting for a Magic Number', where I described her oncologist saying, "Fine, I'll tell you what are your chances of living five years, you tell me what's the cut point. Essentially, above or below, what number are you going to change things in your life? When you tell me that number, I'll tell you whether you're above it or below it." And it was like, "Wow, philosophy from an oncologist, fantastic." Really sunk in with both of us, and that was it. We never asked that question again, he never gave us a number. And I've been greatly rewarded over the years to run into people from here and there who say, "You know, I always hand my patients that article to put that in perspective." And then when she died, I wrote about the sheer horror of what was happening to me. And the title wasn't mine, but it was worked right on point. I found myself in a situation where I didn't want to reveal to her just how bad things were, and it was terribly weak of me. And ultimately, and I describe it in the article, got to a point where I just was ready for it to be over, before it was. And I think it's actually not that hard, to be honest, after you've gone through something like this like I don't really care what people think of me. I went through something really hard. And again, I'm someone with resources, I'm someone with knowledge, I could call her oncologist at two in the morning and he'd answer, that's not something normal people get. And you know, even for me, like this was completely disorienting. And so, that article was very rewarding to write because it allowed me to put it somewhere where I've gotten to revisit it. A couple of years ago, of course, he was young when I published it. He said he had read it; he liked the part about the dog. But I got a lot of notes afterwards from strangers saying that it provided them some comfort that even someone like me went through basically the same experience they went through. And look, this whole, like, "even something like me” seems odd, but I think to the external world, somehow, we're like, "You know, we get those white coats. Stuff is different for us," and of course, it isn't at all. Since that time, and we're all in the same world, so we have the same sets of friends. We probably have many of our overlapping friends who we know have lost spouses. In recent years, I routinely get phone calls from folks like, "I'm going through this, what's the first step?" You know, and it's about everything. "How do I deal with my kid? Should I go dating?" Stuff like that. Dave Johnson: You know, Peter, that article should be required reading for every Oncology fellow. I think it was beautifully written, clearly from the heart. I think your undergraduate degree shows in terms of your writing style, but to write that, I'm sure was emotionally challenging and difficult. In fact, Pat mentioned at the start of our podcast, Trillin's book, About Alice. In a book review that was written in The New York Times, About Alice, Trillin made a comment similar to the one you just made, where people that he didn't even know wrote letters in which they conveyed to him a sense of knowledge of Alice, even though he knew they had never met Alice. And I think your article about your wife conveyed that same sense to anyone who did not meet her. And I think you memorialized her in ways that are really fantastic. But I want to just read something from an article in The New York Times, and this is quoting Trillin. He says, "They may not have known her, but they knew how I felt about her." And he went on to say, "Yes, I got a lot of letters, like the one from a young woman in New York who wrote that she sometimes looked to her boyfriend and thought, "But will he love me like Calvin loves Alice?" I think the same could be written about your relationship with Ruth. And thank you for sharing that. I can't imagine how challenging that must be even all these years later, and I'm glad your son had the opportunity to read that. He should be proud of both his mother and his father. Pat Loehrer: It was a gift to all of us and mankind. You know, again, as I saw that article, there's a photo of you and Ruth on your last vacation. I think it was from Versailles, and I think you were in the Hall of Mirrors. And I think there's a poignant metaphor there about the reflection of your lives and being with her at that time, and we really thank you. We have all experienced this and it's so powerful there. There's this time when you get a result of a test of someone that you know and love and there's this limbo between, they're so naive and life is good, and it really is a time between heaven and hell in which you're the only one there, in which you know that you're going to go in the room now and change their lives forever by sharing this news. And we've been there and we pause, and again, you talked about that - I think being in a car looking at the x-ray. And that's the essence of when you said, the day you started lying to them, which is understandable because you just don't want to shatter that moment there. You know, we pause and reflect on that enormity of the moment there and I thank you deeply for sharing that with us because it's something that we physicians find, and this uniqueness of being a physician, and having someone you care about and knowing something that they don't quite know yet. Thank you for all of that. Peter Bach: The important message is that to patients, it's very isolating. And part of what I think the article did, and this was the message I got at least, was, send a message to other people that you're not alone. That others are going through it, others have gone through it, and I don't know what "it" is in that context, but loss. And there's that wonderful article in The New Yorker called ‘The Aquarium', which is by man who had a sick child-- and I don't remember all the details, but the aquarium metaphor is, I can't remember if he's in the aquarium and the rest of the world's outside or the other way around, but it's that isolation that is particularly frightening. And when I talk with my friends who've gone through it, it's part of it. As I just said, you know, there's a lot of us out there. I don't know if it gives so much reassurance. You know, 40,000 women die a year of breast cancer, so there's a lot of people out there. Dave Johnson: Pat, you had, I think, a final question? Pat Loehrer: Briefly. You know, now I'm asking to be an academic person there, but if you had a young medical student and you were going to try to give them one lesson about communicating bad news to patients, what would that be? Peter Bach: I've obviously been in this situation many times. I'm a Pulmonary Critical Care doc, so I've watched bad news be delivered many, many times. And the first mistake I see people make is trying to fill the silence with words, and I think I made earlier reference to it. One of the key skills doctors need to develop is the ability to listen. And sometimes listening to silence is a version of listening, but it's delivering what you have to say without euphemism, with directness. Not everyone's enamored with it, I am. But then giving time to listen, even just space for people to feel safe, that that communication is part of a relationship, not a sort of text message. You know, in today's metaphor, right, that just arrives and the person moves on. That is really hard for people to do; not experienced doctors, for trainees because it's frightening for a lot of reasons. Over my career, I've certainly rehearsed it many times with people. I made the mistake myself too, of just sort of talking over the thing in the room to avoid, you know, just sort of as you said, the enormity of what you just communicated. Dave Johnson: So, Peter, I think you're right on. I think that's one of the most difficult things to do, is to allow that pause to take place. And so many, even highly experienced physicians attempt to fill that void when it doesn't need to be filled. Been there, done that, been on the receiving end as well as the delivery end of that. It's always challenging. You know, we're out of time, and I'm sad about that because we could go on, I'm sure for quite a long time. Want to end this by asking you, Peter, we talked about a book on the front end, both Pat and I love to read, and we share recommendations all the time. I wonder, is there a book or a podcast, or anything that you think we should read or you think our listeners should know about? And by the way, you can include anything that you wrote if you'd like. Peter Bach: Yeah, it'd be very au courant to pitch my own stuff here, I would never do that. I like to read as well. And so, I just finished Rules of Civility by Amor Towles. Of course, there's a few health events in it, but it's not to do with anything, but, you know, it's a book about New York. I live in New York, so I just enjoyed every single word of it. I'm newly married- Dave Johnson: Congratulations. Peter Bach: -thank you. I feel very lucky. And my wife has noted that I often like to read nonfiction at night. Typically, books about how the world is just going completely to hell. And she's noted that outrage is my happy place, that I sleep extremely well if I read something that's absolutely infuriating. So, the other thing I'll recommend is the book about the Department of Justice has essentially lost its mojo when dealing with corporate crime. If your best soporific is being absolutely furious, it's right up there with a full dose of Ambien. So anyway, those are my two recs. Pat Loehrer: I love it. Yeah, Dave and I both love non-fiction. We love that. So, it's great. Dave Johnson: We've come to an end of another podcast, and we want to thank our listeners for tuning in. We really appreciate your participation. Remember, Oncology, Etc. is an ASCO Educational podcast, where we'll talk about virtually anything and everything. So, if you have an idea for a topic or a guest you'd like for us to interview, please email us at: education@asco.org. Thanks again. You know, speaking of interesting nonfiction, Pat, if ‘pro' and ‘con' are opposite, what's the opposite of progress? Pat Loehrer: Oh, I love that - Congress. Dave Johnson: Yes, Congress. I knew you would get that. Peter Bach: That is a ‘Dad joke' if I ever heard one. Dave Johnson: We don't have good jokes on this show. Pat Loehrer: We're going to have to redo the ending to this because, Dave, you said this was an ASCO Education Podcast. I'm not sure we've taught anybody anything on this one. Dave Johnson: Now, Peter has taught us a lot. Pat Loehrer: That's for sure. Thank you so much, Peter, for a wonderful interview. Dave Johnson: Absolutely perfect. Wonderful. Peter Bach: Thanks for the privilege. It's wonderful seeing you both.   Thank you for listening to the ASCO Education podcast. To stay up to date with the latest episodes, please click, "Subscribe." Let us know what you think by leaving a review. For more information, visit the Comprehensive Education Center at: education.asco.org.   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.

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study." Dr. Carolyn Lam: Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA? Dr. Greg Hundley: Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure. Dr. Carolyn Lam: Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology. However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes. Dr. Greg Hundley: Oh wow, Carolyn, this sounds really informative. So what did they find? Dr. Carolyn Lam: Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts. Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis. Dr. Greg Hundley: Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction. So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily. Dr. Carolyn Lam: All right. So the Paradise MI echo substudy, what did they find? Dr. Greg Hundley: Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial. Dr. Greg Hundley: Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us? Dr. Carolyn Lam: Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction. Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new. Dr. Carolyn Lam: Wow, that's interesting. So what did this paper find? Dr. Greg Hundley: Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting. Dr. Carolyn Lam: Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing. Dr. Greg Hundley: Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke? Dr. Carolyn Lam: Yep. In patients with EF, here we go. Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation. Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place? Dr. Signild Åsberg: Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question. Dr. Jonas Oldgren: My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies. So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?" And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment? Dr. Carolyn Lam: Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used? Dr. Jonas Oldgren: Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence. And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study. Dr. Carolyn Lam: Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results? Dr. Signild Åsberg: Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients. Dr. Carolyn Lam: That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome? Dr. Jonas Oldgren: Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well. So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started. So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention. Dr. Carolyn Lam: Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit? Dr. Signild Åsberg: We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase. Dr. Carolyn Lam: I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds? Dr. Signild Åsberg: We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale. Dr. Carolyn Lam: Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results. Dr. Signild Åsberg: Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that. We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation. Dr. Jonas Oldgren: And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials. So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences. And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients. Dr. Carolyn Lam: Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view? Dr. Signild Åsberg: Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention. Dr. Jonas Oldgren: I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study. Dr. Carolyn Lam: And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week. Dr. Greg Hundley: 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, please visit AHAjournals.org.

Guest host Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, and Dr. Brian Henick, of the Columbia University Herbert Irving Comprehensive Cancer Center, discuss advances in KRAS-mutated lung cancer in the KRYSTAL-1 trial, and the association of ctDNA with overall survival in the NADIM trial, as well as other key advances in lung cancer presented at the 2022 ASCO Annual Meeting.   TRANSCRIPT   Dr. Vamsi Velcheti: Hello, everyone! This is Dr. Vamsi Velcheti, I'm your guest host for the ASCO Daily News podcast, today. I'm an associate professor and medical director for the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Brian Henick, an associate director of the Experimental Therapeutics Program, and assistant professor of Medicine at Columbia University's Herbert Irving Comprehensive Cancer Center. We'll be discussing key abstracts in lung cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the notes and disclosures of all guests on the podcast can be found on the transcripts at asco.org/podcasts. Brian, it's great to speak with you today. Dr. Brain Henick: Thank you so much, Vamsi, and ASCO Daily News for letting me join you to discuss these abstracts. Dr. Vamsi Velcheti: So, let's dive in. So, it's an exciting ASCO Annual Meeting. And I hope you had a great time at the Meeting. So, let's start off with the LBA9009 and KRYSTAL-1 clinical trial. The study showed the activity of adagrasib in patients with KRAS-G12C mutant non-small cell lung cancer and active untreated brain mets. So, what is the key takeaway from this trial? Dr. Brain Henick: Well, Dr. Sabari presented some encouraging data on this important population. As we know, patients with active central nervous system (CNS) metastases represent a population of unmet medical need who are often excluded from clinical trials. So, it's a credit to the investigators for including this cohort. As Dr. Sabari noted, and as Dr. Goldberg emphasized in her discussion of the abstract, the measured CNS penetration of adagrasib compares favorably with other CNS active compounds from other settings. The overall response rate was 35%, with a disease control rate of 80%. But impressively, the median duration of intracranial response and progression-free survival (PFS) wasn't reached. This certainly seems to be a CNS active compound, and we'll need to see how sotorasib stacks up in their comparable cohort. Ideally, we'd have randomized data to prove superiority over the standard of care, but we may be a few steps away from that. Dr. Vamsi Velcheti: So, Brian, in terms of CNS mets, how big of a problem is it in patients with KRAS G12C mutant lung cancers? Dr. Brian Henick: We know that CNS metastases are a big problem for G12C mutant lung cancer. The rates have been quoted as high as up to 42% of patients. And in particular, as you know, Vamsi, a lot of times trials often don't include, specifically, cohorts with active untreated brain metastases. And so, this is a very unique cohort in that sense. Dr. Vamsi Velcheti: I just want to highlight that we really don't know the differential efficacy of sotorasib and adagrasib in the CNS met population because the trials were CodeBreak 100 and other trials and data readouts from sotorasib did not include patients with untreated brain mets. We did, however, [see] CNS progression-free survival data that go in line with sotorasib. So, it's really important to see that data from sotorasib. Dr. Brain Henick: I definitely look forward to seeing that. Dr. Vamsi Velcheti: So, let's talk about Abstract 8501. The primary endpoint that was presented at ASCO [Annual Meeting] was the pathologic complete response to chemotherapy and nivo vs. chemotherapy as a new adjuvant treatment for resectable stage 3, a non-small cell lung cancer. This was the phase 2 NADIM trial. So, what do you think about this study? And what's your key takeaway from the study? Dr. Brain Henick: Dr. Provencio from Spain presented data from this randomized study as you said, of nivo plus carbo taxol compared to carbo taxol as neoadjuvant therapy for potentially resectable stage 3-A and B non-small cell lung cancer. So, I did want to compare this to the randomized data that we have from Checkmate 816, which interestingly allowed for earlier-stage disease as low as 1-B. And they also allowed for more flexibility in the choice of platinum doublet regimens. This study, NADIM 2, employs 2:1 versus 1:1 randomization, which we saw in Checkmate 816. Another important difference was that NADIM 2 required adjuvant nivolumab for 6 months in the study arm, whereas Checkmate 816 didn't include any immunotherapy in the adjuvant setting, but they allowed for a standard of care chemotherapy. In NADIM 2, the control arm didn't include any adjuvant therapy. In keeping with the impressive improvements over historical pathologic complete response rates of about 5%, this chemotherapy-IO regimen yielded a path complete response (CR) rate of 36.8%. It also showed a major pathological response, which again is defined as less than 10% viable tumor of 52.6%, and an overall response rate of 75.4%. So, it looks like there's a benefit that's happening upfront with the immunotherapy and chemotherapy as opposed to this just being an adjuvant phenomenon. This is also in keeping with data that we saw with Checkmate 816, as well as neoadjuvant atezo plus chemotherapy in the phase 2 study that was led by Catherine Shu and colleagues here at Columbia a few years ago. Overall, this is more encouraging data for the neoadjuvant use of immunotherapy. The earlier immunotherapy marches into the treatment course of patients with lung cancer, the greater the cost of toxicity. So, I think an important thing for us to focus on going forward is trying to develop strategies to better identify the patients that are most likely to benefit. Dr. Vamsi Velcheti: So, Brian, I think from a practical standpoint, now that we have approval for neoadjuvant immunotherapy and adjuvant immunotherapy, we have some practical challenges in terms of how we manage our patients. Of course, the new adjuvant is very appealing because it's only 3 cycles of chemoimmunotherapy, but the challenge though, is a majority of the patients don't have a CR, or a significant proportion of the patients have an ongoing response or significant residual disease at the time of surgery. So, the question then would be what do you do after surgery if they're having an ongoing response? Do you think 3 cycles of immunotherapy are inadequate systemic therapy for these patients? Dr. Brian Henick: It's a really important question, Vamsi. I think until the data is mature, we're just kind of limited by the extent of what the data tells us so far, and then we have to kind of do our best as the treating doctor to navigate the patient's situation. So, tools that we'd still have available to us in the adjuvant setting that are approved are things like chemotherapy and radiation, leveraging things like circulating tumor DNA, I think maybe a promising path forward, as well to help guide strategies there, but I think until the data is mature, it has to be highly patient-focused to figure out what seems to be most appropriate there. How are you navigating those situations, Vamsi? Dr. Vamsi Velcheti: Yeah, as you said, it is very challenging. I think we need more data. And of course, the challenge now is like, if you use immunotherapy in the new adjuvant setting, it's very likely you're not going to get insurance authorization for 1 year of adjuvant atezolizumab. So, we really need studies to optimize treatment paradigms here. As you suggested, maybe circulating tumor DNA (ctDNA)-based approaches to look at residual disease, I think, that would be one great way to do it. Let's move on to the next abstract, Brian. I found Abstract 9001 really interesting. It's a U.S. Food and Drug Administration (FDA) pooled analysis that looked at outcomes of first-line immune checkpoint inhibitors, with or without chemotherapy based on the KRAS mutation status and PD-L1 expression. So, what is your take on this abstract and how do you think this is going to impact our practice? Dr. Brian Henick: So, Dr. Nakajima and colleagues explored the observation from individual trials that patients with KRAS-mutant lung cancer seem to have better responses than wild type with immunotherapy (IO) alone. But the favorability of these responses seems to be abrogated with chemotherapy-IO. We know that KRAS accounts for 25% of oncogene-driven non-small cell lung cancer predominantly at amino acid 12. And with the emergence of direct inhibitors of G12C, understanding the clinical features of these tumors may be critical to inform optimal integration of this new class of drugs and also to make sure that we've optimized treatment algorithms for KRAS patients in general. So, this study's authors at the FDA pulled data from 12 registrational clinical trials that were investigating first-line checkpoint inhibitor-containing regimens and they found no significant difference between KRAS wild type and mutant for overall survival regardless of the regimen used. The best outcomes were seen with chemoimmunotherapy regardless of KRAS status. This retrospective analysis does suggest that the notion of there being lesser benefit from chemoimmunotherapy from Dr. Gadgeel's study might not hold up in the overall population, but I think it raises important questions, like, are all KRAS mutations alike? The absence of KRAS mutation status for a majority of patients included in these studies limits the interpretation of the data. And also, the absence of commutation status makes it a little harder to interpret. And other important questions remain such as how G12C inhibitors will factor in? What were your thoughts, Vamsi? Dr. Vamsi Velcheti: No, I completely agree with you, Brian. I think we need more data and we know that commutation status is a very important aspect in terms of KRAS-directed therapies. And of course, with a lot of promising data from these KRAS inhibitors, there's an interest in moving these drugs into the front-line therapy for patients with KRAS mutations. But I think it's going to be quite challenging to incorporate them into the front-line therapies and we clearly will need better characterization of these patients with KRAS mutant [lung cancer] to further personalize treatment in the frontline setting for these patients. So, let's move on to the next abstract. This is the lung map study, Abstract 9004. This is a study sponsored by the National Cancer Institute (NCI), the lung map study, looking at overall survival from a phase 2 randomized study of ramucirumab and pembrolizumab, what's the standard of care in patients with advanced non—small cell lung cancer previously treated with immunotherapy. So, what were your key takeaway points here from this study? Dr. Brian Henick: So first of all, it's very exciting to see data from this very ambitious long map sub-study yield a positive result. Whereas many of the arms of this study were biomarker-guided, Dr. Reckamp presented the results from pembro plus ramucirumab as compared to the standard of care in unmarked patients with non-small cell lung cancer who had progressed after prior treatment with chemotherapy and immunotherapy. The data seems to suggest that pembro plus ramucirumab may be better tolerated than the standard of care chemo-containing regimens, as the experimental regimen had fewer serious adverse events. Pembro plus ramucirumab had a median overall survival of 14.6 months as compared to 11.6 months in the control arm and this was statistically significant. The PFS difference wasn't significant, but there was a late divergence in the curves. Dr. Bestvina nicely summarized some of the study's limitations such as the mixture of control regimens used, and there were really interesting signals that were found on subgroup analysis, such as benefit in those with mixed histology tumors, STK11 mutant tumors, and those who received chemotherapy prior to immunotherapy. The subgroups deserve further attention in the future. For now, this regimen may be an appealing option as an alternative to chemotherapy for the right patients. What do you think? Dr. Vamsi Velcheti: Yeah, I agree, Brian. I think it's a really promising combination. We've always seen some synergy with VEGF inhibitors and immunotherapy in multiple studies and multiple tumor types. So, we really need to develop better ways to select patients for VEGF combination-based approaches in lung cancer. So, let's move on to another interesting study. This is Abstract 9000. This explores the outcomes of anti-PD-L1 therapy with or without chemotherapy for first-line, metastatic non-small cell lung cancer with a PD-L1 score of greater than 50%. So, this is an FDA pooled analysis. So, what were your key takeaways from this abstract? Dr. Brain Henick: I thought this question was really well suited for a large pooled retrospective analysis and our colleagues at the FDA didn't let us down here. The question really was what's the optimal approach for patients with non-small cell lung cancer with greater than 50% PD-L1 in view of the absence of direct comparisons between these arms in prospective studies? I thought one of the most striking findings from Dr. Akinboro's presentation was the dismally low rate of underrepresented minority patients that were included in these registration trials. As far as the findings for the patients who were studied, although the Kaplan-Meier curves for overall survival showed early separation, the difference wasn't statistically significant. Subgroup analysis revealed a trend towards better outcomes for immunotherapy alone among patients who are [age] 75 and above, suggesting that this may need to be parsed out as a unique population in subsequent studies. But in all, our equipoise as a field on whether to include chemoimmunotherapy-based first-line regimens should persist and should be guided, in my opinion, largely by clinical considerations. Can the patient tolerate chemotherapy? Do you need a rapid response? Are there other things that you thought in hearing all this, Vamsi? Dr. Vamsi Velcheti: Yeah, absolutely. I think I am still struggling with the decision of whether to add chemotherapy for patients with greater than 50%. To a large extent, it's actually a clinical decision. In some patients who have a large disease burden, I tend to kind of opt for adding chemotherapy to immunotherapy in the front-line setting. But of course, we need more data here. And this is actually a very helpful piece of information from the FDA. And as you pointed out briefly, Brian, I think the fact that there are very few underrepresented patients in the pooled analysis, I think kind of speaks to the need for addressing increased diversity in clinical trial accruals. I think this is a great segue to also talk about Abstract 9012, talking about disparities in access to immunotherapy globally. This is a study from India looking at 15,000 patients who were checkpoint inhibitor eligible and who have very low rates of uptake of immunotherapy. This is something that reflects the global team of the ASCO Annual Meeting talking about disparities and improving access to treatments in underserved minority populations here in the United States, and also globally, in the developing world, the disparities in terms of access to care are humongous. So, what are your thoughts, Brian? And also, if you could highlight some of the work that you're doing at Columbia about disparities, I think that would be great. Dr. Brain Henick: Absolutely! I think access to medications is a really humbling topic for those of us who are involved in developmental therapeutics, particularly with the transformational impact we've seen with the advent of immunotherapy over the last decade-plus. Dr. Ravikrishna's presentation is therefore extremely important. He described very low rates of uptake of immunotherapy by indication. And perhaps most strikingly, the discrepancy in uptake by patients' ability to pay for therapy with the vast majority of immunotherapy received by those who are private is very concerning. Even if the definition of restricted access was permissive, for example, I didn't see mention of the cancer stage as an eligibility factor, the fact that this represents a single referral center's data doesn't bode well for uptake elsewhere. So, I think we need to continue to work as a field on prioritizing strategies to help overcome these gaps, but good quality data such as this study is an important first step. And to that point, Vamsi, I'm very excited to be working with you in collaboration on an observational study for patients with lung cancer from underserved minority populations with lung cancer in New York City so that we can better characterize access to care, efficacy, and toxicity in this population. Dr. Vamsi Velcheti: Thank you, Brian. I'd really like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate it. Brian, thank you so much for joining us. Dr. Brain Henick: My pleasure. Thanks for having me. Dr. Vamsi Velcheti: And thank you to all our listeners for joining in today. You will find links to all the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you so much.     Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Brain Henick: None disclosed. 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.

This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Centre and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter. Dr. Carolyn Lam: So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI. Dr. Greg Hundley: Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn? Dr. Carolyn Lam: A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%. Dr. Carolyn Lam: In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI. Dr. Carolyn Lam: And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction. Dr. Greg Hundley: Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype. Dr. Greg Hundley: The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia. Dr. Carolyn Lam: Cool, Greg. So what did they find? Dr. Greg Hundley: Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions. Dr. Carolyn Lam: Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg? Dr. Greg Hundley: You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation. Dr. Carolyn Lam: Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University. Dr. Carolyn Lam: I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found? Dr. Ratika Parkash: Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control. Dr. Ratika Parkash: One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study. Dr. Carolyn Lam: That's great, Ratika, so thanks. And what were the results? Dr. Ratika Parkash: The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting. Dr. Ratika Parkash: So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066. Dr. Carolyn Lam: Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place? Dr. Sean Pokorney: Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure. Dr. Sean Pokorney: You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data. Sean Pokorney: When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators. Dr. Sean Pokorney: And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size. Dr. Sean Pokorney: And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical. Dr. Carolyn Lam: That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well. Dr. Ratika Parkash: Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings. Dr. Ratika Parkash: I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only. Dr. Ratika Parkash: So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients. Dr. Ratika Parkash: Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have. Dr. Ratika Parkash: And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events. Dr. Ratika Parkash: In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study. Dr. Ratika Parkash: We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that. Dr. Ratika Parkash: The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies. Dr. Ratika Parkash: The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that. Dr. Carolyn Lam: You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts? Dr. Sean Pokorney: I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm. Dr. Sean Pokorney: And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful. Dr. Sean Pokorney: I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial. Dr. Ratika Parkash: Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years. Dr. Ratika Parkash: And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study. Dr. Sean Pokorney: Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data. Dr. Sean Pokorney: So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results. Dr. Ratika Parkash: Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time. Dr. Ratika Parkash: The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available. Dr. Ratika Parkash: There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm. Dr. Sean Pokorney: Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF. Dr. Sean Pokorney: So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications. Dr. Sean Pokorney: I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy. Dr. Ratika Parkash: Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach. Dr. Sean Pokorney: Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself. Dr. Sean Pokorney: So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring. Dr. Ratika Parkash: Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful. Dr. Ratika Parkash: So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention. Dr. Carolyn Lam: Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on. Dr. Carolyn Lam: Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week. Dr. Greg Hundley: 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, please visit AHAJournals.org.  

In the second of this two-part conversation Drs. Patrick Loehrer and David Johnson sit down with Dr. Deborah Schrag, the current Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center to continue the discussion of her roles as a leader, researcher, oncologist, public health expert, and more. If you liked this episode, please subscribe. Learn more at https://education.asco.org, or email us at education@asco.org.     TRANSCRIPT Dr. Dave Johnson: Hi everyone, welcome back to Oncology, Etc. an ASCO educational podcast. My name is Dave Johnson. I'm at UT Southwestern Medical Center in Dallas. And I'm here with my good friend Dr. Pat Loehrer who serves as a director of Global Oncology and Health Equities at Indiana University. In the second half of our conversation with Dr. Deborah Schrag, the current chair of Medicine at Memorial Sloan Kettering Cancer Center in New York. In part one, we heard about Dr. Schrag's early life and background, as well as the importance of affordable cancer care and much more. Let's jump back into the conversation and hear about her current goals and initiatives at Memorial Sloan Kettering. I have a question for you. Jumping ahead a little bit. But I mean, you're such a role model for all of us. But you're now in a very powerful position as head of medicine at the preeminent cancer center in the world. So, I'd be interested in knowing what are your top initiatives? What did you come to this role wanting to do short-term and long-term? I'd be curious to hear from you about that. Dr. Deborah Schrag: Yeah. So, I have lots of specific initiatives, all the things that are probably very similar across medical cancer centers. We have to figure out the role of immuno-oncology. We have to figure out the role of CAR T-cell Therapy. There are lots of specific things, but let me tell you about three sort of overarching principles and things that I think we need to think about. So, one of the reasons why I decided to leave my job where I really focused on training researchers and building a research program to lead a department of medicine that has a mix of clinicians, educators, and investigators is that there's really a profound sense of exhaustion and disconnection. I'll use the word even burnout or people get the sense of losing the joy in the practice of medicine. And as corny as it sounds, and I know I'm going a little corny here, Dave. But I really want to help bring back and connect people to the joy in the practice of medicine. It's the joy that we experience when we crack a tough case, when we help a patient, when our patients make us laugh, when our patients and their families make us cry, when they drive us bananas, when they cook us food that is inedible, just reconnecting us to the joy, to the stories. I really wanted to try to be a different kind of leader because I felt that I could make a contribution to the field of academic medicine in general and oncology in particular, by working with faculty to set them up to tap into that joy, because I know they all started with it. I know they all went into medicine because they care about those human stories, because they do want to make a difference. This past week, a fellow intern of mine who you may know, passed away. His name was Paul Farmer. He was the head of Partners in Health and he was an infectious disease physician. There's a book about him by Tracy Kidder that's really moving. There's also a documentary about him called, Bending the Arc, which I would highly recommend. Paul was an incredible inspiration, just incredible, but he brought so much joy to the practice of medicine. I remember when Paul was going to some of the poorest places on the planet, specifically Cange, Haiti. He got an idea that he needed to bring chemotherapy because there were large cancers that were untreated. And he wanted to get leftover chemotherapy from the Dana-Farber. So, in the 1990s, when I was a fellow, he would ask me whether I could get him any leftover Taxol. I was like, ‘Paul, I can't do that. It's not safe. You can't take leftover Taxol to Cange'. And he said, ‘Deb, just wait, the drugs will be oral soon, and then I'll get it'. But guess what? Paul came back to me in 1999, and capecitabine had been approved. The oral equivalent of 5-FU. He held my feet to the fire. He said, ‘Every time you have a dead patient, if there's any leftover capecitabine, I want you to get it for me'. Inspirational leadership, connecting people to the joy in the practice of medicine. I would say that's number one. There's no one simple formula or way to do that. It's hard work. It requires a team I think a lot more teamwork into the practice of medicine. I think we're coming out of a hard two years where we've been confined to Zoom boxes. But it's a lot easier when we can sit together in a room and have a pizza and a beer on a Friday afternoon. But we have to figure this out, and we will, step by step. The other big thematic area, I think, has to do with the patient experience. Dave, I mean, when I started out as a fellow, patients with advanced lung cancer were living for 10 months, 10-12 months, that was a pretty good run with advanced metastatic non-small cell lung cancer. Well, these days, it's 2-3 years, and there's even quite a tale of patients who were living 4-5 years. And that is a long journey. It's no longer the 800-meter sprint, it's a half marathon, turning into a marathon and even an ultra-marathon. So, the way we deliver care needs to change. So, we're really rethinking here, how we deliver care. So, as an example of some, if you go back to the 80s and 90s, cancer chemotherapy was something that happened in the hospital. And in the last quarter century, we've transitioned that to an outpatient practice. I think in the next quarter century, we won't transition all of it, but we will transition a lot of it to home. As an example, I'm struck by when patients undergo IVF, they get handed some Lupron and are taught how to self-administer Lupron every day, so they can undergo a fertility cycle. But when those same women get breast cancer, they have to come into the clinic and sit and wait and take half a day off of work to get the same Lupron. The same is true for men with prostate cancer. Why is that? It's because of policies, and it's not safety, it's not patient-centered. So, I think we have an opportunity to change the patient experience. I think we'll be able to give immunotherapy at home, and HER-2 agents at home. We have to do the trials and make sure that it's safe, but we have to make cancer care more patient-centric and improve the experience. And that's just essential when it's a marathon that we're asking our patients to run, not these 12-month sprints. Families need this also. So, those are a few of the challenges that I want to take on. Joy in medicine, patient experience, and of course, the physician-scientist pathway needs to be strengthened. Dr. Pat Loehrer: I love it. You can imagine between Dave and me, I think that resonates so much about having joy in medicine. I've not heard other people talk about that, but I really think that's an important vocation. But I'm going to ask you something else too because, in the efforts of being joyful and being a role model for that, there's the other side of it, where you can't actually let your hair down, and really be depressed, if you will, or down because you can't let the other side see that. And so, who do you lean on if you will, your confessor that you can talk to when you're feeling down when you're trying to fight the anti-joy part of your job? Dr. Deborah Schrag: I have lots of friends outside of medicine. And I've always found that that's really helpful to make time for friends outside of medicine. They help connect me to humor and other things. I'm coming up on a big high school reunion. My high school classmates and I still meet for picnics in Central Park. And there are about 120 in our graduating class. And I think we'll have about 110 of us getting together. We still have picnics with 40-50 people attending. So, there's nothing like old friends from childhood who now do all kinds of different things. So, that's really helpful. But I've also found that my mentors and colleagues who trained me and who know me really well, are a great source of advice. So, leaders in academic medicine, and I've always found that I've been able to get advice from people who were senior and leaders, people such as Dr. Mayer, Dr. Benz, Dr. Jim Griffin, and also junior colleagues. I now increasingly as I get old, I rely more and more on my trainees and my mentees. So, some of the folks I know best are people who I trained. So, I'll just give you one example. Many of you may know Ethan Basch. We worked together when we were both just coming up. I was an assistant professor. He was a couple of years behind me. I mentored him. Well, he's now chief of the Division of Oncology at UNC. He and I have written lots of grants together. We're really partners now. But it's been a lifelong professional friendship. Sometimes when I just need to let my hair down, I get on the phone with Ethan, and yeah, there's a little bit of commiserating. But I'll give you an example that runs through Dave. Some really valuable experiences had to do with being asked to serve on committees. I think it's great. I just want to give a shout-out to ASCO. Some of my earliest professional relationships were with superstars that I met through ASCO. So, people like Joe Simone, reading his Simone's Maxims everyone needs to read Simone's Maxims if you haven't. There was a guy by the name of Christopher Desh, who sadly passed on. But he was an ASCO member who practiced at the Virginia Commonwealth University back in the late 1990s. Boy, did that guy understand the joy in medicine, some of the early folks who started QOPI. Being introduced to those individuals who practiced in different parts of the country and who had different kinds of challenges - having that sort of rich network has been incredible. At some point, I think through such a connection, maybe it was through Dr. Mayer, I was referred to Dr. Johnson, who was then running the American Board of Internal Medicine committee that wrote the oncology exam. I participated in that for a few years that was led by Dr. Johnson. And I met incredible people on that committee, including Dr. Johnson, just Dr. Johnson's stories could inspire anyone and get them back on track just in terms of the humor and the joy and the love, and really the pride in the profession. But I met Jamie Von Roenn that way, who's now leading educational efforts at ASCO, she was on that committee. Lynn Schuchter became a good friend of mine as a result of that. So, I would just say, sometimes you need to get out of your own space. And sometimes I need to get out of Dodge, as they say, I need to get out of New York, get out of Boston, and being connected to colleagues across the country has been so rewarding. I have a network of friends at other institutions who I rely on. Serving on external advisory boards is a great place to meet people. Study section, if anyone has the opportunity to be on study section. That's a fabulous opportunity. So, I think participating in peer review, showing up at meetings, serving on ASCO committees, or ASH or AACR. These are really important experiences. And I will say in my leadership role, I'm really trying to make it clear to faculty that I encourage them to take time to participate in these activities and attend these events and even travel because the traveling is important, too. I could not have gotten the same dose of Dave Johnson, if I had not actually gone to the meeting, spent all day writing board review questions, and then having a nice meal afterward. That was part of the experience. I don't know what you would say, Dave, but that was my view. Dr. Dave Johnson: So, one of the things that Osler talked about was the fellowship of the profession, and how important it is to have those relationships. Even if one can't physically be with that individual, developing that spiritual relationship is really critically important. I'm so glad you brought this up and expanded on it in the way you did because I think it's absolutely critical to retain the joy of medicine. It's our colleagues, as well as our patients that make it such a marvelous, majestic profession, in my view. Dr. Pat Loehrer: I was going to just add something if I could. So, Deb, replace me on the ABIM, just to let you know, because we had certain slots on there. One of the not sure if it was the rules or guidelines that were mandated is that everyone needed to take the oncology boards, even though we wrote the questions, we had to take the test. And you knew that and you had such unbridled enthusiasm for this. I still remember this deeply, and that not only did you recertify for the oncology board, but you also studied to take the medicine boards too. Your love of medicine is so contagious. And I'm sure everyone at Memorial benefits from this. Dr. Deborah Schrag: Thank you. That's very nice to say. I do, I love the stories. I've been rounding with the house staff on the inpatient service. I think both of you know, inpatient oncology, as we're able to do more and more in the outpatient setting, our inpatients are very, very sick. And we often get a front-row seat to what I would call the social determinants of health challenges. In other words, if you've got relatives and resources, you may be able to be at home. But if you have severe pain or symptoms, and you lack the relatives, or you live on a fifth floor, walk-up, or just don't have the resources to get the home care that you need, you're more likely to be in our hospital. But as I round with the house staff, I find myself asking them to tell me more about the patient stories. Because when I round and they tell me that it's a 74-year-old with peritoneal carcinomatosis, jaundice, and abdominal pain. I'm so old that I've seen so many hundreds of those patients and the management hasn't changed very much. But what's really the privilege is to understand the journeys that got people where they are, and to learn a little bit about who these people are. I try to do that when I round with house staff and I find that it makes the experience better for them. I have to say that I do worry about how we train young physicians in oncology because what they see on the inpatient side is really the hardest of the hard, that's obviously less true in a leukemia service, where they're delivering lots of curative therapy or a stem cell transplant service. But in solid tumor oncology, it's really hard. I think it's something we have to have to tackle. We have to rethink education and medical oncology. I'm hoping that we're going to do that. That's also on the bucket list, by the way. I think we have to do that as a profession. And I know both of you are passionate champions and advocates for education, as is ASCO. But I think it's really imperative that we do that if we are to keep attracting talent. And then I just want to make one more point, which is that New York City is one of the most diverse places in the United States. I don't know about the planet, because I don't know the whole planet. But in the United States, we are incredibly diverse. But the oncology workforce does not yet look like that. So, we have a lot of work to do to train a much more diverse workforce. We're doing well with respect to gender, very well. We're literally about 50/50, we may even have a little bit higher proportion of women on the faculty here at MSK. And I think that's true nationally as well. But with respect to Blacks and Hispanics, and other underrepresented communities, Native Americans, we've got a long way to go. And we have a pipeline problem. And that's going to be hard. But it's hard work that we have to do, and I know you guys are working on that in your own centers as well. Dr. Dave Johnson: Let me follow up on that. What attributes are you looking for in trainees and newly hired faculty? Whether they be junior or senior faculty? What are the characteristics or attributes you seek that you think predict, or certainly you want your individuals to possess? Dr. Deborah Schrag: We all want people who have everything, but I would say creativity, the willingness to take risks, and the ability to ask a question. I say this to the trainees, frankly, I say it to my own children as well. ‘It's okay, take a harder course. Yes, you may get a B minus by trying something new and different, that doesn't play to your strengths. But try something new. Take risks. Yes, the trial may fail. Yes, you may not get that grant.' But I think a willingness to take risks, a willingness to put yourself out there, a willingness to stretch. I'm also looking for people who can work in teams because there is no aspect of medical care that happens in MSK, I suspect that it's also true that maybe medicine in Antarctica, but even medicine in Antarctica is probably a team sport. Medicine has become a very complicated team sport. It's a very complicated dance with pharmacists, nurses, and APPs. It takes a village to give a course of immunotherapy. It is very complicated. And so, when people like to control things and like to do everything themselves, they're going to have a hard time. And that's true I find for teaching, laboratory investigation, wet lab, dry lab, most good, impactful, important science in oncology these days, clinical trials, wet, dry, all of it gets done in teams. Teams that have people with different levels of training, different skill sets, early stage, late stage, people who are quantitative, people who can write, people who can program, people who can do lab experiments, and people who know what an organoid is. People who know how to program an in R. All different kinds of skill sets but they have to be able to work in teams. People who can't do that are going to struggle to achieve maximum impact. I'm not saying that there isn't room at the end for the occasional genius person who likes to work solo. But that's not really what we need to move the needle. So, I need team players. I think there is a big emphasis on collegiality. Of course, we want smart and we want brilliance. But sometimes a drop less brilliance and a drop more collegiality and being able to work together in a team, it goes a long way and it's the difference between doing something impactful and not. That's what I look for. I also think that it takes all different kinds of people. And no one has to excel at everything, but it's great for people to be able to excel at something. So, passion, drive, and ability to ask questions, and not being afraid to occasionally fail and having some tolerance for that and trying to make sure that leaders are able to tolerate that, too. We have to be able to. Dr. Dave Johnson: Yeah, I think those are great suggestions. We're getting near the end of our time today, and we have a lot more questions to ask. But what's your biggest fear, as the head of the Department of Medicine, looking to the future, what causes you to lose sleep at night? Dr. Deborah Schrag: I think the business of medicine. If medicine turns into something that feels just like [inaudible] work, and losing physicians, if we don't respect physicians' need to take care of themselves, to take care of their families, and yeah, to find that joy, then we will not attract the top talents. I think we need great minds and great hearts and people from all walks of life to enter the profession, because that's the talent that we need, to quote my friend, Paul Farmer, ‘Bend the arc'. And you know, we need to bend Kaplan-Meier curves in the right direction. And we need the talent to come into the profession, and if they see that we are not happy and not thriving, the next generation is going to go elsewhere. I don't want to begrudge my wonderful endocrinology colleagues. We need people to tackle diabetes, and we need great surgeons and great anesthesiologists, too. So, it's not just oncology. In medicine, I'm responsible for all kinds of discipline. And boy, we need a lot of cardio-oncologists because we've created all kinds of new challenges. So, it's all of the sub-disciplines of medicine, but I think physician well-being and attracting talent to the field is really essential and making sure that the business side of medicine doesn't take over and destroy the core promise and premise of academic medicine. It is a spectacular profession and calling, and it has led to so many advances that have really changed the world. And we have to, I think, preserve the good in that. My fear is that that gets further eroded. Dr. Pat Loehrer: Just one last question from me. Thank you for all your wonderful comments. But I think I have to ask this because it's such an unusual thing as they brought up at the beginning that you're the first female Head of Medicine at Memorial and Lisa DeAngelis is the first Physician in Chief. And so, although there is gender equity in medicine, there is not gender equity and leadership around the academic world. And this is a very unique situation there. Can you reflect a little bit about the significance of this and perhaps, lessons learned, particularly if you're speaking to a younger version of yourself or a young woman who's thinking about a career? What are the lessons between you and Dr. DeAngelis mean? Dr. Deborah Schrag: I'm not sure I've been at it long enough to have lessons. I'm just so grateful. So, I'm not in the generation that was a trailblazer. I'm a beneficiary. So, I've had the privilege of being trained by Dr. Jane Weeks, by Dr. Judy Garber. I, myself, had so many great mentors who were women. I would say to women, that you can have it all. You just may not be able to have it all at once. Women and men have to make choices. Can you have a lab and be a laboratory investigator? Yes. Can you do that and have a family? Yes. I think running a high-power lab and having a gigantic clinical practice and running clinical trials, I think the three-legged stool and the so-called triple threat is really, really hard. But I think it's hard for women and men. What I would also say to women is you don't have to be the boys - be yourself. I think the best advice I can give to leaders is to be authentic. Because everyone, men, women, people smell a phony and no one likes to phony. So, I think if you know how to partner, you understand that it's a team sport. I think women do that really well. So, I think being authentic, and I think women need to hear that, you don't have to emulate male role models. You have to be yourself. I would love to emulate the two of you. I have to thank both of you because the Indiana Miracle and Dave from his Vanderbilt days, Vandy, as Dave likes to call it, from his Vanderbilt days to his Texas days, like, the two of you are such incredible thought leaders and inspirational leaders in oncology, but I can't be you. The best we can be is sort of the best version of ourselves but we can be inspired by the great qualities that we see in other leaders and carry a little bit of that with us. So, I think that goes for women and for men. Dr. Pat Loehrer: Thank you! Well said, and I appreciate the thoughts. We've kind of gone through this and we're going to have to wrap it up. One of the questions that we often times ask our visitors is if there's a book that they're reading, a documentary that they're watching, a movie they're seeing, or anything you'd recommend? Dr. Deborah Schrag: That's a good question. So, yes, actually. One of the ways that I learn about leadership that I find, actually a fun way that's both relaxing and educational, is to read a biography. I love reading biographies. I'm going to name two. And these are popular books - for scholars these may not be. First really fun book is ‘The Splendid and the Vile', by Erik Larson. It's a book about Winston Churchill in 1940, and how he has to try to persuade the United States to enter World War Two, but it's really about a particular year in history and Winston Churchill. Dr. Dave Johnson: It's a great book. Dr. Deborah Schrag: It's called, The Splendid and the Vile. I just learned so much about leadership from that book and the decisions that Winston Churchill makes in his bathtub. So, just read that book and think about what Winston Churchill does in his bathtub. I can't lead from my bathtub, I live in a New York City apartment, but that's one. Then more recently, I guess there's a little German theme happening here, is, The Chancellor. It's about the life of Angela Merkel. It's long, I haven't finished it yet. But it's incredible. What a story, East Germany, her leadership style, how she studies chemistry, how she rises. It's a fantastic book. It's called, The Chancellor. So, I will recommend that one. Then the last one, my beloved nephew who's like a son to me. He's about 36 years old, and he has ALS. And he's completely paralyzed. He is on a vent and he has two little kids. But he released a documentary that actually won at the Tribeca Film Festival called, Not Going Quietly, which is about a cross-country trip that he made. He's a pretty inspirational character, despite the fact that my nephew was completely locked in, he communicates only with his eyes. He is living a remarkable life. I think that documentay, I know this is a shameless plug for my nephew, but he's a pretty inspirational character. I don't necessarily agree with 100% of his policy prescriptions and recommendations. But there are lots of ways to make meaning in the world. So, that's another documentary. Dr. Pat Loehrer: That's incredible. Thank you so much for sharing that. I'm going to look it up. People think cancer is the worst thing you can get but there are worse diseases to have. Dr. Deborah Schrag: Yeah, I think this one might change your idea. And then I would also say Paul Farmer's Bending the Arc. I think for young physicians who haven't seen that movie, I would recommend Bending the Arc. Dr. Pat Loehrer: Thank you. Dr. Deborah Schrag: Thank you! It's been great to chat with you. Dr. Pat Loehrer: It's great. So, that's all the time we have for today. And I really want to thank you, Deb, for joining us and for all your insight. It's been wonderful. I also want to thank all our listeners for tuning in to Oncology, Etc. This is an ASCO Education podcast where we'll talk about just about anything and everything, if you've heard. If you have an idea for a topic or guest you'd like to see on the show or a host that you would like not to see on the show, just email us at education@asco.org. Thanks again. And Dave, I just have a riddle for you here. How do you make an octopus laugh? Dr. Dave Johnson: Show him your picture. Dr. Pat Loehrer: Ten-tickles. That's all we have for today. You guys have a good evening. Take care.   Thank you for listening to the ASCO Education podcast. To stay up to date with the latest episodes, please click subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive education center at education.asco.org.   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.

Jeffrey A. Zonder, MD, hematologist-oncologist at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan, discusses data from the first-in-human study testing REGN5458 as a monotherapy for relapsed/refractory multiple myeloma patients (NCT03761108). Data from the phase 1 portion of this study were recently presented at The American Society of Hematology Meeting & Exposition (ASH 2021).Multiple myeloma is a rare blood cancer associated with uncontrolled growth of plasma cells. While the disease is treatable, relapses are common and some patients are refractory to first line treatment.As Dr. Zonder explains, REGN5458 is a BCMA x CD3 bispecific antibody that is currently being investigated in a phase 1/2 clinical trial. Data presented at ASH 2021 was related to the phase 1 portion of this study which is assessing the safety, tolerability, and dose-limiting toxicities (DLTs) of REGN5458 in patients with relapsed/refractory multiple myeloma as well as determining a recommended phase 2 dose regimen.As of data cut-off (June 10, 2021), 68 patients were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3–400 mg. Patients had a median of 5 prior lines of systemic therapy and the median duration of follow-up was 2.4 months. Treatment-emergent adverse events (TEAE) were reported in 66 patients (97.1%), and Grade 3 or more TEAEs were reported in 52 (76.5%) patients. The most frequent TEAEs were fatigue in 29 patients (42.6%), and cytokine release syndrome (CRS) in 26 patients (38.2%). No patient had Grade 3 or more CRS or discontinued treatment due to CRS. There were no Grade 3 or more neurotoxicity events. As Dr. Zonder notes, responses were observed at all dose levels and a maximally-tolerated dose was not reached at any level. Amongst patients treated at the 96 and 200 mg dose levels, the response rate was 73.3%. Across all dose levels, 92.6% of all responders achieved at least a very good partial response and 48.1% of responders had a complete response (CR) or stringent CR. Patients without extramedullary plasmacytomas responded more frequently than those with them. The Kaplan–Meier estimated median duration of response was not reached. The probability of duration of response ≥8 months was 92.1% with responses ongoing up to 19 months at the latest data cut-off.Overall, REGN5458 continues to show an acceptable safety and tolerability profile as well as promising durable responses in triple- to penta-refractory patients with relapsed/refractory multiple myeloma. To learn more about multiple myeloma and other rare cancers, visit checkrare.com/diseases/cancers/

In our standard graphics, we usually present summary statistics only. The exception is the Kaplan-Meier plot showing also individual patients. Showing individual patients effectively tells us so much more about e.g. clusters, outliers, and extreme values.

Aging-US published a Special Collection on Eye Disease which included "Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis" which reported that uveal melanoma is an aggressive intraocular malignancy that often exhibits low immunogenicity. Metastatic uveal Melanoma samples frequently exhibit monosomy 3 or BAP1 deficiency. In this study, the authors used bioinformatic methods to investigate the immune infiltration of uveal melanoma samples in public datasets. The Kaplan-Meier method and log-rank test were used to assess the prognostic value of particular immune cells and genes in samples. These authors used CIBERSORT and ESTIMATE with RNA-seq data from The Cancer Genome Atlas and the GSE22138 microarray dataset to determine the sample-level immune subpopulations. Dr. Zhaoyang Wang and Dr. Xianqun Fan said, "Immune heterogeneity within the tumor microenvironment has been linked to the drug sensitivity and prognosis of patients with various cancer types." Profiling of immune signatures might uncover biomarkers for targeted therapy and clinical outcome assessment. Uveal melanoma (UM) is the most common aggressive intraocular malignancy in adults, and originates from the uveal tract. Monosomy 3 tumors were found to be enriched for genes in immune pathways such as interferon signaling, T cell invasion and cytotoxicity. Mutation of GNA11/GNAQ was not found to significantly alter the immune infiltration and HLA Class I expression in UM patients. Characterizing the immunological features of UM may provide novel immune biomarkers for prognostic assessment and immunotherapy. Enhancing the cytolytic functions of infiltrating lymphocytes can significantly improve antitumor immunity. However, due to the low levels of cytotoxic cells in the tumor microenvironment, non-responsiveness to immunotherapy remains a clinical challenge. The Wang/Fan Research Team concluded in their Aging-US Research Output that gene expression profiling of UM patients treated with immune checkpoint blockers has advanced the application of genomic data to tumor immunology. The authors hope that large sequencing data from UM patients undergoing immune checkpoint blocker treatment will emerge in the future. The immune features reported herein should be considered for integration into prognostic models or explored as predictors of adjuvant immune therapy responsiveness in patients with BAP1-deficient UM. The Volti/Vinciguerra Research Team concluded in their Aging-US Research Output, "we suggest that strategies aiming at decreasing the expression of histone variant macroH2A1 [32], might effectively hamper the aggressiveness of UM cells, by inhibiting their mitochondrial phosphorylation. This could be a novel promising therapeutic strategy against UM [51]." Full Text - https://www.aging-us.com/article/102693/text Correspondence to: Zhaoyang Wang email: zhaokekewzy@hotmail.com and Xianqun Fan email: fanxq@sjtu.edu.cn Keywords: immune subtype, uveal melanoma, bioinformatics, immune cell fractions, TCGA About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. To learn more about Aging-US, please visit http://www.Aging-US.com or connect with @AgingJrnl Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Today's episode is a lecture our host, Dr. Vinay Prasad of University of California San Francisco, gave recently on censoring patients in Kaplan-Meier plots. Back us on Patreon! www.patreon.com/plenarysession Check out our YouTube channel: www.youtube.com/channel/UCUibd0E2kdF9N9e-EmIbUew

Two recent publications to discuss: 1. The publication of a study discussed on our ASCO '21 Pod on acalabrutinib vs. ibrutinib and patient implications (https://ascopubs.org/doi/pdf/10.1200/JCO.21.01210) 2. A good illustration of the "crossing of the curves" and interpreting Kaplan-Meier curves using alloHSCT vs. 5-aza in MDS patients. https://ascopubs.org/doi/pdf/10.1200/JCO.20.02724

Harry's guest this week is Jeff Elton, CEO of a Boston-based startup called Concert AI that's working to bring more "real-world data" and "real-world evidence" into the process of drug development. What's real-world data? It's everything about patients' health that's not included in the narrow outcomes measured by randomized, controlled clinical trials. By collecting, organizing, and analyzing it, Elton argues, pharmaceutical makers can it design better clinical trials, get drugs approved faster, and—after approval—learn who's really benefiting from a new medicine, and how. Concert AI, which has offices in Boston, Philadelphia, Memphis, New York, and Bangalore, specializes in providing “research-grade real-world data” and AI-based analytical services to companies developing cancer drugs. Before joining Concert AI, Elton was managing director of strategy and global lead of predictive health intelligence at Accenture, and before that he was a senior vice president of strategy and global chief operating officer at the Novartis Institutes of BioMedical Research. He's the co-author with Anne O'Riordan of a 2016 book from Wiley called Healthcare Disrupted: Next Generation Business Models and Strategies.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:• Launch the “Podcasts” app on your device. If you can't find this app, swipe all the way to the left on your home screen until you're on the Search page. Tap the search field at the top and type in “Podcasts.” Apple's Podcasts app should show up in the search results.• Tap the Podcasts app icon, and after it opens, tap the Search field at the top, or the little magnifying glass icon in the lower right corner.• Type MoneyBall Medicine into the search field and press the Search button.• In the search results, click on the MoneyBall Medicine logo.• On the next page, scroll down until you see the Ratings & Reviews section. Below that, you'll see five purple stars.• Tap the stars to rate the show.• Scroll down a little farther. You'll see a purple link saying “Write a Review.”• On the next screen, you'll see the stars again. You can tap them to leave a rating if you haven't already.• In the Title field, type a summary for your review.• In the Review field, type your review.• When you're finished, click Send.• That's it, you're done. Thanks!Full TranscriptHarry Glorikian: I'm Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.Harry Glorikian: In the world of drug development, there's a tendency to think that the only data that matter are the data that get collected from patients during randomized controlled clinical trials. That's the type of study that drug companies use as the gold standard to test the safety and effectiveness of new drugs and that the FDA uses to make drug approval decisions. But it's just not true. Way before clinical trials begin, there's a ton of genomic or proteomic or chemical data that can go into identifying new drug candidates, as we've learned from many of our previous guests on the show. And today my old friend Jeff Elton is here to tell us about another important kind of data that get collected before, during, and even after clinical trials that can have a huge impact on how drugs are used.It's called real-world data, and it basically means everything about a patient's health that isn't included in the narrow parameters and outcomes measured by clinical trials.Jeff is the CEO of a startup here in Boston called Concert AI that specializes in organizing and analyzing this real-world data. And his argument is that when you pay attention to real-world data, it can help you to design better clinical studies. It can help support the core clinical data that drug companies submit to the FDA when they're applying for approval. And after approval, it can help show who's really benefiting from a new medicine, and how. Jeff has been thinking about the importance of real-world data for a long time, at least since 2016, when he leading predictive health intelligence at Accenture and he published a book called Healthcare Disrupted. The book argued that real-world data from wearable devices, the Internet of Things, electronic medical record systems, and other sources could be combined with advanced analytics to change how and where healthcare is delivered. In our interview, I asked Jeff to explain how Concert AI is helping patients and how the predictions he made in the book are playing out today.Harry Glorikian: Hey, Jeff, welcome to the show. Jeff Elton: Thank you Harry. Pleasure to be here. Harry Glorikian: Yeah, it's been a long time since we've actually seen each other. I mean I feel like it was just yesterday. We were you know, interacting. Arshad was there and we were talking about all sorts of stuff. It's actually been quite a few years and, and, and you have now transitioned to a few different places and, and right now you're running something called Concert AI. And so, I mean, let's just start with what is Concert AI, for everybody who's listening. Jeff Elton: Yeah. So Concert AI is a real-world evidence company. We'll spend a little bit of time breaking that down. We are very focused on oncology, hematology, urological cancers. So we kind of tend to stay very much in that space.And within the real-world evidence area, we really focus on bringing together high credibility research grade data. This usually means clinical data. Genomic data can include medical images combined with technologies that aid gaining insights out of those particular data and that kind of align with our own various use cases.A use case could be designing a clinical study, it could be supporting a regulatory submission. It could be gaining insight, post-approval, about who's benefiting, who's not benefiting. And you know, our whole mission in life is accelerating needed new medicines and actually improving the effectiveness of current medicines out there.Harry Glorikian: So who's like, I don't know, the user, the beneficiary, in a sense, of this.Jeff Elton: So, you know, we like to think we have a very heavily clinical workforce. You know, we always put the patient first. So I'm actually gonna say that a lot of the reason why we're doing things is that we have the benefit to be stewards, combined with provider entities, of focusing on questions that matter for patient outcomes.So the first beneficiary is patients. I think the second beneficiary are biomedical innovators. We're trying to kind of support those innovations. We're trying to understand how to go into the clinic. We're trying to understand how to design those clinical trials to have them be more effective. We're trying to understand how to show that relative to the current standard of care, they offer a range of incremental therapeutic benefit. A lot of medicines become improved once they're actually already approved. And so we actually spend time doing a lot of post-approval research that actually begins to improve the outcomes by beginning to kind of refine the treatment approaches.And then the clinical communities we work very closely [with]. We're a very close working partner with American Society of Clinical Oncology and their canceling program. We're in a 10-year relationship with them that allows us to do work in truly high need areas. We did a COVID-19 registry jointly with ASCO that worked off of some of the data we brought together because it you know, COVID-19 uniquely hit cancer and particularly hematological malignancy patients.We do work with them in health disparities, making sure that racial, ethnic, and economic groups can be the beneficiaries of new medicines and are appropriately part of doing clinical trials, clinical studies. And then we work directly with provider communities who oftentimes are seeing the value of the work we're doing and making sure that for research purposes, we have appropriate access to data, information to conduct that research.Harry Glorikian: Yeah. I want to get into, you know, I think we're going to, I'm going to hit on some of that later, but I just want to make sure everybody's sort of on a level playing field with some of these wonky terms we use. How do you define real-world data and real-world evidence. I mean, I know what the FDA defines it as. I'm just curious. Jeff Elton: Yeah. So yeah. And FDA does have some, they have some publications really there that came out at the end of 2018 that actually began to lay out a framework around that, which I would encourage folks to reference. It's actually a very well-written document.So real-world data is sort of what it sounds like. It's the data. Right. And You know, if you were a clinician, if you were sitting in a clinical care environment, you probably wouldn't be using the word real-world data because those are the data generated through your treatment of the patient. So clinicians sometimes actually kind of pause for a moment to say, what's real-world? It's the things I'm doing. And in fact, you know, real-world data would be structured data in a structured field. It's a lab value that may have come in from the laboratory information system or a drop down menu. Did they smoke or not? Which can be a fixed field in an EMR. All the way over to physician notes, to appended molecular diagnostic reports, to imaging interpretation reports.So all those are forms of data. Now, evidence is a little bit about also what it would sound like. Data are not evidence. You have to actually, and in fact, to generate evidence, I want to have to trust the data. I have to believe those data are an accurate reflection of the source systems they came from. I have to believe they're representative or appropriate for the question that I'm actually trying to address. And then I have to make sure that the methodologies I'm using to analyze something, either comparing the effectiveness of two drugs relative to each other, actually then when I look at that analysis, I'm willing to either make a regulatory decision or a guideline modification.And the intent of evidence is either to support a regulatory decision or something that can inform practice of medicine or nature of treatment. So there's a bar, right, that one has to achieve to actually become evidence. But I think evidence is the right goal by what we're trying to do.Harry Glorikian: So you know, in the past, I mean, because I've, worked with companies like Evidation Health and so forth right there, some of this data was in paper form, right. Not in electronic form. So, what holes in the current system of, say, drug development would better real-world data or real world evidence help fill or, or drive forward.Jeff Elton: Yeah, that's a super good question. And, you know, Harry, you were kind of going back to your, I mean, you were one of the primary, leading individuals around that when the days of personalized and individualized and precision medicine, and even some of molecular medicine kind of came around. In fact, that's probably where you are my first point of interaction.And I come back to that concept because when you, when you're looking at data—and again, not all data are kind of created equal here—when I think about setting up and designing a clinical study, so now I'm with an experimental therapeutic or I'm thinking about moving it in. If it worked in one solid tumor and I suspect that same molecular pathway or kind of disease mechanism may be at work in another one. And so I want to kind of think about doing a pan tumor strategy or something of that nature. When I actually, when I, if I can bring together molecular diagnostic information, aspects of the individual patients, but do it at scale and understand the homogeneity, the heterogeneity and the different characteristics in there, I can design my trials differently and I can make my trials more precise. And the more precise the trials are, the higher the likelihood that I'm going to get meaningful outcomes. The outcomes here that are meaningful is what actually helps medicines progress. It's actually getting those questions to be as narrow and as precise and as declarative in their outcomes as possible.And so a lot of these data can actually be used to help guide that study design. Now, if I also have very rare cancers or very rare diseases—so this would apply even outside of oncology, although most of our work is oncology related—even if I'm outside of that, if I'm in very rare, oftentimes finding, you know, putting a patient on a  standard of care therapy as a control oftentimes may not be in the patient's best interests. And so this notion of either a single arm or having an external control or having a real-world evidence support package, as part of that, may be part of what can occur between the sponsor and actually the FDA, et cetera, for kind of moving that through.But, you know, this has to be done individually around the individual program and the program and the characteristics have to kind of merit that, but these are big deals. So we feel that these are forms of data that can complement what would have been traditional legacy approaches to give more confidence in the decisions being made in the evaluation, the ones actually coming, too.Harry Glorikian: Yeah, I can hardly wait. I mean, maybe it's a dream, but I can hardly wait until we get rid of first-line and second-line and we just say, okay, look, here's a battery of assays or whatever. This is what you should be taking. No more first line or second line. I mean, these are sort of in my mind, I mean, almost arcane concepts from, because we didn't have the tools in the past and now we're starting to move in that direction.Jeff Elton: Yeah. So, Harry, just to, maybe to build on that a little bit. So if you look at some of our publications and things that we presented at this last ASCO, there's work one can do when you look at different features of patient response, et cetera. We're a company, but we also have a very strong data science backbone to what we do. And AI and ML applications. There are features that sometimes you can predict metastatic status. You can predict rate of response. You can predict progression. Now the very fact that I can make that statement kind of indicates that as you started thinking about the paradigm in the future, particularly when I start doing it liquid tumor, biopsies and surveillance mechanisms where I can see response much more rapidly in less invasive ways, you are going to start even over the course of this next five years, I think some of these will start to start influencing practice patterns in some very positive ways for patients, Harry.Harry Glorikian: From your lips to his or her ears. It needs to move faster. But, but it's interesting, right? I feel like you've been on this path for quite some time, like, I want to say since you're at least since your book in 2016, if not before. Jeff Elton: Yeah. So, you know yeah, you and I, in fact, you and I interacted first, I think we were kind of in the hallways, first interaction of what had been the Necco candy factory on Massachusetts Avenue in the Novartis building, where I was working in the Novartis Institute for Biomedical Research at the time.And Even prior to that, I think I did my first work back in the days of Millennium Pharmaceutical when it was still a standalone company, doing work in precision medicine and personalized medicine all the way through. And obviously Novartis's strategy was looking at pathway biology and actually using that as the basis of actually understanding where in a pathway system one could actually target and actually understanding that it is a system, it's got redundancy both in a bad, in a positive way. How do we use it to progress new medicines? So there's been an aspect of this that's always been kind of a little bit hard. I think I kind of made a decision to kind of pivot much more to a large scale data-centric, insight-technology-centric approach, and actually at scale, bring some of that back to the biomedical innovators. But yeah, it's been a progression over time and some of this it's a field that I feel, you know, strong passion around and will stay committed to for the duration of whatever my professional career looks like.Harry Glorikian: So can you give us maybe an example? I mean, I know some of it may be confidential. How does the data that you're providing, say, improve maybe drug safety or effectiveness? Jeff Elton: So you know, we're doing a project right now that that's safety related and I'll kind of try to keep it such that it I'm not betraying anybody's confidence. Eventually this will be in a publication, but it's not at the point yet. We're looking at a subpopulation that had severe adverse events, cardiac adverse events in the population. And originally the hypothesis was, it was a relatively homogeneous group. And we brought together some of our deepest clinical data, which means we have many different features of intermediate measures of disease, recurrence, progression, response, adverse events, severe adverse events. And we also brought some of our data science and AI solutions to it. And one of the major insights that came out of that is actually it wasn't a single homogeneous group. One group was characterized by having a series of co-morbidities that then linked to this significant adverse event and the other were purely immunological based.And so therefore actually in both cases, they're screenable, they're predictable. They're surveillable. And monitorable. And so therefore, but the actions would be very different if you didn't know what the two groups are. So in this particular case, we could discriminate that now. Well, we'll take that into more classical biostatistical analysis and do some confirmatory work on that, but that has significant implications on how you're going to kind of screen a patient survey of patients, look for whether or not they exhibit that area, and how you would kind of handle it, manage that. That would improve the outcome significantly of that subpopulation.So that's one example. In other areas, some of our data was actually being used as part of a regulatory submission. It was a very, very rare population in lung cancer. And it was unclear exactly how nonresponsive they were to the full range of current standard of care. And we were actually illustrating that there was almost a complete non-response to all current medicines that were actually used against this particular molecular target because of a sub mutation. And that actually was part of the regulatory submission. And that program both actually got breakthrough designation status, and that actually supported that and actually got an approval ahead of the PDUFA date. So when you start pulling some of these pieces together, they work to again, provide more confidence and interpretation and more confidence in decision-making. And in this particular case, certainly accelerated medicines being available to patients. Harry Glorikian: Oh yeah. Yeah. Drive value for patients and drive value for the people that are using the, the capability to get the product through. So, you know, we're talking about data, data, data. At some point, you've got to turn this into a product or a service of some sort or, or some, or maybe a SaaS as, as, as you guys might look at it, but you've got something called, you know, Eureka Health, right, in your product lineup. Can you give us an idea of what that is? I think it's a cloud-based SaaS product. You call it research-ready real-world data. So I'm just curious how that works. Jeff Elton: Yeah. So we do think.. So if you think about what we're trying to do, we're trying to allow a level of scale and a level of precision and depth on demand in the hands of individual researchers, from translational scientists, folks in clinical development, post-approval medical value and access. Kind of in that domain. And so each of those have different use cases. Each of those have different kind of demands that they'll place on data and technology for kind of doing that.We're trying to move away from the world of bespokeness, because by nature of bespokeness, the question has its own orientation. The data is just unique to the question and that utility later is very low and, you know, in a way, what we'd rather do, what have we learned about what actually kind of create utility out of data, and let's make sure that we're covering the use cases of interest, but let's do it at very large scale. And that scale itself and the data we even represent at that very large scale is in itself representative and actually has significance whether it's on a prevalence basis of sub cohorts of disease or not. Now, the reason why I'm spending so much time developing that is when you put that in the hands of the right people, you're avoiding bias, but you're also giving utility at the same time and so you're actually improving their ability to conduct rapid question interrogation, but also structure really good research questions and have the discipline if I have a good research methods right around that. So we do structure those as products.And so, so actually one of the things we think of is, the work that we do in non-small cell lung cancer is an extremely large data set. It also has high depth on the molecular basis of non-small cell lung cancer. And it's created in a way that actually allows you to make those questions from translational through post-approval medical and doing that.Eureka is the technical environment. It is a cloud environment we are working in, and it actually allows you to do on-the-fly actually insights. So, outcome curves, which are called Kaplan-Meier and a few other measures. I can compare groups. I can compare cohorts. I can ask questions. It's actually exceptionally fast.And so this ability to navigate through a series of questions, its ability to make comparisons of alternative groups of patients on different classes of questions and finally get down to the patient cohort of interest that you may want to move into in the next phase, your research is done a lot faster. Now we took that, and now we're integrating more AI and ML into that. So we now have created probably what's one of the leading solutions for doing clinical study design. So we can optimize different features of that study design. We can actually release lab values. We can change parameters. There's a level of kind of fitness, ECOG scoring. We can actually modify that and show what the changes would be in the addressable patient population, and actually optimize that study design all the way down to the base activity level. And we're basically creating a digital object that's rooted on huge amounts of data. Underneath the 4.5 million records runs inside that particular area.There is no other solution in oncology, hematology that gets anywhere to that depth of information that can reflect, with different optimization, to the endpoint and even reflect statistical power. Now we're integrating in work around health disparities. How do you assure that if it's a disease like multiple myeloma, which may disproportionately affect black Americans, that I'm actually getting adequate representation of the groups that in fact, actually may be afflicted by the disease and actually assure the design of the study itself assures their representativeness actually in that work?Harry Glorikian: This dataset, what are some of the features of it? What is it? What sort of information does it have in it that you would be pulling from? Because my brain is like going on all sorts of levels that you would pull from, and some of it is incredibly messy.Jeff Elton: Yeah. So you are absolutely right. And so there have been expressions in the field of people who do work in real-world data that the real world's messy you know, fields may be empty. Do you know, as an empty field, because nothing got put there where's the empty field, because in that electronic medical record environment empty means it was not true of the state of the patient. That may sound like a nuanced thing, but sometimes empty actually is a value and sometimes empty is empty. And so you start getting into some things like that, which you start thinking about, like, those are pretty nuanced questions, but they all have to do with, if you don't know which it is, you don't know how to treat and move the data through.So back to your question here a little bit. What we actually, the sources of where we bring data from are portions of a clinical record. So, you know, we work under businesses, the work we do is either research- or quality-of-care-focused. And so, you know, we work actually, whether it's with the American Society of Clinical Oncology and et cetera, appropriately under all HIPAA guidelines and rules for how you interact with data around doing that. So I'll put that as a caveat because methods and how you do that security and everything else is super, super important. We have a clinical workforce. These are all credentialed people. Most of them have active clinical credentials. Most of them were in the clinic 10 to 15 years and even still interact on it. So a lot of my people feel they're still in clinical care. It's just happens to be a digital representation pf the individuals that are in there. And we're seeing, whether it's features of notes, depth of the molecular diagnostic information, radiologically acquired images that may show how the tumor progressed, regressed, et cetera, that's in there, any other, the medications, prior treatment history, comorbidities that may confound, actually, response. So all those different features are brought together, but if you don't bring it together consistently, we have tens of thousands of lines of business rules, concepts, and models that we try to publish around about how you bring a concept forward.So if you want to bring a concept forward, want to do it consistently, we come out of 10 different electronic medical record environments, and we're, we're actually interacting with the work of 1,100 medical oncologists and hematologists, et cetera. You have a lot of heterogeneity. Handle that heterogeneity with a clinical informatics team into a set of rules as it's coming forward so that everything comes to the point that you can have confidence in that, you know, in that particular analysis and that presentation.So there's something called abstraction, which is a term applied to unstructured data—and unstructured just means a machine can't read it on the fly. And so we're actually interacting with that, which could have a PDF document or something else. And from that, we use the business rules to then develop something that now is machine-readable, but actually has a definition behind it that one can trust, that one can, that kind of comes from some published basis about why did you create that variable? So I could measure outcomes of interest progression-free survival, adverse events, severe, whatever the feature of interests can. Help me answer the question we try to kind of bring through. So we're usually creating about 120 unique variables that never would have been  machine-readable, in addition to the hundred, that probably were machine-readable when we bring that together. Harry Glorikian: So you're using a rule-based AI system, maybe not just a straight natural language processing system, to parse the words.Jeff Elton: Yeah. So natural language processing gets a little tricky. We do. We have, actually, excellent natural language processing. We'll sometimes use that for pre-processing, but you have to be careful with natural language processing. If it has context sensitivity, and if you're parsing for sets of reliable terms, it can actually be relatively accurate. If I'm doing something like a laboratory report that's so discreet, so finite, and it's so finite with how many alternatives you have with the same concept, it works really well. When you start getting into things that are much more nuanced, you actually start to have a combination of technology with the expert humans to actually have confidence in the ultimate outcome.Now we do have some very sophisticated AI models. Like I'll give you an example. When you're looking at a medical record, usually metastatic status has just done a point of first but diagnosis in cancer care. So if the patient actually progressed and they made through there that they don't update the electronic medical record because they want to maintain what the starting point was when therapy was administered.But a biomedical researcher wants to know it at a point in time. So we have models that can literally read the record and bring back that status at any point in the time of disease progression. Now, would that work up to the grade of, say, for regulatory submission? No, but for a rapid analysis to pull back your question of interest and have it done in minutes, as opposed to weeks or months it works exceptionally well.Harry Glorikian: Understood. Understood. So now you and I both know that clinical trials, you know, are available only to a certain portion of the population really participate for  a whole bunch of reasons. And then if you go down to sort of, you know, equality or, or across, you know, the socioeconomic scale, it, it gets even, it gets pretty thin, right? You guys, I, I think you've been pushing around inequality and cancer care and you have this program called ERACE which I think stands for Engaging Research to Achieve Clinical Care Equality. So help me out here. What is that? Jeff Elton: So we are, as an organization we're super privileged to have a very, very diverse workforce. And you know, men, women all forms of background races, ethnicities, and we really value that. And we've tried very hard to build that in our scientific committee. And I think when the public discourse around kind of equity, diversity, inclusiveness came forward, and you know, as you know, Harry, this has been a unprecedented period of time for just about anything, any of us. I mean, COVID-19 and social issues. You know, things of that nature. It's, it's really been a very, very unprecedented time in terms of how we work and how we interact and the questions.Our organization and our scientists actually came forward to me and said, you know Jeff, we have a tremendous amount of data. We have partners like American Society of Clinical Oncology and some of the leading biopharmaceutical researchers in the world. And we've got technology, et cetera. We want relevance. We really want what to make contributions back and we believe that actually, we can do some research that no one else can do. And we can actually begin to deliver insights that no one has the capability to do. Would you kind of support us in doing that? And so we put together the ERACE program and it actually was named by a couple of our internal scientists.And the program actually now is being collaboratively done. We've done a couple of webinars, with you know, some of our partners and that's included, you know, folks from, whether it's AstraZeneca, Janssen, and BMS, et cetera. It's become something around, how can we rethink how research takes place and actually assure its representativeness for all groups, but particularly in specific diseases. It impacts different groups differently. And so can we make sure it reflects that? Would we be generating the evidence so that they can in fact be appropriate beneficiaries earlier? And a lot of this came from when we looked at aspects of diagnostic activity we could say that, you know, black American women have a higher incidence of triple negative breast cancer and a few other diseases. When we look at patterns of diagnosis and activity, unfortunately, the evidence that we even have is not substantially in the practice of what we're actually seeing sometimes when we begin reviewing our data. And so we began confederating through our own work. We now have actually set up research funding. So we actually now will fund researchers who come in the academic community. If they come up with research proposals that have to do with, you know, health related disparities, whether it's economically based, or if it's racial, ethnically based. Those questions. We've got an external review board on those proposals. We'll provide them data technology and financial support to get that research done. We're doing it with our own group and we're doing it collaboratively with our own kind of biopharma sponsor partners kind of as well. So for us right now, it's about confederating an ecosystem, it's about building it into the fabric about how research questions are framed, research is conducted, clinical trials are conducted, and then actually those insights put into clinical practice for the benefit of all those groups. And so, you know, it's even changing where we get our data from now. So it's, it's like an integral part of how of everything we do. Harry Glorikian: So you saw, I don't want to say an immediate benefit, fooking at it this way or bringing this on, but I mean, you must have seen within a short period of time, the benefit of, of, I don't want to say broadening the lens, but I can't think of a better way to frame it. Jeff Elton: We were surprised how quickly, whether it was academic groups or others, rallied around some of the concepts and the notions. And we were surprised how quickly we were able to make progress in some of our own research questions. And we were pleased and astonished, only in the best ways, that we saw industry and biomedical research, the whole biomedical community, attempting to integrate into their research and the questions that they asked actually different ways of approaching that.And in fact, it's probably one of the most heartening areas. You couldn't have legislated this as quickly as I believe leading industry biomedical innovators decided it was time to kind of change portions of the research model. And you made a, Harry, you made a statement earlier on that. It's not just about kind of us analyzing data. Sometimes bow you find that to broaden actual, say, clinical trial participation, I actually have to go to sites that historically didn't conduct clinical trials. I may need to have investigators that are trusted, because some of the populations we may want to interact with don't trust clinical research and have a long history about why they didn't trust clinical research.So you're changing a social paradigm. You're changing research locations and capacity and capability for that research. So we're now moving research capacity out into community settings in specific communities with this idea that we actually, we actually need to bring the infrastructure to the people and not assume again, that people want to kind of go to where the research historically was conducted because that wasn't working before, you know? Harry Glorikian: At some point, you turn the crank enough, you start to influence, you should be able to influence, you know, standard of care and all that stuff, because if you're missing data in different places, you've got to make sure that we fill these holes. Otherwise we're never going to be able to diagnose and then treat appropriately.Jeff Elton: Generate the evidence that supports actually doing that and do it on an accelerated basis, but also that it gets confidence for those decisions. Absolutely. That's part of our goal. Harry Glorikian: Yeah. So I want to jump back in time here and sort of go back to your your Healthcare Disrupted book. You know, I feel like, you know, we're on the same page because I think the message was, you know, pharma, devices, diagnostics, healthcare, they need to rethink their business model to respond to this digital transformation, you know, which is obviously something in my own heart. I've been sort of banging that drum for quite some time.In particular, you argued in the book that real-world data from EMRs, wearables, the Internet of Things could be combined to change how and where healthcare is delivered. Is there a way in which like Concert AI's mission reflects the message of your book? Can I make that leap?Jeff Elton: I appreciate the way you asked the question and I think if you said our principles and perspectives about that, we need to kind of focus on value and outcomes, and then we're going to be bringing insights, digital cloud, and a variety of other tools to underpin how we work and operate. Absolutely.And in fact, I think, you know, positively. I had a lot of engagement and did a lot of interviews, even as we were putting the book together, which took place over a couple of months ago, it was probably, you've done your own books. Whatever you think it's going to be, it's a lot longer. So I'll leave it at that. I have recovered from the process now, but I think we had a lot of engagement, whether it was with medical community, biopharma, leadership, community, et cetera. And I think that alignment is some of the alignment we have with our partners today. It's actually around some of the same principles.What I couldn't have predicted, in fact, I was a couple of years ago and this probably would have been towards the tail end of 2019, I was already starting to think about, okay, I've recovered from the first writing. How did I do? And what would I say now? And at the time I was beginning to say certain things seem to be taking shape slightly more slowly than I originally forecast, but then COVID-19 happened. And all of a sudden certain things that we kind of had thought about and kind of had put there actually accelerated. And in fact, I think, you know, out of adversity, you'd like to say we bring sources of strength we didn't know we would kind of be beneficiaries of. But out of that, you could argue this concept of say a decentralized trial activity.So we have, let me pick up, you know, I'm one company, but let me pick a parallel company that I have respect for, say, Medable as an example, and Michelle [Longmire] leads that company, it does a very nice job, but that's the idea. Everything could be done remotely. I can actually do a device cloud around the individual. I can do a data collection and run RCT-grade trial activity. Now that doesn't work super well in oncology, hematology, et cetera, where I'm, you know, I'm doing chemo infusion and I have to do very close surveillance, but that concept is an accelerated version and got broader adoption and actually was part of some of the COVID-19 kind of clinical studies and capability. And it's not going to revert back. So actually what happens is you find it has a level of efficiency, a level of effectiveness and a level of inclusiveness that wasn't available before, when it had to do facilities-based only. Now we ourselves now we're asked to accelerate, we bring technologies and integrate them into provider settings for doing retrospective analysis. But actually during that period, not only did we bring our clinical study design tools and use AI and ML for doing that, which led to, we've supported the restart of many oncology studies now, and actually the redesign of studies to be able to move into different settings that they never were in before.And actually now we're beginning to use some of our same approaches for running prospective studies, but from clinically only derived data sources. It's a very different paradigm about how you conduct clinical research. So when you think about this, there are unpredictable shocks, you know, which, you know, some of may have called Black Swan events or whatever you may ascribe to it, that actually are now consistent with everything we did. But actually accelerating it and in a weird way back on trajectory, if you will. But I think, yes, everything we're doing was informed by a lot of that seminal work and research and foundation about what worked in health system and didn't how are people being beneficiaries or not? How do we need to change how we do discovery translational clinical development? And we're very committed to doing that. Harry Glorikian: Yeah. I mean, it's interesting cause you almost answer my next two questions. I'm really hoping it doesn't slide backwards. That's one of my biggest fears is, you know, people like to revert back to what they were used to.Jeff Elton: But you know, maybe to encourage you and me. So one of the things, if you take a, let's take a look at a teleconsult. So during COVID-19, HHS opened up and allowed as a coded event, doing a digital teleconsult for kind of digital medicine, telemedicine, and that was put into place on an emergency basis by HHS. And then before the outgoing HHS had that, it's now made permanent. And it's now part of the code that actually will continue to actually be a reimbursable event for clinicians. That was actually super important during COVID-19. What's not that well known is, not only did that allow people to be seen, but hospital systems were really financially distressed because most of their work was informed by kind of, you know, elective procedures and things of that nature. And that couldn't take place. But the teleconsult became a very important part of their even having economic viability, which you can't underestimate the importance of that during a pandemic. Right. So now that's part of how we're going to work. My personal view is, now that people are using digitally screening tools, they have decentralized trials, some of the solutions that we're putting into place, AI-based, bringing RWE as part of a regulatory submission, I don't see anything going back. And the work we're doing is if we can start putting 30 to 50% time and cost improvements and add more evidence around a decision, more robustly than we did before, that's not going backwards at all.Harry Glorikian: Good. That's that makes me. I'm hoping that we're all right, because we've been saying this and beating this drum for quite some time.It's interesting, right? Because I don't think I've gotten over the whole writing thing because I've got a new book coming out in the fall. So you know, I, I couldn't help myself. I hope, you know, we. We're able to give the listeners sort of a view of where this whole world is changing, how data's changing it.I mean, I've had the pleasure of talking to people about digital twins and that sort of data. And I believe that this, we're gonna be able to make predictions, as you say off this data almost proactively. It's interesting because I do talk to some people who are in the field that look at me strange when I say that, but after working with different forms of data in different places for so long, I can see how you can look at things predictively and sort of, you know, decide what's, you know, see what's going to happen almost before it happens for the most part, if you have a big enough data set. Jeff Elton: So we do a lot of prediction thing in the AI and ML world. And we predict, you can actually be relatively accurate on who's going to adhere and not adhere. You can begin to look at the biological response to being placed on a new therapy and understand whether that response is kind of in a direction that, that patient's going to remain on that therapy, or you need to discontinue to be placed on a new therapy.And you're right. And in fact, some of these features…well, the question, we use it from generating insights to design and hopefully improve outcomes, et cetera. That's a rapid process. I mean, I've seen things in the last three years in setting up Concert AI that would have taken me a decade to have seen in previous methods. But we're still not as fast and as effective as we can be.And the very fact that I can in my digital laboratory, if you will, create AI/ML to predict whether that patient is going to be discontinued or continue on to that course of therapy. Some of that needs to be brought into confidence tools that can start to inform parts of practice as well. They're not ready for that. They have to ascend to that. But when you look at these, some of these, whether it's coming in as software, as a medical device, sets and solutions to augment, are going to add a huge, huge amount of utility. And you're finding a lot of interest, even biomedical innovators are looking for predictive tools, too, complement their medicines.And you know, we're doing a couple of things that would be definitely considered in a more confidential area around doing that right now. And I have to tell you I've been so pleased and it's just for me, it's so, so catalyzing of our energy to be brought into this, to see people willing to reshape the paradigm about how they do things that actually will reshape how medicine's delivered and care provided too. Harry Glorikian: Oh yeah. I mean, look, ideally, right, I think every physician wants to give the patient the optimal therapy. Not pick the wrong one and have to redo it again. But, but I think a lot of these tools are also gonna lend themselves to adjudication.Jeff Elton: Absolutely. Harry Glorikian: Right? And that is a huge paradigm shift for everybody to wrap their head around. And I think we're going to get pushback from some people, but I can't see how you don't end up there at some point. You can see where it's going. You know, what's going to work, here's the drug. And if it doesn't work, here's the data to show [why] it didn't work.Jeff Elton: Well, and actually and Harry, to your point, right now you're thinking about how payers authorized the treatment that's proposed by our clinician for super expensive medicines. Right? But if I'm an oncology, I can tell you right now that claims data as a single data source can't tell you much about whether that patient responds, whether they're being treated according to NCCN ASCO guidelines or not. So you're wondering what's the basis of that. Whereas I can actually look at the data and I can understand how that patient presents and I can see what's actually the intended treatment. And you can immediately say that perfectly makes sense, given how everything's matched up and I can continue to kind of say what that response is it consistent with what I would have hoped for placed in that patient on that specific treatment. So to your point, this is going to change all sorts of things.Harry Glorikian: I love it when it changes on that level, it just makes me all happy inside. So, Jeff, it was great catching up with you. I hope when this pandemic is open, we can get together in person and you know, have a beer. Maybe we'll even bring Arshad because I think he's been working in this whole data area with a number of companies for a while now. Jeff Elton: Yeah. Would love it.Harry Glorikian: Excellent. Jeff Elton: All right. Harry Glorikian: Thank you.Jeff Elton: Thank you too.Harry Glorikian: That's it for this week's show. You can find past episodes of MoneyBall Medicine at my website, glorikian.com, under the tab “Podcast.” And you can follow me on Twitter at hglorikian.  Thanks for listening, and we'll be back soon with our next interview. 

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021.    Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10.  The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS).  While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients.  “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.”     Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude   Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.”   Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).”   Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors."   Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers.   Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

Dr. Stephen Liu, associate professor of medicine and director of Thoracic Oncology and Developmental Therapeutics at the Georgetown Lombardi Comprehensive Cancer Center, highlights key abstracts in lung cancer featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Stephen Liu. He is an associate professor of medicine and the director of thoracic oncology and developmental therapeutics at the Georgetown Lombardi Comprehensive Cancer Center. Dr. Liu joins me to highlight advances in lung cancer featured at the 2021 ASCO Annual Meeting. Dr. Liu has served in a consulting or advisory role for Genentech, Pfizer, and AstraZeneca, among other organizations. His full disclosures and those relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Liu, it's great to have you on the podcast today. Dr. Stephen Liu: Thanks for having me. ASCO Daily News: Dr. Liu, a lot of people were talking about the IMpower010 study during the annual meeting. That's abstract 8500, an interim analysis that showed really promising results for patients with resected non-small cell lung cancer. Can you tell us about this practice-changing study? Dr. Stephen Liu: Well, IMpower010 was a global randomized phase III trial, and I think this really was one of the highlights of the ASCO Annual Meeting from a lung cancer standpoint. As a reminder, our current standard of care is cisplatin-based chemotherapy for patients with resected stage II to III non-small cell lung cancer and for select patients with stage IB. We know from decades of experienced multiple phase III trials, large meta-analyses, that the risk of recurrence is quite high for resected stage II/III lung cancer. And the use of up to four cycles of cisplatin-based chemotherapy does lead to an improvement in survival, and that's our standard of care. That survival improvement, however, is modest, with an absolute improvement and 5-year survival of about 5%. And so we've been trying to improve outcomes in this setting for quite some time. We know from last year's ASCO that the subset of patients whose tumor harbors an EGFR mutation received some benefit from disease-free survival with the use of adjuvant osimertinib. IMpower010 presented at this year's ASCO by Dr. Heather Wakelee looks at the use of immunotherapy as a complementary adjuvant therapy. And we knew from press release that this study had met its primary endpoint. This was our first chance to look at the data first-hand and really see how it would impact practice. And I think the data were quite impressive. It's a fairly simple design. This study included patients with completely resected stage IB to IIIA non-small cell lung cancer, either histology. Note that this used AJCC version 7, and so the stage IB that were included had a size of at least four centimeters, and that's the subset that seems to derive the most benefit from chemotherapy. Now patients received cisplatin-based chemotherapy one to four cycles first. And those who received at least one cycle of chemotherapy were then randomly assigned 1 to 1 to receive 1 year of atezolizumab, PD-L1 inhibitor, or best supportive care. This was a large study, over 1,000 patients randomly assigned. It began enrollment in 2014. So it did include some EGFR and some ALK when maybe we didn't know quite as much about including those patients in these studies, but the EGFR was about 12%, the ALK was 3%. Some were unknown EGFR and ALK status, but these were likely the squamous histology, as those numbers line up. The PD-L1 testing, importantly, was done by the VENTANA SP263 assay, looking at tumor cell expression only, which is a fairly straightforward assay. And what we saw after a median follow up of almost 3 years was that in the primary high-risk population stage II to IIIA resected non-small cell lung cancer with the PD-L1 expression of at least 1%, the use of adjuvant atezolizumab significantly improved disease-free survival. And the hazard ratio there was 0.66. If we look at the 2-year disease-free survival (DFS) rate, it improved from 61% with best supportive care to 75%, and at 3-year DFS from 48% to 60%. So an improvement in the 3-year DFS rate and a hazard ratio of 0.66. The fourth plot showed that signal was greater in node-positive. As expected, no signal in that ALK subset, though it was small. But this is a pretty substantial improvement in disease-free survival. When we look at these Kaplan-Meier curves, they split immediately, really right at the first scan. And when we look at a study like this, this phase III trial, it reminds us how poor our current standard is; how many patients do suffer relapse and recurrence and death from this potentially curable cancer. Atezolizumab clearly improving outcomes in this subset. We then saw analyses of the resected stage II to III across PD-L1 strata, so positive and negative. And there the hazard ratio, as expected, less impressive, 0.79. If we look at the forest plot there, the hazard ratio for PD-L1 high, using that 50% cutoff we're used to, was substantial at 0.43. So overall, the DFS and PD-L1 positive 0.66 and the PD-L1 high 0.43. So no report on the PD-L1 low, which is what we're waiting for, that one at 49%, presumably not as impressive as 0.66. And we'll wait for those data to come out. But PD-L1 positive, a clear benefit. PD-L1 high, a substantial benefit. That's really where the formal analyses stopped. The stage IB to IIIA overall population was too immature for analysis, and overall survival was not yet formally tested. This will take a few years to breathe out. They did provide an early look at overall survival. And in that stage II to IIIA PD-L1 positive, there was the right trend, with a hazard ratio of 0.77, though not statistically significant. We did see these curves start to come apart at about 12 to 18 months, which is what you would expect if this study ultimately would lead out to be positive. We do want to wait for OS results. But one has to wonder, is a DFS benefit this substantial enough to change practice? And atezolizumab not yet approved in this setting, but the trial did meet its primary endpoint. And to me, for PD-L1 positive, and certainly for PD-L1 high, I do think these data aren't practice- changing. ASCO Daily News: Absolutely. Well, another trial that attracted a lot of attention was the CheckMate-816 trial. That's Abstract 8503. What can you tell us about the surgical outcome data reported in CheckMate-816? Dr. Stephen Liu: So CheckMate- 816 was a randomized phase III trial that looked at neoadjuvant therapy. So this also focused on resectable lung cancer. This is an area where we hope for cure, but for some of the more advanced stages, we don't necessarily expect it. Much room for improvement. We saw the IMpower010 data showing adjuvant immunotherapy improved DFS. Here we're looking at the neoadjuvant space. And at AACR in 2021, Dr. Patrick Forde presented some of the early PCR results. And that showed the pathologic complete response rates with neoadjuvant nivolumab plus chemotherapy for three cycles was superior to chemotherapy alone for three cycles. So the addition of nivolumab to chemotherapy improved the pathological CR rate from 2% to 24%. Really astounding. What Dr. Jonathan Spicer presented at ASCO 2021 were the surgical outcomes from that study. And we see that adding immunotherapy to chemotherapy significantly improves the pathologic CR rate. Does it come at a cost? Does it lead to more surgical complications? This is always a concern with neoadjuvant therapies. We've got someone in our clinic with a resectable lung cancer. If we mismanage that patient, we may lose the window for resection. So we always worry about delayed surgeries, canceled surgeries, more complicated surgeries. There have anecdotally been reports of increased perihilar fibrosis after neoadjuvant immunotherapy. Wouldn't that lead to longer, more complicated surgeries? And what we saw, frankly, was a bit surprising, for me. Surgery consistently easier, better in the experimental arm really across the board. The rates of going to surgery, completing surgery, 83% with nivolumab/chemotherapy, versus 75% with chemotherapy. So more patients going to surgery, fewer canceled surgeries. If we look at the type of surgery, minimally invasive surgery rates 30% with nivolumab/chemotherapy, [and] 22% with chemotherapy alone. Conversion to open thoracotomy was more common in the chemotherapy alone at 16%, the additional nivolumab 11%. And the complete R0 resection was achieved in 83% with nivolumab/chemotherapy, 78% with chemotherapy alone. Adverse events delayed surgery in six patients getting nivolumab and chemotherapy. It's important to watch that. But it was nine patients in getting chemotherapy alone. And if we look at the duration of surgery, and certainly there are many confounders in a statistic like this, but the surgery was shorter with nivolumab, certainly not lengthening the surgery. 184 minutes for nivolumab/chemotherapy, 217 [minutes] with chemotherapy alone. So these data are very reassuring to someone with a potentially resectable cancer. And I think that when I take a step back and look, maybe these results do make sense. Maybe this is what I should have expected. If we give a treatment that is more effective, that is a higher response rate, it works better. Those patients are less likely to have progressive disease, and the surgery should be more straightforward if there's less cancer to resect. So the CheckMate-816 surgical data, we've been waiting for this shoe to drop, and it was very reassuring. Perioperative immunotherapy is going to be an important part in the management of stage II/III non-small cell lung cancer in the years to come. Now going forward, we'll need to compare these adjuvant and neoadjuvant approaches and the relative merits of either strategy, but these results, I thought, were very reassuring. ASCO Daily News: Excellent. Well, moving on to the PACIFIC trial, Abstract 8511, this study reported improvements in 5-year overall survival and progression-free survival for unresectable stage III non-small cell lung cancer. What are your takeaways from this study? Dr. Stephen Liu: Sure. The PACIFIC study is a randomized phase III trial that's really set our standard of care for unresectable stage III locally advanced non-small cell lung cancer. This is a group where our standard of care, historically, has been concurrent chemoradiation, with the goal of cure, though, unfortunately, not necessarily the expectation, with recurrence rates quite high. We saw years ago the addition of 1 year of durvalumab improved progression-free survival, then ultimately improved overall survival compared to placebo. This was a fairly straightforward study. It enrolled unresectable stage III non--small cell lung cancer after chemoradiation, who did not have evidence of progression after completing therapy, to receive 1 year of durvalumab or placebo, a 2 to 1 randomization. The results markedly positive, leading to U.S. Food and Drug Administration (FDA) approval and really our new standard of care. These are long-term survival data, and it was presented by Dr. David Spigel. These are really important. Immunotherapy, the whole appeal of the strategy is the durability, the induction of memory T cells, meaningful long-term survival. Will this increase the rate of cure really is what we're going for. And when we saw the survival benefit with durvalumab, we knew that we were curing more patients. Long-term follow up is important to make sure that we don't have late recurrences, that we really are curing and not just delaying a recurrence for some patients. And in this analysis, with a 5-year follow up, we see durvalumab improve the median survival from 29 months with chemoradiation alone to 48 months with the addition of durvalumab. That's a hazard ratio of 0.72, 28% reduction in the risk of death, pretty substantial. That 5-year survival rate was 43% versus 33%. And importantly, these were very similar to the 4-year data that were presented by Dr. Corinne Faivre-Finn at World Conference in Lung Cancer, really very little drop off between year 4 and 5. And we refer to that as flattening of the tail, where the events are early, and at some point, they kind of stop happening. It's really what we want to see. While survival is what we hone in on, in an abstract like this, we also need to pay attention to progression-free survival (PFS). And the PFS rate at 5 years was 33% with durvalumab, versus 19% with chemoradiation alone. So 33% with no evidence of progression at 5 years. And if you are cured from lung cancer, then you can't have progression. So one in the three patients with no progression at 5 years, I think, is very reassuring, that PFS hazard ratio of 0.55. So prior to ASCO21, durvalumab was our standard of care. Now we just have longer term follow up to really solidify that choice. These are important data for patients and families to set expectations right, but our clear standard. Still, though, room for improvement in that 5-year PFS rate of 33%. We would like to see that higher, and ongoing strategies hopefully will help push that up. ASCO Daily News: Excellent. Some great survival data in the PACIFIC trial. Well, Abstract 9007 sparked a lot of interest as well. This is an expansion study of patritumab/deruxtecan in patients with EGFR-mutant non-small cell lung cancer. That's a difficult drug to pronounce, so I'm sure you'll do a better job. What can you tell us about this? Dr. Stephen Liu: Well, yeah, all these antibody drug conjugates do have tricky names, and so they are kind of fun to say. So patritumab/deruxtecan is a HER3 antibody drug conjugate. I suspect it will be better known as HER3-DXd, a little easier off the tongue. This was a study that looked at this agent in patients with EGFR-mutant non--small cell lung cancer after TKI therapy. And when we turn our attention to targeted agents, we have really transformative drugs with very wide therapeutic windows, little toxicity, very high efficacy, [and are] really game changers in patients with driver positive non--small cell lung cancer. But as we know, these treatments aren't cures. And we do expect resistance to osimertinib. The third generation TKI has been pretty heterogeneous. And once patients progress in osimertinib, the next standard therapy really is chemotherapy. And there's a bit of a drop off, with more toxicity, [and] less efficacy overall. So this remains an unmet need. Many studies are looking at different strategies there. We've seen the addition of MET inhibitors if MET is amplified for certain subtypes, RET, BRAF, for example, the addition of the targeted agents. This study, Abstract 9007 presented by Dr. Pasi Janne, looked at the HER3-DXd antibody drug conjugate. So patritumab/deruxtecan has a monoclonal antibody targeting HER3, a proprietary linker, and then a topoisomerase 1 warhead. And this was a phase I study that looked at 57 patients with EGFR-mutant lung cancer after TKI therapy mostly, but 90% were coming off of osimertinib. And what we saw, I thought, was very encouraging. This is a small, early study. These are very selective patients. But the response rate here almost 40%, disease control rate 72%, and the median progression-free survival with monotherapy of patritumab/deruxtecan was 8.2 months. These numbers may change as the studies get larger, but there's a clear signal of efficacy for patients who'd received chemotherapy before and then moved on to patritumab/deruxtecan. The response rate didn't really drop off, 37%. So even those that were more heavily pretreated, we're seeing a clear signal with response rates that really are higher than chemotherapy. What was, I think, most important, we saw efficacy of patritumab/deruxtecan across multiple different mechanisms of resistance. And so it wasn't one biomarker select. It really was active, very versatile agent. And really, I think that's what we need. While biomarker-driven resistance will be something we always hone in on and try to focus, we do need something that's much more versatile for rapid implementation. And this is having a lot of potential. [It was] very well tolerated. If we look at treatment-emergent adverse events, only one person stopped from a TEAE. Only 4% stopped due to TEAEs, so very well tolerated treatment. Response was also durable. One response listed was after 4 years of therapy, and so the potential for long-term disease control, long-term responses. So clearly an active drug. This is an area where we need a lot of drug development. Well tolerated, only 4% stopping due to adverse events and a nice signal of activity. Our next steps will be to make this a larger study to look in more patients to really hone in on the mechanisms and where this really is working. Can we widen that therapeutic index? And can we look at combinations? Is there a role to continue TKI with this, maybe for better CNS coverage or activity? That's what we'll see in the years to come. ASCO Daily News: Excellent. Well I'd like to ask you about a trial that you were involved in, the ARROW trial, Abstract 9089. Can you tell us about this impactful study? Dr. Stephen Liu: Yeah, sure. The ARROW trial is a study that I've been a co-investigator on for many years. This was presented by Dr. Giuseppe Curigliano. And this looks at a RET inhibitor called pralsetinib, originally when we first got involved called BLU-667. RET fusions are present in about 1% of non- small cell lung cancer. These are important events, because we know from other studies, such as the immunotarget registry led by Julien Mazieres,  that RET-positive lung cancers don't seem to respond as well to immunotherapy. However, in the past, the kinase inhibitors, the targeted agents we had the targeted RET, weren't very good. They had response rates around 30%, 40%, a lot of toxicity. These are drugs like vandetanib, cabozantinib. With the introduction of selective RET inhibitors, we've seen striking efficacy and much better tolerability. And we now have two approved RET inhibitors in this space--selpercatinib and pralsetinib--both receiving FDA accelerated approval based on their respective single arm studies. What we saw at ASCO 2021 from Dr. Curigliano was an update on the RET fusion positive lung cohort of ARROW. Again, this was a phase I/II trial looking at pralsetinib given at a dose of 400 milligrams by mouth once daily. We look at the patients with RET fusion-positive lung cancer. Now we just have longer follow up and more patients. And overall, the cohort exceeded 200 patients, so 216 patients for a pretty rare driver. And the response rate, 69%, very durable. The duration of response, 22 months. So really solidifying the efficacy and confirming the role in patients with RET fusion-positive lung cancer. If we break those data down a little bit, patients who had prior chemotherapy, which was 125 patients, response rate was 62%. The disease control rate, 91%. These responses are quick. The median time to responses is 1.8 months, so really that first scan. And that's what we see with targeted therapy. And we look at these waterfall plots, and I encourage you to take a peek at that. It's exactly what we want to see, the vast majority of patients, almost all patients, with some reduction and some with a quite substantial reduction. Again, the disease control rate after chemo was 91%. So really, the waterfall plot has that look that we seek for effective targeted therapy. The outcomes were even better in the first-line setting. Response rate originally 79% as first-line therapy. But the way the trial was originally written, it only included frontline patients who weren't eligible for chemotherapy for whatever reason. So that's going to be a more selective cohort. That was changed with an amendment. And once that was removed for people that were eligible for whatever frontline therapy you wanted to give, really our real world first line cohort, the response rate was 88%, disease control rate of 96%. So to think of a response rate in almost 90% of patients really gives us that confidence we want when we have a driver that we detect when we start a new agent. We're very confident that we're going to see efficacy in these drugs, very well tolerated, very few patients stopping due to a adverse event. A disease control rate of 96% in that first-line setting gives me the confidence to really use this in the first-line setting. ASCO Daily News: Absolutely. Well, as you know, the Annual Meeting this year focused on equity in cancer care. And there were a number of studies presented in the lung cancer space. I just wanted to get your thoughts on how this issue was addressed at the Annual Meeting in the lung cancer setting. I'm thinking of Abstract 9005 that looked at racial disparities. What are your thoughts on this issue? Dr. Stephen Liu: Yeah, this was an important abstract, I think. And the theme that Dr. Lori Pierce set of equity really was met by several different abstracts and was a recurrent focus for many important and really overdue discussions. Abstract 9005 was presented by Dr. Debora Bruno, and this really looked at disparities in biomarker testing. And we just talked about advances for EGFR-mutant lung cancer for RET fusion-positive non--mall cell lung cancer. We have many, many more, but we can only offer these agents if we know the target is present. And if we don't do proper biomarker testing, our care will not be optimal. If we don't know the molecular genotype of the cancer, we can't treat it properly. We are just guessing, and we're much more likely to deliver an ineffective therapy. We are potentially making subsequent therapies more dangerous. Knowing the right biomarker is critical to the proper management of non-small cell lung cancer. And if we don't have that, the outcomes will not be as good. The testing really is critical for the management of lung cancer. And what we saw from this abstract was there are disparities in how patients with non-small cell lung cancer are being tested, which simply isn't acceptable. This was a retrospective analysis that looked at Flatiron data, recent data, 2017 to 2020, a large data set, almost 15,000 patients with non-small cell lung cancer. Demographics were 66% white, 9% Black. If we look at biomarker testing specifically, patients who were Black were less likely to be tested, less likely to have proper biomarker testing, 73% versus 76%, less likely to have full next generation sequencing with a 10% difference, and less likely to get tested early. We know that testing really influences treatment from the jump right away. And if we don't have that information, our outcomes won't be as good. Our Black patients weren't being tested properly, weren't being tested in a timely manner. And more data showed that clinical trial participation was also decreased among Black patients, 4% involvement for white patients, 2% with Black patients. And these were actually very similar to what we saw in Abstract 9001 that was presented by Dr. Akinboro from the FDA. And that looked at patients who'd received chemoimmunotherapy. This was a pooled analysis looking at different PD-L1 cohorts. And what was noted on the demographics is that in the phase III registrational landmark studies, Black patients only represented about 2% of patients there as well. So strikingly similar numbers and a gross under-representation. It really is inexcusable and something we need to address. And we need to correct, because this is showing that our care is simply not up to par.  Trial participation is how we move the field, but many cases, especially in lung cancer, a field that moves so quickly, a clinical trial often represents the best possible option. And Black patients simply aren't enrolling in studies. And I think some of the disparities in clinical trial participation likely reflect some of the disparities in clinical trialists. And I think that if we continue to improve diversity in our workforce, in our oncology subspecialty, that'll be an important step into rectifying this. But this is something we need to look at critically. We need to assess all of our processes and think how we can do better today, and not tomorrow. ASCO Daily News: Absolutely. Thank you so much, Dr. Liu, for highlighting these really critical points and sharing your valuable insight on all of these impactful studies in lung cancer. Thank you so much. Dr. Stephen Liu: My pleasure. Thanks for having me. ASCO Daily News: And thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Stephen Liu Consulting or Advisory Role: Genentech, Pfizer, Lilly, Bristol-Myers Squibb, AstraZeneca, Takeda, Regeneron, G1 Therapeutics, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Inivata, PharmaMar, Daiichi Sankyo/UCB Japan, BeiGene, Amgen, Turning Point Therapeutics, Elevation Oncology, and Novartis Research Funding (institution): Genentech/Roche, Pfizer, Bayer, Merck, AstraZeneca, Blueprint Medicines, Lilly, Rain Therapeutics, Alkermes, Bristol-Myers Squibb, Turning Point Therapeutics, RAPT, Merus, Elevation Oncology, and Erasca, Inc Travel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, and MSD Oncology   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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Oncotarget published this trending research paper on April 13, 2021, entitled, “Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib,” by researchers from the University of Texas MD Anderson Cancer Center, Massachusetts General Hospital, and Harvard Medical School. The majority of circulating insulin–like growth factor (IGF) is synthesized and secreted by the liver, and levels of IGF dramatically decrease in chronic liver disease and HCC. IGF can be a helpful tool to determine the prognosis of patients with advanced HCC while undergoing treatment with sorafenib. Researchers also use the Child-Turcotte-Pugh (CTP) qualitative scoring system to assess severity of liver cirrhosis, hepatic reserve, guide treatment decisions, and to stratify patients with HCC into three groups (A, B, and C). CTP class A has a better prognosis compared to classes B and C. “Assessing liver reserve in HCC is of a great value as a tool for stratification of patients in clinical trials as well as to predict HCC outcome and guide therapy decisions in routine practice.” In the researchers’ prospective study, 171 patients with HCC from the University of Texas MD Anderson Cancer Center were screened and included in this study. Of the patients, 116 were classified in CTP group A. Patient IGF/CTP scores were calculated and the researchers used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. Based on CTP and the IGF/CTP scores, researchers reclassified group A patients into AA and AB risk groups, which differed significantly in terms of OS and PFS. The researchers followed up with all patients in the study until disease progression or death. Unfortunately, during the follow-up period, 100 patients passed away. “After IGF/CTP scoring, 87 of 116 CTP class A patients were reclassified as IGF/CTP-A (AA) and 29 patients were reclassified as IGF/CTP-B (AB).” Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27924 DOI - https://doi.org/10.18632/oncotarget.27924 Full text - https://www.oncotarget.com/article/27924/text/ Correspondence to - Ahmed O. Kaseb - akaseb@mdanderson.org Keywords - IGF-1, Child-Pugh, sorafenib, liver reserve, hepatocellular carcinoma About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

En el caso de remdesivir cada vez existe más evidencia sobre su beneficio en pacientes graves. La revista The New England Journal of Medicine, publica el artículo en noviembre 5 de 2020. Remdesivir para el tratamiento de Covid-19 - Informe final. Donde se mostró que remdesivir fue superior al placebo al acortar el tiempo de recuperación en adultos hospitalizados con Covid-19 grave. RESULTADOS 1-Un total de 1062 pacientes fueron aleatorizados (541 asignados a remdesivir y 521 a placebo). 2-Los que recibieron remdesivir tuvieron una mediana de tiempo de recuperación de 10 días, en comparación con los 15 entre los que recibieron placebo. 3-En un análisis que utilizó un modelo de probabilidades proporcionales encontró que los pacientes que recibieron remdesivir tenían más probabilidades que los que recibieron placebo de tener una mejoría clínica el día 15. 4-Las estimaciones de mortalidad de Kaplan-Meier fueron del 6,7% con remdesivir y del 11,9% con placebo el día 15 y del 11,4% con remdesivir y del 15,2% con placebo el día 29. 5-Se informaron eventos adversos graves en 131 de los 532 pacientes que recibieron remdesivir (24,6%) y en 163 de los 516 pacientes que recibieron placebo (31,6%). CONCLUSION final Los datos muestran que el remdesivir fue superior al placebo al acortar el tiempo de recuperación en adultos que fueron hospitalizados con Covid-19 y tenían evidencia de infección del tracto respiratorio inferior. Como una conclusión personal me gustaría que tengan en cuenta que el remdesivir solo tuvo impacto en disminuir los días de hospitalización y no tuvo el impacto que se esperaría sobre la mortalidad de los pacientes. Comparado con el impacto que tuvo la dexametasona en este caso. Y eso explica probablemente la principal razón del por qué en este momento estemos usando la dexamentasona en los protocolos de atención de paciente COVID hospitalizados y no estemos usando el remdesivir. REFERENCIA https://www.nejm.org/doi/pdf/10.1056/NEJMoa2007764?articleTools=true https://www.nejm.org/doi/full/10.1056/NEJMoa2007764 https://www.fda.gov/news-events/press-announcements/la-fda-aprueba-el-primer-tratamiento-para-el-covid-19 ADAPTACION PARA AUDIO-OYENTES: Medicina en una página. ================================================ PODCAST CORONAVIRUS. COVID-19 Este es un podcast en el que desde el ojo de la ciencia. Aprenderemos del coronavirus y de la enfermedad covid-19. Recuerden al enemigo es mejor conocerlo. Para acabarlo. Esta es una producción de: Medicina en una página. medicinaenunapagina@gmail.com Dirección y Conducción: John Jarbis García Tamayo. Médico y cirujano, Epidemiólogo y Pedagogo Universitario. Portada: Gracias a Sam Balye por compartir su trabajo (foto-portada) en https://unsplash.com/. Música: https://www.youtube.com/audiolibrary/music?nv=1

COVID-19, Fish Oil and AF risk, SGLT2 inhibitors and renal outcomes, and TAVR vs SAVR are the topics discussed by John Mandrola, MD, in this week’s podcast. https://www.medscape.com/twic COVID-19 EMA Launches Review of Clot Risk With AstraZeneca COVID Vaccine https://www.medscape.com/viewarticle/947393 AZ Vaccine Safe Overall but Questions Remain over Unusual Clots https://www.medscape.com/viewarticle/947733 Fish Oil and AF Dose-Related AF Risk With Omega-3 Fatty Acids? https://www.medscape.com/viewarticle/947542 Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation https://jamanetwork.com/journals/jama/fullarticle/2777469 Omega-3 Fatty Acids and Atrial Fibrillation https://jamanetwork.com/journals/jama/fullarticle/2777450 SGLT2i and Renal Outcomes Ertugliflozin: Renal Benefits in Additional VERTIS CV Analyses https://www.medscape.com/viewarticle/947668 Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes https://www.nejm.org/doi/full/10.1056/NEJMoa2004967 Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial https://link.springer.com/article/10.1007/s00125-021-05407-5 TAVR vs SAVR TAVR vs SAVR in Low-Risk Patients: What We Do and Don't Know https://www.medscape.com/viewarticle/946173 Mortality in trials on transcatheter aortic valve implantation versus surgical aortic valve replacement: a pooled meta-analysis of Kaplan-Meier-derived individual patient data https://pubmed.ncbi.nlm.nih.gov/32236543/ Outcomes 2 Years After Transcatheter Aortic Valve Replacement in Patients at Low Surgical Risk https://www.jacc.org/doi/full/10.1016/j.jacc.2020.12.052 Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement https://www.nejm.org/doi/full/10.1056/NEJMoa1910555 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature discussion, actually our whole issue, is going to involve the flozins, empa, dapa, et cetera, but that feature discussion will get some results from the EMPEROR-Reduced trial. Well Carolyn, how about we grab a cup of coffee and this is your area, so we're going to let you run with it today. Dr. Carolyn Lam: Man, and I can't wait to talk about this. Yes, the sodium-glucose cotransporter 2 inhibitors or SGLT2 inhibitors, are indeed now the foundational therapies for patients with heart failure with reduced ejection fraction. Initially developed to improve glucose control in patients with type II diabetes, SGLT2 inhibitors have beneficial cardiovascular and renal effects in patients with diabetes, HFrEF, chronic kidney disease. Well, today's issue contains two pre-specified subgroup analyses from DAPA-HF and EMPEROR-Reduced, both trials evaluating SGLT2 inhibitor effects on renal outcomes, as well as cardiovascular outcomes, by baseline renal function in patients with HFrEF. The first paper comes from Dr. Jhund and colleagues from the University of Glasgow and it is revolving around the DAPA-HF trial. Dr. Greg Hundley: Ah Carolyn, tell us a little bit about DAPA-HF. Dr. Carolyn Lam: Gladly. In DAPA-HF, the SGLT2 inhibitor, dapagliflozin, reduced the incidence of the primary composite outcome of cardiovascular death or worsening heart failure in patients with HFrEF, with and without diabetes and an estimated GFR of greater or equal to 30. Of more than 4,700 patients with a baseline GFR, 41% had a GFR less than 60. The effect of dapagliflozin on the primary and secondary outcomes did not differ by GFR category or examining GFR as a continuous variable. The pre-specified composite renal outcomes, which in DAPA-HF was a more than 50% sustained decline in GFR, end stage renal disease or renal death. Now this composite renal outcome was not reduced by dapagliflozin, but the rate of decline of GFR between days 14 and 720 was less with dapagliflozin. Dr. Greg Hundley: Carolyn, what's the take home message here? Dr. Carolyn Lam: Dapagliflozin slowed the rate of decline in GFR in patients with HFrEF, both in patients with and without diabetes. There was no difference in the efficacy of dapagliflozin by baseline renal function in preventing the risk of cardiovascular death or worsening heart failure. Dr. Greg Hundley: Okay, well now how about the EMPEROR-Reduced trial? Dr. Carolyn Lam: All right. Well, let me remind you first that in EMPEROR-Reduced the SGLT2 inhibitor empagliflozin also reduced cardiovascular death or heart failure hospitalization and total heart failure hospitalization and slowed the progressive decline in kidney function in patients with heart failure with reduced ejection fraction with and without diabetes. Now, more than 3,700 patients were randomized, of whom 53% had chronic kidney disease, defined as a GFR less than 60 or a urinary albumin to creatinine ratio above 300 milligrams per gram. Empagliflozin reduced the primary outcome and total heart failure hospitalizations in patients with and without chronic kidney disease. Empagliflozin also slowed the slope of GFR decline and the risk of the pre-specified composite kidney outcome, now defined as a sustained, profound decline in GFR, chronic dialysis or transplant, was reduced similarly in patients with and without chronic kidney disease. Dr. Carolyn Lam: The effect of empagliflozin on the primary composite outcome of cardiovascular death and heart failure hospitalization, as well as the key secondary outcomes of total heart failure hospitalization and GFR slope, were consistent across the broad range of baseline kidney function measured by clinically relevant GFR subgroups or by albuminuria and including patients with a GFR as low as 20. Above all, empagliflozin was well tolerated in these patients with chronic kidney disease. All of this is discussed in a beautiful editorial by doctors Carnicelli and Robert Mintz. Dr. Carolyn Lam: Now, can I tell you about yet another paper with the SGLT2 inhibitors? This time a pre-specified comparison of the effect of empagliflozin in patients with and without diabetes. Dr. Greg Hundley: Ah, great Carolyn. What did this study find? Dr. Carolyn Lam: Well, this is from Dr. Stefan Anker from Berlin and colleagues, including myself and of the more than 3,700 patients enrolled in EMPEROR-Reduced, 50% had diabetes, 34% had pre-diabetes and 16% had normal glycemia. Empagliflozin reduced the risk of the primary outcome similarly in patients with and without diabetes. Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total heart failure hospitalizations, on the decline in EGFR over time or on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with pre-diabetes or normal glycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome. Empagliflozin also did not lower HbA1c in patients with pre-diabetes or normal glycemia and was not associated therefore with an increased risk of hypoglycemia. Dr. Greg Hundley: Carolyn what's the take home message here? Dr. Carolyn Lam: Well, empagliflozin significantly improved cardiovascular and renal outcomes in patients with HFrEF, independent of baseline diabetes status and across the continuum of HbA1c. Dr. Greg Hundley: Very nice Carolyn. Well, my paper comes from professor Wai Ho Tang and it's a basic science paper. Carolyn, aberrant expression of circular RNA or CircRNA, contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs. In this study, the authors investigated whether CircMAP3K5 could act as a competing endogenous microRNA-22-3p sponge and regulate neointimal hyperplasia. Dr. Carolyn Lam: Wow, that's interesting. And what were the results? Dr. Greg Hundley: Carolyn, the authors identified that CircMAP3K5 is a master regulator of TET2-mediated, vascular smooth muscle differentiation. Targeting CircMAP3K5, microRNA-22-3p and the TET2 axis, may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis as well as atherosclerosis. Dr. Carolyn Lam: Oh, nicely summarized. Thanks Greg. Well, we've got other papers in today's issue. There's an ECG challenge by Dr. Frész on acute coronary syndrome with tall R waves and inverted T waves in the precordial leads, an ignored entity. We have an exchange of letters between Drs. Vandecasteele and Zhao regarding the article, Cardiac Over Expression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure. Dr. Greg Hundley: Thanks Carolyn. I have some Research Letters. The first Research Letter is entitled, “Cardiovascular Toxicities Associated with Loperamide: An Analysis of the World Health Organization Pharmacovigilance Database,” and the corresponding author is Dr. Pierre Ollitrault. The second Research Letter is entitled, “Incessant Pericarditis as a Risk Factor for Complicated Pericarditis and Hospital Admission,” and it comes from Professor Massimo Imazio. And then finally, there's a White Paper (Frontiers) for atrial fibrillation screening research priorities from the NHLBI workshop with the corresponding author being Dr. Emelia Benjamin from Boston University School of Medicine. Well Carolyn, how about we jump in to more SGLT2 and another feature discussion? Dr. Carolyn Lam: Yes, can't wait. Thanks Greg. Dr. Greg Hundley: Well listeners, we're now to our feature discussion and we have with us today, Dr. Milton Packer from Baylor University Heart Vascular Center in Dallas and also our own associate editor, Dr. Justin Ezekowitz from Edmonton. Milton, welcome and wanted to ask you first off, tell us a little bit about the background that got you to want to perform this study. And what hypothesis did you want to address? Dr. Milton Packer: Greg, first of all, I'm delighted to be here with you and Justin. And as everyone knows, SGLT2 inhibitors have had a remarkable track record in trials of type II diabetes, trials of chronic kidney disease and now trials of patients with heart failure and a reduced ejection fraction. And in these trials, SGLT2 inhibitors have had two important benefits. The first benefit has been a reduction in serious heart failure events, primarily a reduction in heart failure hospitalizations. And the second has been a reduction in serious adverse renal outcomes. And that has been now shown consistently in trial after trial in diverse populations. Dr. Milton Packer: Now we carried out a trial called EMPEROR-Reduced with was the trial in patients with heart failure and a reduced ejection fraction. It was a sister study, so to speak, with a very parallel trial called DAPA-HF, which was carried out with dapagliflozin. And both DAPA-HF and EMPEROR-Reduced were studies, were trials of SGLT2 inhibitors, dapagliflozin and empagliflozin in people with heart failure and a reduced ejection fraction. And they produced remarkably consistent results. And specifically a reduction in serious heart failure events and serious adverse renal events. Dr. Milton Packer: But the trial studied complimentary patient populations. We studied patients that were a bit sicker than patients in DAPA-HF. And Greg, what's really fun is that each trial designed its own case report forms so that we collected information that the investigators were really interested in and they were not necessarily the same types of information across the two trials. One of the things that was really interesting about EMPEROR-Reduced was we were really interested in these heart failure events. We wanted to understand them. We wanted to understand whether they occurred as outpatients, inpatients. If they occurred as inpatients, what kind of hospitalizations were these? Were these serious hospitalizations? Were these short term, very mild hospitalizations? This paper, the hypothesis in this paper was to take a look at what empagliflozin did in patients with heart failure and reduced ejection fraction, specifically with respect to outpatient and inpatient worsening heart failure events. Dr. Greg Hundley: Very nice. How many patients did you include? What were the characteristics of the study population? And what was the design? Dr. Milton Packer: We enrolled, randomized 3,730 patients. All patients had heart failure with a reduced ejection fraction. All were receiving all appropriate treatments for heart failure. Interestingly, 20% were receiving nephrolysin inhibitors, which is really a very high percentage, but they were also receiving inhibitors, renin-angiotensin system beta blockers, mineralocorticoid receptor antagonists and they were patients who had an average ejection fraction of about 27%, which is much lower than most heart failure trials recently. They also had meaningfully elevated levels of natriuretic peptides. These were sicker patients and they had a much higher placebo event rate. They were randomized double-blind, one to one ratio to either placebo or empagliflozin. Dose was 10 milligrams once daily. And this was added to all previously existing therapy and patients were followed for double-blind therapy for an average duration of 16 months and we recorded prospectively information on outpatient and inpatient heart failure events. Dr. Greg Hundley: Very nice. What did you find, Milton? Dr. Milton Packer: We originally reported that in this trial, there was a reduction with empagliflozin on heart failure hospitalizations and that reduction was about 30%. We wanted to know, well, what else was going on with respect to these heart failure events? And so we asked the question, well, did empagliflozin reduce urgent and emergency room visits for heart failure? Did empagliflozin change the types of hospitalizations? We recorded the use of positive inotrophic drugs, vasopressor drugs, vasodilator drugs, cardiac devices, intervention, surgical interventions. And we found out that across the entire spectrum of heart failure outcomes, there was a reduction in serious outcomes with empagliflozin and they all were around a 30% reduction in risk. They varied a little bit from about 28 to 33, but approximately all were in the same ballpark. And what was really interesting was we had a fair number of hospitalizations where patients required IV inotropic drugs, vasopressors, mechanical intervention, they were reduced by 30% with empagliflozin. Hospitalizations associated with intensive care reduced by 30% with empagliflozin. Dr. Milton Packer: And then we looked at outpatient events. Outpatient intensification of diuretics reduced by 30, 33% with empagliflozin. We looked at New York heart class. And what was really interesting was that patients treated with empagliflozin had a 20 to 40% greater likelihood of showing improvement in New York heart class and a 20 to 40% lower likelihood of showing worsening in New York heart class. And those benefits, we're seeing within 28 days after randomization. This early effect is really interesting and it's generated a lot of discussion. And so we looked at our Kaplan Meier curves for the composite of cardiovascular death, heart failure hospitalizations, urgent care, emergent care visits, and we found that the two curves separated quite early and reached statistical significance only 12 days after randomization. This is a very early effect. I want to add that this early separation of curves has been reported previously with beta blockers, with mineralocorticoid receptor antagonists, with neprilysin inhibitors and now we can add this early separation with SGLT2 inhibitors. Dr. Greg Hundley: Very nice, Milton. Well, I'd like to turn now to our associate editor, Dr. Justin Ezekowitz. and Justin you've seen a lot manuscripts come pass through your hands. What attracted you to this manuscript? And then how do you put the findings that Milton has just described in the context with the other results that we have been witness to regarding SGLT2 inhibitors? Dr. Justin Ezekowitz: Thanks Greg. And also, thanks Milton for letting us look at this remarkable manuscript as I do think the clinical implications for a manuscript like this are quite profound. The first thing that really strikes me is we often get worried about looking at a number of different end points. Within a clinical trial, we often don't want to have too many looks at the data because of the risk of finding something that is spurious, is high, but in this case, the way the data was collected and the exploration is quite valuable. We can look at any one of the combinations of clinical end points that actually have direct clinical relevance for a clinician and the patient. And this paper really explored that in a lot of data, in a lot of depth and also helped us by putting the caveats around these findings that this is exploration, but it does anchor it in the SGLT2 world, but also the heart failure world. Dr. Justin Ezekowitz: And Milton, I think one of the striking findings that you showed and it's buried in many of the great figures and tables, is that one in two patients had something happen in the next year. In the next 12 months, that patient walking into an office for a routine followup, one in two had something and the reduction was pretty remarkable across the end point. Milton, I wanted to pick your brain on this one, just to understand when you look at the intensification of diuretics, that was anything from adding another 20 milligrams of furosemide, to doubling or tripling that. Do you think these findings are pretty ubiquitous across the patients enrolled? Or do you think they're a niche finding in only some patients at the highest risk? Dr. Milton Packer: Well, we actually looked at that. We actually looked at whether baseline variables influenced the effect on intensification of diuretics and it was across the board. Well, let me just say, across the board in the patients that we studied and obviously can't make reference to people we didn't study, but we didn't find any particular subgroup that responded particularly well with respect to either a hospitalizations or diuretic intensification or New York heart class changes. But Justin, there's one thing that you just said that is so important. And that is, our patient population was characterized by their physicians, 70% as having class II heart failure. And a lot of physicians think that class II heart failure represents a stable population, clinically stable population. And as you said, one in two patients in our study during followup had worsening heart failure, either represented as an inpatient or outpatient event. A class II patient with heart failure and reduced ejection fraction, even though they're getting optimal medical therapy, is not a clinically stable patient. Dr. Greg Hundley: Very, very interesting finding. Well, just to ask each of you, maybe Milton first and then Justin next, Milton, what do you think is the next study that we need to perform in this patient population using this class of drugs? Dr. Milton Packer: We're really excited about a new phase of heart failure research with SGLT2 inhibitors, which is to look at the impact of these drugs in patients with heart failure and a preserved ejection fraction. DAPA-HF and EMPEROR-Reduced were trials of inpatients with hard failure and a reduced ejection fraction. But we really, about half patients with heart failure, have an ejection fraction of greater than 40%. We really need to understand what SGLT2 inhibitors can do for these patients. And here's the good news. And there are two large scale trials that are both nearing completion. And the first of those trials will be reporting out in about nine months from now with the next trial following about six months later. We will in the next 12 to 18 months, have two major large scale trials of these drugs in a population which is highly different and yet complimentary to the patients who have been studied to date. Dr. Greg Hundley: Justin, how about you? Dr. Justin Ezekowitz: Well, to compliment what Milton is suggesting, I think that's one area. And I think the other area is in implementation science. Now that we have four big classes or groups of drugs, is to how to start these and how to optimize these efficiently in the first month to two months or even three months so the patients can get the benefit for all these medications. And I think what we need to really study is how do we do that? Because we have the drugs but the implementation is where we're not quite there yet. If we get the implementation and testing, randomized strategies and how to do it, I think we may be able to help more patients globally than with the addition of even any new drug that may come out onto the markets soon or in the future, as that remains one of our challenging topics. Dr. Greg Hundley: Well listeners, we want to thank Dr. Milton Packer for bringing this study to us at Circulation and also our own associate editor, Dr. Justin Ezekowitz and really highlighting how the initiation of this SGLT2 inhibitor, empagliflozin, at 10 milligrams per day, in a heart failure reduced ejection fraction population with an average left ventricular ejection fraction of 27%, resulted in a 12 day, at 12 days into therapy, a separation of the development of adverse heart failure related events that was then sustained over the next 16 months. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to wish everyone a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

This week's episode features authors David Kasss and Kavita Sharma as they join Greg to discuss their article "Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: I am so excited about today's feature paper. It talks about my favorite topic, heart failure with preserved ejection fraction, or HFpEF, this time giving us really novel myocardial gene expression signatures in human HFpEF. Can't wait to go to that, but I also can't wait to share about some of the really cool papers in today's issue. Dr. Carolyn Lam: Now, we know that mitral valve-in-valve and valve-in-ring are alternatives to surgical reoperation in patients with recurrent mitral valve failure after a previous surgical valve repair or replacement. But, what are the outcomes after transcatheter mitral valve-in-valve or valve-in-ring procedures? And what is the clinical significance of post-procedure residual mitral stenosis or regurgitation? Well, we're going to find out in today's paper. Dr. Dvir from Hebrew University in Israel and authors examine the midterm outcomes in the Valve-in-Valve International Data registry, which is a multicenter collaboration and rolling cases performed between March, 2006 and 2020, in 90 centers worldwide. Dr. Greg Hundley: Wow, Carolyn. So what did they find? Dr. Carolyn Lam: Well, a total of 1079 patients were included with a median follow-up of 492 days. 4-year Kaplan-Meier survival rate was 62.5% in the valve-in-valve, versus 49.5% in valve-in-ring procedures. Significant residual mitral stenosis occurred in 8.2% of the valve-in-valve, and 12% of the valve-in-ring patients. Significant residual mitral regurgitation was more common in valve-in-ring patients. The correlates for residue mitral stenosis were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual mitral regurgitation was a valve-in-ring procedure. Significant residual mitral stenosis and residual mitral regurgitation were both independently associated with repeat mitral valve replacement. Dr. Carolyn Lam: So, significant residual mitral stenosis and/or mitral regurgitation were not infrequent after mitral valve-in-valve and valve-in-ring procedures, and we're both associated a need for repeat valve replacement, so strategies to improve post-procedural hemodynamics in mitral valve-in-valve and valve-in-ring should certainly be further explored. Dr. Greg Hundley: Very nice, Carolyn. Well, my first paper, it really involves results from the American Heart Association COVID-19 Cardiovascular Disease registry, and it comes from our own associate editor, Dr. Justin Grodin from UT Southwestern Medical Center. So Carolyn, obesity may contribute to adverse outcomes in coronavirus disease, or COVID-19. However, studies of large, broadly-generalizable patient populations are still lacking in the effect of body mass index, or BMI, on COVID-19 outcomes, particularly in younger, adults remains uncertain. Dr. Carolyn Lam: Yeah. It is an important question. And so, what did they find? Dr. Greg Hundley: Well, Carolyn, obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if they're young. So individuals less than age 50 years. Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals, regardless of age. Dr. Carolyn Lam: Wow. An important public health message. Well, my next paper is a basic science one from doctors, Rayner and Karunakaran from University of Ottawa Heart Institute in Canada. For the first time, they investigated the role of RIP kinase 1, a coordinator of NF-kappa B inflammation and cell death, in atherosclerosis. Dr. Carolyn Lam: They found that RIP kinase 1 expression was highly expressed in early atherosclerotic lesions in humans and mice. In vitro, both basal and TNF alpha stimulated NF-kappa B activity, and resultant inflammatory gene expression was reduced in macrophages and endothelial cells when RIP kinase 1 was silenced. In vivo therapeutic administration of RIP kinase 1 antisense oligonucleotide markedly reduced atherosclerotic lesion size and macrophage content. Dr. Carolyn Lam: Together, these findings suggest that RIP kinase 1 drives inflammation in early atherosclerosis, and targeting RIP kinase 1 therefore provides a novel preventive strategy to treat atherosclerosis. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. Kristin Stanford from The Ohio State University. So, Carolyn, brown adipose tissue is an important tissue for thermogenesis, making it a potential target to decrease the risk of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified brown adipose tissue as an endocrine organ. Dr. Greg Hundley: While brown adipose tissue has been implicated to be protective in cardiovascular disease to this point, there are no studies that identify a direct role for brown adipose tissue to mediate cardiac function. This study was performed to address this issue. Dr. Carolyn Lam: So what did they find? Dr. Greg Hundley: Okay, Carolyn. The authors found that transplantation of brown adipose tissue improves cardiac function via the release of the lipokine 12,13di-HOME. Sustained overexpression of 12,13di-HOME using tissue nanotransfection negated the delirious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13di-HOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13di-HOME increase mitochondrial respiration. So, Carolyn, these results identify an endocrine effect of brown fat to enhance cardiac function. Dr. Carolyn Lam: So interesting. Well, there are other very interesting types of papers in today's issue. There's an exchange of letters between Drs. Gui and Nahrendorf regarding the article Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes. Dr. Carolyn Lam: In cardiology news, Tracy Hampton highlights articles from Nature Biomedical Engineering on AI-based eye movements for cardiovascular risk prediction, from Science on the metabolic profiling of the failing and non-failing heart, and from Science Translational Medicine on the heart healing effects of extracellular vesicles. Dr. Carolyn Lam: There's an On My Mind paper by Dr. Pelliccia on gaps in evidence for risk stratification for sudden cardiac death in hypertrophic cardiomyopathy, as well as a Research Letter by Dr. Brown on the association of inducible myocardial ischemia with long-term mortality and benefit from coronary artery bypass graft surgery in ischemic cardiomyopathy, which is a 10-year follow-up of the STICH trial. Dr. Greg Hundley: Nice, Carolyn. Well, my articles: Professor Himbert has an In-Depth article on the current indications for transcatheter mitral valve replacement using transcatheter aortic valves, valve-in-valve, valve-in-ring, and valve in mitral annulus calcification. There's a Research Letter from Dr. Martin (Than) regarding the single troponin rule-out of myocardial infarction. And finally, Professor Isser has an ECG challenge involving chest pain with ST-segment elevation in a young woman with a broken heart. Dr. Greg Hundley: Well, now how about we proceed to that feature discussion? Dr. Carolyn Lam: Yay. Let's go, Greg. Dr. Greg Hundley: Well, listeners, we want to bring you to our feature discussion today, and we have with us Dr. David Kass and Dr. Kavita Sharma both from Johns Hopkins University in Baltimore, Maryland. David, could you tell us a little bit about the background related to this study and what hypothesis did you want to test? Dr. David Kass: Sure, Greg. My pleasure to be here. We have long had an interest in the syndrome we know as heart failure with preserved ejection fraction, going back, really, decades, and the difficulty in assessing what's really wrong with the heart in this syndrome has been that we get so little information from the tissue itself, that most of the studies that have been done have been done at the macro level and physiology level and epidemiology level. Dr. David Kass: But at Johns Hopkins, Kavita Sharma, who now heads up our heart failure transplant group, had established a clinic, a HFpEF clinic, one of the very few in the United States, and the availability of both the patients through the clinic, and then as part of this, right heart catheterizations associated with endomyocardial biopsies being obtained, was really a very extraordinary opportunity to examine tissue at a molecular level, essentially for the first time. There's been no other data set quite like this one. Dr. David Kass: So, we had already established both a patient population, very, very well-phenotyped, very much symptomatic, and we had a tissue bank. And as part of a consortium, a network consortium grant that was sponsored by the American Heart Association, called the Go Red for Women Network, we had a project that basically was focused on trying to better understand HFpEF. Dr. David Kass: The impetus was really, no one knew anything about what's going on in the heart at the molecular level. Really. There had not been transcriptomic analysis ever done before, and there were plenty of questions that we thought this might be able to answer. Among them, how really different are these hearts from patients who have, what we'll call, garden-variety heart failure, heart failure with a low ejection fraction? That's seemingly not so controversial now, but actually there's still controversy as to exactly what's wrong with these hearts, and so we thought we would be able to tease that out. Dr. David Kass: Then it's also been, I think, widely discussed that this is a very heterogeneous disease or syndrome, really, that has a lot of different factors, comorbidities, that are associated with it. So question two was really, how cohesive is the molecular signature that you might see in the myocardium? Is it going to be hopelessly heterogeneous as well, in which case, what does that say about our possibility to develop drug therapies when the underlying biology may be very, very heterogeneous? And if not so heterogeneous, question followup would be, what signatures might be there in subgroups that we could identify, and with subgroup analysis then, help us target in a more personal medicine fashion, ultimately, a therapeutic for the syndrome? Dr. Greg Hundley: Very nice. So, David, how did you assemble a study population, and what was your study design? Dr. David Kass: In this sense, this was very much an ongoing effort by Dr. Sharma and what was the HFpEF clinic team. Back, probably about 4 years ago, maybe even more, she had started to become interested in this and had amassed a clinic population while she was a resident, and then as a senior resident became more and more interested in this and this became her fellowship project when she was a cardiology fellow at Hopkins. Dr. David Kass: And by the time I became more involved with this, basically she had it in operation with study nurses and seeing patients. It was very clinically-oriented. There was some sort of more, I would say, population-level data being collected and studies being done, but nothing like quite what we did here. But that was there. Dr. David Kass: So, in terms of a study design, this was almost more a biobank. At this point, there was a cadre of patients she had been following. She had been following this group for some time. Basically, in a freezer we had endomyocardial biopsies under an IRB-approved protocol that had been obtained, and in part we were sort of waiting to get enough tissue together so we had a large enough data population and enough sample, and then really thinking through what might we be able to look at in these pieces, knowing full well that very little had been done. So almost anything we came up with, and we've been doing quite a few other things now as well, was going to be new, so I suppose the simplest study design of all. Dr. Greg Hundley: So, what did you find? Dr. David Kass: Well, going through those initial questions. Question number one, is there a unique molecular signature? We're looking at using what's called RNA-Seq, which is the newest generation of RNA gene expression analysis, in these myocardial biopsies. The answer was, yes, actually. There was a very unique signature. And this was all done using what we call agnostic bioinformatics approaches, where you just give the data, you give all the genes that are different between HFpEF and a control group, we had a control group, donor hearts. You look at basically the HFrEF group, the people with low ejection fraction, versus control. What are those differentially expressed genes? And of course you have your control. Dr. David Kass: So there are three groups and you get a series of little dots in what's called principal component analysis, and it was very clear, right from the beginning, that these groups separated, and this was just purely a statistical approach to say, are they different? Dr. David Kass: And then we asked further, are they still different even if we adjust for what are the common comorbidities and the things that differentiated, often, HFpEF from other forms of heart failure, specifically age, sex, having a large body mass index, having diabetes, these were all things that were more prevalent and more severe in the HFpEF group. So we adjusted for these things, again, sort of statistically, and redid this, and it's still absolutely separated. So question one, are they different at the transcript level? Yep. They're different. Dr. David Kass: And then, question two is basically, despite the heterogeneity, if you start digging into the genes, what kinds of genes are being differentially regulated? Is there a signature that becomes cohesive and consistent among the patients within the HFpEF group? The answer to that was, yes. And this too was very interesting because we also did an adjustment for the comorbidities, and what we found were the genes that were upregulated in HFpEF, that actually turned out mostly to be down-regulated in the other form of heart failure. Genes specifically associated with the manufacturing of ATP by mitochondria, the ATP synthase genes, those genes were significantly upregulated in HFpEF, but once you adjusted for body mass index, a lot of those pathways disappeared. So, the class of genes that were up regulated was in fact related to comorbidities. Dr. David Kass: Then we did the opposite. We looked at those genes that are down-regulated, and found that a large group of genes that were quite different, that are not on the tip of most people's tongues for what goes on in heart failure, mostly associated with protein processing, trafficking, autophagy, the process of protein recycling, endoplasmic reticular stress, which was something that the journal senior editor, Joe Hill, had talked about and published about earlier in the year in a mouse paper where he first came up with this idea that ER stress might be important. Well, looks like it's important in these humans. So, we found some unique signatures. Dr. David Kass: And then the last thing I suggested we would look at is whether we could get subsets from the molecular signatures, and the answer to that was, yes. Here we kind of threw the genes at a program and said, "You come up with clusters, purely based on the genes." That's it. No clinical information whatsoever. What it came out with were three groups, and very interestingly, there was a mortality difference between these groups just based on their transcript. One of the groups looked at pretty close, or closer, to HFpEF to reduced EF heart failure, and indeed, the genes that it came up with were typical of hypertrophy and remodeling and matrix remodeling, and that was the one with a group with the highest mortality. And then there was sort of a very different group with small hearts, relatively low levels of natriuretic peptide, an inflammatory pathway signature. Not the kind of thing we're to looking at and say, "Oh yeah, this is obviously heart failure," and yet they were equally symptomatic, tended to be a few more on the female side than male side. Dr. David Kass: So, I think, in the end, that study was very successful for all the things we were trying to do, really. That it's distinctive, that there are subgroups that we can identify at the transcriptome level, despite the heterogeneity, and we've got a list of genes now, pathways, really, that look to to be uniquely relevant. Dr. Greg Hundley: Very nice summary. Well, let's turn to your colleague, Dr. Kavita Sharma, who is also with us today and helped assemble this wonderful cohort. Kavita, how would you put these findings in the context with some of the other literature that's been published in heart failure preserved ejection fraction? Dr. Kavita Sharma: Hi, good morning. Thanks for the opportunity. That's a great question. The idea of trying to phenotype HFpEF has really been around, for now, a couple years, and that's driven by the fact that we have no therapeutic agents to date that have really affected outcomes in this population, in spite of the fact that half of all heart failure is classified as HFpEF and we have many therapies for HFrEF, or low ejection fraction patients. Dr. Kavita Sharma: And the thought is that, perhaps, it's a heterogeneous population and we're lumping to many different types of patients together. And so there have been a number of efforts to date to try to phenotype this population, but most of these have been centered around clinical comorbidities, and distinct groups have been identified, but without a clear sense of what is driving mechanistic differences between the groups, and then how to take it to the next step to target therapeutic agents to specific populations within HFpEF. Dr. Kavita Sharma: I think this is a big step closer to trying to really understand how we can target therapies. So, we've seen efforts at phenotyping and there are some overlap between the three groups that we identified from our RNA sequencing work, but this is now giving us a clue as to how to target mechanisms of disease. Dr. Greg Hundley: Very nice. Well, Kavita what do you see is the next study to perform, really, in this space, to follow your work? Dr. Kavita Sharma: Our goal is to really perform a comprehensive, as we call it, omics approach to phenotyping and HFpEF. We are actively looking at metabolomics, both from the blood and the tissue in collaboration with investigators at U Penn, we hope to also look at proteomics, and eventually single cell sequencing, as well as really trying to understand some of the actual myocyte-level contractility issues. And this is work that actually has just come out as well from our group, looking at sarcomere function in HFpEF from the right ventricle. Our hope is that each of these areas is going to further our understanding of myocardial deficits, so to speak, and areas that we could target for therapies. Dr. Greg Hundley: Very nice. David, do you have anything to add to that? Dr. David Kass: No. I think Kavita said it very, very well, and clearly the goal is to ultimately develop a more mechanistically-driven, personalized approach to the subsets of HFpEF so that hopefully we get a therapy that actually is going to work. These are not tiny subsets of this group. Remember this is half of all heart failure and that's a big number, and even a subgroup that might represent one-quarter of half of all heart failure is still a big number, and so none of this is ever going to be like an orphan disease suddenly where we're dealing with a very small group of people. Dr. David Kass: But even if it was, it would still be a major step forward, but it's not going to be that. I think what you're going to hopefully come up with, with a signature that can be targeted and with the therapy that's effective on the basis of that, is going to, I think, help a large population. Dr. Greg Hundley: Well, listeners, we want to thank Dr. David Kass and Dr. Kavita Sharma, both from Johns Hopkins University in Baltimore, Maryland for bringing us this new information related to RNA sequencing to really help better phenotype patients with heart failure and preserved ejection fraction, so that in the future, we may have therapies that can help this patient population. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.13.381442v1?rss=1 Authors: Nagy, A., Munkacsy, G., Gyorffy, B. Abstract: Cancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR=4.26, p

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.16.384339v1?rss=1 Authors: Ngah, Y. E., Cho, F. N., Etagha, B. S., Fusi, N. G., Francisca, N., Ikomey, M. G., Ibrahim, N. Abstract: Introduction The incidence of hepatotoxicity is life-threatening and can result to an end-stage liver disease in long-term patients on combined antiretroviral therapy (cART). Our study sought to evaluate the incidence and predictors of cART-induced hepatotoxicity (CIH) among long term users on cART in a rural District hospital. Methods This was a hospital-based cross-sectional study in the Bali District Hospital. Spectrophotometric method was use for the quantitative measurement of alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels. Patients with elevations of both ALT and AST were considered CIH. The Chi ({chi} 2 ) square test, ANOVA and Kaplan Meier log-ranked/ survival analyses were used to analyse the data. Results Of the 350 participants enrolled [156 (44.6%) males and 194 (55.4%) females], aged 43.87 {+/-} 0.79 years (range 20 - 84 years) included in this analysis, 26 (4.4%) experienced moderate CIH. We observed 57 (16.3%), 62 (17.7%) and 238 (68%) elevated levels ALT + AST, ALT and AST respectively. Two independent predictive factors of CIH were, the male sex and alcoholism during the study period. Conclusion The prevalence of CIH in HIV-infected patients in Bali was lower than that observed in previous studies. The duration of therapy had no influence on the frequency of CIH. Alcoholism and smoking showed significant differences in the development of CIH. Copy rights belong to original authors. Visit the link for more info

This week’s episode includes author John McMurray and Associate Editor Brendan Everett as they discuss the effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction. TRANSCRIPT BELOW: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, I hear you might have an interesting feature paper? Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward to this one, because we cannot get enough of the DAPA-HF study. This is another very important prespecified analysis, looking at the effect of dapagliflozin on outpatient worsening of patients with heart failure with reduced ejection fraction. Very important stuff coming right up, but first, I've got two papers looking at congenital heart disease that I'd like to share with you, Greg. Have you got your coffee? Dr Greg Hundley: Yeah, I do. Let's get going. Dr Carolyn Lam: Well, as you know, the mechanisms of congenital heart disease associated right ventricular dysfunction are not well-understood. And so, in this first paper, Dr Reddy from Stanford University and colleagues assessed lipid peroxidation, a potent form of oxidative stress, as well as mitochondrial function and structure, in right ventricular myocardium, collected from patients with and without right ventricular failure. And what they found, was that right ventricular failure was characterized by increased oxidation of membrane phospholipids, known as lipid peroxidation and its products, such as 4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and mitochondrial proteins, and was associated with decreased myocardial energy generation and mitochondrial structural disruption with increasing severity of right ventricular hypertrophy and right ventricular failure. Mechanistically, the authors showed that 4-HNE was sufficient to decrease energy generation by inhibiting electron transport chain complex activities and mitochondrial dynamics. Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So clinically, what are the implications? Dr Carolyn Lam: I thought you'd ask. Well, since standard heart failure therapies, such as ACE inhibitors and beta blockers, are ineffective in the treatment of right ventricular failure, developing therapies focusing on new targets, such as what we talked about, the lipid peroxidation, could improve right ventricular function in congenital heart diseases by improving mitochondrial energy generation and cardiomyocyte survival. Dr Greg Hundley: Ah, very interesting, Carolyn. Dr Carolyn Lam: Thank you. The next paper, also very interesting, this time focusing on Tetralogy of Fallot, the most common cyanotic congenital heart disease. Now, this is from Dr Marijon from Hôpital Européen Georges-Pompidou in France and colleagues who highlighted, first, that sudden cardiac death represents an important mode of death in these patients with Tetralogy of Fallot, yet data evaluating the ICDs in these patient population, really, has remained scarce. And so, they use the nationwide French registry to include 165 patients with Tetralogy of Fallot with an ICD initiated in 2010 by the French Institute of Health and Medical Research. 63%, by the way, of these ICDs, were used for secondary prevention. Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they find? Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% overall, 7.1% in the primary prevention, and 12.5% in the secondary prevention cohorts, respectively. 43% of patients presented with at least one ICD complication, and, importantly, QRS fragmentation was the only predictor of appropriate ICD therapies. So, even before you asked me, Greg, the take home message is, patients with Tetralogy of Fallot and an ICD, experience high rates of appropriate therapies, including those implanted for primary prevention. The considerable long-term burden of ICD-related complication, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria, including QRS fragmentation, might improve our risk prediction. Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot there. Well, I'm going to steer us to two other papers in the issue, and the first one is from the world of basic science, and it's from Dr John Cooke from the Houston Methodist Research Institute. So Carolyn, the angiogenic response to ischemia restores perfusion, so as to preserve tissue. Something we all know. A role for mesenchymal to endothelial transition in the angiogenic response is controversial, and this study utilized a murine model of hindlimb ischemia and an in vivo Matrigel plug assay, together with lineage tracing studies and single-cell RNA sequencing, to examine the transcriptional and functional changes in fibroblasts in response to ischemia, to determine if resident fibroblasts contribute to angiogenesis. Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts contribute to angiogenesis? What did they find, can't wait? Dr Greg Hundley: Yeah, Carolyn. So, in both mice and human-isolated fibroblasts, these author studies indicated the presence of subsets of tissue fibroblasts, which seemed poised to contribute to the angiogenic response. And the expansion of these subsets with ischemia was dependent upon activation of innate immune signaling, and this signaling contributed to recovery of perfusion and preservation of ischemic tissue. Really interesting findings. Didn't suspect the fibroblasts as being the contributors here. Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another one. Dr Greg Hundley: Yes. So the next study is from Professor Phillips Tsao from Stanford University School of Medicine. Well, Carolyn, this is a genome-wide association study, and it's from the Million Veteran Program, testing 18 million DNA sequence variants in patients with abdominal aortic aneurysms. In the study, they identified 7,642 cases and 172,172 controls in veterans of European ancestry, with independent replication and another study in 4,009 72 cases and 99,858 controls. Dr Carolyn Lam: Wow. Dr Greg Hundley: So it's nice, they have a replication study. The authors then use Mendelian randomization to examine the causal effects of blood pressure on abdominal aortic aneurysms. And they examine the association of abdominal aortic aneurysm risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and lastly, derived a genome-wide polygenic risk score to identify a subset of the population at greater risk for disease. Dr Carolyn Lam: Wow. So a GWA study with replication to identify those at risk for abdominal aortic aneurysms in huge cohorts. What did they find? Dr Greg Hundley: Well, Carolyn, this study was managed by one of our experts in GWA studies, Dr Wendy Post, and through GWAs, the authors identified 14 novel loci, and there were already 10, so it brings the total number of significant abdominal aortic aneurysm loci to 24. So a new finding there. And in their Mendelian randomization analysis, they demonstrated that a genetic increase of 10 millimeters of mercury in diastolic blood pressure, as opposed to systolic blood pressure, likely had a causal relationship with the future development of abdominal aortic aneurysms. They observed that 19 of those 24 aortic aneurysm risk variants associate with aneurysms in at least one other vascular territory. And then lastly, a 29 variant polygenic risk score was strongly associated with abdominal aortic aneurysms, independent of family history and smoking risk factors. So Carolyn, in conclusion, the authors in this study identify novel abdominal aortic aneurysm genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of abdominal aortic aneurysms, independent of their family history. And their data suggests that perhaps extending current screening guidelines to include testing for those with high polygenic abdominal aortic aneurysm risk, would significantly increase the yield of many of our current screening algorithms, as you know, that predominate based on smoking and age. Dr Carolyn Lam: Wow. Very, very impressive and convincing data. Thanks, Greg. Let me tell you about other papers in today's issues. There's a research letter by Dr Tiburcy on inhibition of prolyl-hydroxylase domain enzymes, and how that protects from reoxygenation injury in the engineered human myocardium. There's another research letter from Dr Ohbe, entitled, The Risk of Cardiovascular Events after a Spouse's ICU Admission. And, one more from Dr Ganatra, on chimeric antigen receptor T cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Dr Greg Hundley: You know, Carolyn, our research letters, they really pack a punch. Such very interesting research, in a nice concise format. I've got some other publications. So first, there's an On My Mind piece from our own Charlie Loewenstein, and also Dr Solomon from Boston, Massachusetts, involving, Severe COVID-19 as a Microvascular Disease, does endothelial exocytosis drive COVID-19? And next, there's a case series entitled, ECMO Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani. And then finally, Carolyn, a very nice ECG challenge from Dr Bansal, related to identifying the location of an AV block. Well, Carolyn, I'm really excited to get onto your feature discussion. Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks at a prespecified analysis of DAPA-HF. My goodness, I don't think we can get enough of the data from DAPA-HF, and we have none other than be corresponding author, Dr John McMurray from University of Glasgow, to discuss this exciting paper, as well as our associate editor, Dr Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. So John, today's feature paper, all about outpatient worsening of heart failure. Could you please start by defining what we meant by that, and why is it so important? Dr John McMurray: Our interest in this actually started back when we did PARADIGM and we had collected, in a not very systematic way, information about episodes of outpatient worsening, so by that, I mean episodes of worsening symptoms and signs, not leading the patient to go to the emergency department or be admitted to hospital. The sort of worsening that a patient might tell you about in your outpatient clinic, say they're a bit more breathless or they've got a bit more ankle swelling, and you do something about it. And that's the critical part. You decide to increase their dose of diuretic, add another drug. And in PARADIGM, we find that those episodes, first of all, were quite common, and secondly, and most importantly, we're actually prognostically very significant. They were associated with worse outcomes. So in that HF, we decided that we would collect these more systematically, we would try and define them a little bit more robustly, so we would require the investigator to report worsening signs and symptoms, and we also wanted evidence that additional treatment had been given and then that had been sustained for at least a month, because, as you know, diuretic dose can increase and decrease. Then we prespecified, as you said, Carolyn, that we would then incorporate those manifestations of worsening, as an additional component to our primary composite endpoint, which was cardiovascular death, heart failure hospitalization, worsening of heart failure requiring intravenous therapy, so an urgent visit for that, that would often be in an emergency department, and then in addition to that, this further manifestation of worsening as the extra component to this broader composite outcome that we hoped would encompass the whole range of worsening of heart failure that a patient might experience. Dr Carolyn Lam: Thanks so much, John, and you actually preempted my question of how it differed from the original primary outcome that included urgent heart failure visits, intravenous diuretic use, but not these nuance outpatient intensification of heart failure therapy that I really salute you for prospectively collecting information on. So could you summarize what you found, please? Dr John McMurray: Well, first comment to make, Carolyn, is that we included those urgent visits requiring intravenous therapy, because, as you know, in the U.S., I think there is a move to try and avoid admission and to treat patients in the ambulatory care setting or non-ward setting. Although, I have to say, as it turned out, those episodes of worsening were very infrequent. There was, I think, 33 in total in DAPA-HF, compared to almost 600 of the other episodes of worsening. The ones that we almost feel at a brainstem reflex level when we see patients in our clinics. So what did we find? Well, we find that when you add those episodes of worsening, then, of course, you considerably increase the proportion of patients who have, from what you might call, the most trivial manifestation, worsening the events we just talked about, all the way through to the very worst, in other words, death, from cardiovascular causes, in fact, so much so, that by about two years of follow-up, the Kaplan-Meier rate for that expanded composite endpoint was about 33%. And, as you know, Carolyn, we're talking about a trial that enrolled patients who were very well-treated by conventional standards and who, by and large, had mild symptoms, but 70% were NYHA class II. And yet, within two years, if you take into account all of these different manifestations of worsening, we had about one-in-three people in the placebo group that deteriorates, and we reduced the risk of deterioration with dapagliflozin, we reduced the instance of that expanded composite endpoint by 27%, and that was a highly statistically significant result. And if you like numbers needed to treat, then for that expanded very broad composite endpoint, the number needed to treat over the median follow-up of 18.2 months, was only 16. And by the way, we did confirm that those outpatient worsening events were prognostically significant as well. Dr Carolyn Lam: Very good. Brendan, could I bring you in on this? It's got such great implications, maybe you could share a little bit about what the editors thought when we saw this paper? Dr Brendan Everett: One of the key things that the editors thought when they reviewed this, was the fact that, as you pointed out, you collected these outpatient worsening episodes prospectively across the trial and did so in a very rigorous and systematic way. And I think for those of us who take care of patients with heart failure, which of course is most cardiologists, these kinds of episodes where your patient calls you and their weight's gone up, or where they've gotten a little more short of breath, then you, over the phone, intensify their diuretic regimen, are incredibly common, and, of course, bothersome to the patient and challenging for the clinician who's caring for the patients too. So I think, in that sense, it's a really important paper. That was the other aspect, I think, that the editors were interested in. But the impact, the clinical impact on day-to-day care of patients with heart failure, was substantial. The other part that I found intriguing, because of course, when you're caring for individual patients, you don't have a sense, necessarily, of what these episodes mean in a broader population for those patients' overall risk of bad outcomes. So you mentioned it right at the end when you were speaking a moment ago, about the association of these outpatient intensifications of oral diuretic therapy and their association with future bad outcomes within the trial. Could you tell us a little bit about what those were and why they ended up seeming so important, both to patients and to you as the trialist? Dr John McMurray: We write about these being common, in fact, in the placebo group in DAPA-HF. I think it was 14% of patients had one of those episodes of outpatient worsening. And again, as you correctly identified, in the majority of cases, the therapeutic intervention by the physician, was simply to increase the dose of diuretic, although, actually about 40% of people also, at some point, had the addition of another drug. So, in terms of the significance of those events, in PARADIGM, we find that they appeared to be associated with almost the same impact on mortality as being admitted to hospital with worsening heart failure. But in fact, in DAPA-HF, where we collected more of these events, so maybe we collected, perhaps, the more severe cases in DAPA where we collected them systematically, we find that the prognostic impact wasn't quite as large. So for example, if you were admitted to hospital with heart failure during DAPA-HF, then you were six-times more likely, subsequently, to die in that rather short follow-up period, than if you had no manifestation of worsening. On the other hand, if you had an outpatient episode of worsening, then it was around a three-fold higher risk of death than if you had no manifestation of worsening. So, my take home from this was that these episodes really do matter to patients. Not only, of course, do they matter because it means the patient doesn't feel so good, but they matter because that patient suddenly is on a different prognostic trajectory, and you can change that by intervening. So these events are common, they're prognostically bad news, and fortunately, we can reduce them. And maybe the last thing to say, which I also didn't mention, I apologize, was that, of course, if you look at that expanded endpoint, as you can imagine, because there's so many events now, you see the effect of treatment very, very quickly. So by day 27 after randomization, in other words, by day 27 after starting dapagliflozin, we had a statistically significant reduction in the occurrence of that comp standpoint, that then remained significant thereafter. Dr Brendan Everett: Thanks, John. I had one other question that I hope doesn't take us too far into the weeds, but I think as a clinician, when you care for these patients, you try to intensify their outpatient therapy, and when that seems to fail, the patient then becomes admitted to the hospital. And I thought it was very interesting and thoughtful the way that you approach that problem, in other words, you have potentially, of this composite endpoint, you have the outpatient worsening that comes first, and then it's followed, in many cases, by a hospitalization for heart failure. How did you tease those two apart? And what analyses did you do to make sure that what you were really measuring was the effect of the outpatient intensification, rather than really just a prelude to a hospital? Dr John McMurray: Very good question, Brendan. So, obviously, we were concerned about the possibility of double counting, so we did a primary analysis in which we built in a blanking window. So, for example, if you had an episode about outpatient and you or I increased the patient's oral therapy, but within 30 days, they were admitted to the hospital, then in our analysis, that patient only counted once, and the event that counted was the hospital admission, not the outpatient episode of worsening. And then, as I said, we did a number of sensitivity analyses where we adjusted the length of that blanking period, because we recognized, obviously, that some people, that episode of outpatient worsening that you intervene for, your intervention may not work and they may still get hospitalized. So we try to, as you obviously identified when you read our manuscript, we tried to counter that by not double counting episodes of outpatient worsening that were closely adjacent to the hospital admission. Dr Carolyn Lam: Could I end with just one quick question? You've published many times with us at Circulation, and I'd like to think that that's from a very good experience with us, with working with us, and I've noticed even in this discussion, it's just so interesting the exchange. And so, John, could you say a few words about publishing in Circulation, and why do it? Dr John McMurray: Well, obviously it's our leading cardiovascular journal. As I was being trained as a fellow, it was every fellow's aspiration to publish a paper in Circulation. So reputationally, obviously, it's very, very important. But why do I like Circulation other than that? Well, first of all, you handle papers quickly and efficiently. I think you're very fair. I really like the reviews. So I would say one of the greatest frustrations most authors, and certainly I know that from my own experience, is when you get poor reviews. I don't think I get those from Circulation, so you obviously have a much higher quality review. I like the way the editors give you guidance about the manuscript and how to respond to the reviewers. That's really, really helpful, because sometimes you think, "Well, that reviewer’s comment doesn't make sense. Do I have to really do that?" But often, your replies to me, come with guidance about how to handle the different reviewers’ comments. So, all in all, it's fair. I would say that's always important. Everybody will not get every paper accepted, but I think you get a very fair response from Circulation. It's good. It's thoughtful. So, that's fine. Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on behalf of Brendan as well, and kudos to him because obviously he managed this paper so well. Thank you, audience, for joining us today on Circulation on the Run. So don't forget to tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association.

We were overwhelmed by questions from our event with Doug and Emma! This is a bonus follow up conversation that further digs into measuring productivity through “Waterlining” and Kaplan Meier estimating, hashtags in communication, remote 1:1 best practices, and Doug shows us some of the creative ways he applies Zapier integrations for his personal productivity! "What it does is it forces a debate as to A what's most important and B do we really want that thing below the line waterline? Because what happens sometimes is people are super excited about this thing. And then when you see this rank list of stuff, you're like, Oh, but wait a second. There's like running the business stuff below the water line. We actually have to get that up and staff that..." - Doug Gaff DOUG GAFF - VP of Engineering @ Zapier Doug is the VP of Engineering at Zapier, the software solution that helps your other software work together more effectively. As the leader of an organization with over 100 engineers, he has learned a lot about effective management and leadership. Doug currently resides in the Greater Boston Area. EMMA TANG - Engineering Manager @ Stripe Emma is an Engineering Manager in Data Infrastructure at Stripe based in San Francisco. Her team focuses on building distributed computation infrastructure to support Stripe's business. At Stripe, we believe in investing in our remote culture, and have built out the remote engineering hub, and tripled the number of remote engineers in the last year. SHOWNOTES How to Measure Productivity - Waterlining and Kaplan Meier (2:44) Waterlining as a tool to discuss priorities (9:10) Using hashtags to understand intent and to increase the bandwidth of communication (11:02) Best practices for remote 1:1’s when you don’t see the productivity levels you want (17:37) Tips for onboarding new grads (23:03) Doug’s remote work routine and lifestyle (24:47) Doug’s favorite Zapier integrations to increase productivity (29:21) Takeaways (33:45) ELC SUMMIT 2020 Accelerate your growth as an engineering leader at the ELC Summit! Learn from 100+ incredible speakers. Talks cover tons of well-rounded curated topics. There will be opportunities for hands-on practice through workshops (+ other programs), and speed networking with other eng leaders through our own custom-built platform! More details and tickets @ http://elcsummit.com Join our community of software engineering leaders @ https://sfelc.com/ --- Send in a voice message: https://anchor.fm/engineeringleadership/message

Dr. Hayes interviews Dr. Canellos on his involvement with CHOP, MOPP and CMF as well as his role as Chief of Division of Med Onc at SFCI/DFCI for 25 years. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Hello. Today my guest on the podcast is Dr. George Canellos. Dr. Canellos was instrumental in early treatments for breast cancer, lymphomas, -- and chronic leukemias, and he's generally considered one of the so-called Gang of Five with the National Cancer Institute in the 1970s, along with Drs. Vince DeVita, Robert Young, Bruce Chabner, and Philip Schein, who ultimately demonstrated that chemotherapy could be used to cure a fraction of patients with Hodgkin's and non-Hodgkin's lymphomas. Dr. Canellos was raised in Boston, and he attended Boston Latin School. He then received his undergraduate degree at Harvard and his medical degree at Columbia in New York City. But he remained a Red Sox fan, so he returned to Boston for his residency in internal medicine at Massachusetts General Hospital. But he then trained in oncology at the National Cancer Institute where he stayed until 1974 when he once again returned to Boston to join the faculty of the then Sidney Farber Cancer Institute where he served as the Chief of Medical Oncology until 1995. He is currently the William Rosenberg Chair at Medicine at the now Dana Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. Dr. Canellos has authored over 300 peer-reviewed papers and too many reviews and chapters to name. Most importantly, he served as the Second Editor in Chief of the Journal of Clinical Oncology, a role he filled from 1987 until 2001. And during that time, he directed the Journal to become the leading journal in our field. Perhaps even more importantly, he served as ASCO President in 1993 and 1994, and he's been recognized as an ASCO Oncology Luminary, and he's been recognized with the Statesman Award and the Distinguished Service Award for Scientific Achievement from our society. Dr. Canellos, welcome to our program. Good to talk to you. Great to talk to you. You know, I spent a lot of time with you at the Sidney Farber and then Dana Farber Cancer Institute, and I've heard you say, and I've also read, that you originally seriously considered becoming a surgeon because of the work you did with Dr. Oliver Cope, one of the leaders in surgery of our last century and especially related to thyroid and other cancers. So what led you to get away from surgery and become a medical oncologist? Well, I served as a surgical intern at Mass General at that time, which was a lot of exposure to serious illness and surgery. But it dawned on me. Two things dawned on me. One is that if one was interested at all in malignancy that surgery really wasn't the answer, certainly, in any way. And in those days, of course, even radiotherapy was not the answer. And so the other thing I realized, that I had the manual dexterity of a California fur seal. I didn't really feel, being left-handed, I didn't feel that I really had the dexterity required to do some of the complicated surgery that was going on in those days because I held retractors as an intern for some very long operations that really didn't achieve more than taking out a gallbladder. It took three hours. Now, we can do it with a laparoscope in a half an hour, probably. So I switched into medicine at Mass General and stayed in medicine at Mass General. And being inspired to really think about other treatments for malignancy in those days, there were very few really textbooks available that talked about chemo. There was some. I would nip up to the library of the hospital rarely and try to read about them. There were new drugs coming out at that time, but there was very little really known about the action of the drugs and the potential of the drugs that might have existed at that time. Then I went to NCI, as one had to because there was a doctor draft. And two years of residency in medicine, I actually went to the medicine branch of the NCI. And there, under Emil Frei III, another investigator named Freireich, Jay Freireich, who were around at that time and running the program, such as it was, we first were experience-- I was thinking that I would do research there, and I did. But at the same time, the Clinical Associate Program entailed a year of clinical exposure, of clinical care, and I had several colleagues. The first major colleague was Vincent DeVita who really, at that time, decided to approach a treatable more solid malignancy, as acute leukemia of childhood was being approached, with combination chemotherapy. However, there weren't many drugs that were very active at that time. There were some. An alkylating agent, nitrogen mustard, steroids, a vinca alkaloid that had just been relatively new introduced for adult disease. And there was no procarbazine. Of course, it hadn't been invented yet, but methotrexate. And so the first combination regimen that came out of that program was MOMP, M-O-M-P, and that had some activity, but it was only given for a relatively short period of time. Eventually, the tolerance of patients to these drugs was considerable, a considerable issue, because we didn't really have granulocyte support. There were a lot of things that we'd take for granted now that were not available then. So the toxicity of some of these programs, such as the M-O-P-P Program when procarbazine came along, the MOPP program was considerable. But the interesting thing is the patients that we had were generally on the younger side, younger than 45, let's say, and they could tolerate the therapy. And I found that, honestly and subsequently, with testes cancer, that younger people who get a lot of toxicity from these drugs, despite that, if they think there may be a cure around the corner, will tolerate it. And you don't hear a great deal of complaints about it, about the toxicity, interestingly. But the older patients, of course, are far more vulnerable. Their bone marrow reserve not being great, these regimens were quite toxic. But, fortunately, the first targeted disease was Hodgkin's disease, and it's generally a disease confined to younger people, in general. About 20% of them are in the older group. But we first tested the aggressive chemotherapy, known as MOPP, in the younger patients, actually. But what was surprising to us, and surprising to everybody, was the fact that they failed to relapse as they were all expected to do at that time. In the single drug agent era, of course, Hodgkin's disease would relapse eventually. As house officers, we just expected that to happen. Now, the training in the major academic hospitals in those days, oncology was not an important part, or even a desired part, of the program, if you will. And so most who arrived at a place like NIH really didn't have much background at all in the treatment of cancer because they probably didn't see it all that much. I know I didn't. As a surgeon, yes, but not as internal medicine. I was going to ask you that. When you were at Mass General and you said you noticed that surgery wasn't curing people, there couldn't have been anybody around that was mentoring you or said, why don't you-- how did you even hear about-- No, no, there wasn't. There were some docs there who really cut their teeth on giving hormones to breast cancer patients, and that was about it. But very few people were giving-- I couldn't think of anybody who was giving-- one person who was giving chemotherapy, a lady, a fine lady, fine physician actually, but on the private side, but nobody on the academic side that amounted-- So what made you-- What made you say, I'm going to go to the NCI and learn how to do this? I mean, that seems like that was completely out of the blue. Well, you weren't given much choice. Of the two institutes, I applied at the Heart Institute and the Cancer Institute. The Cancer Institute accepted me, and the same with Vince DeVita. He applied to the Heart Institute but got into the Cancer Institute. And we were both there, probably you could say, as our second choice at the time. Because-- Yeah, that's interesting. Yeah. Very little was known about oncology as a field, and there we were. On the other hand, seeing these patients at least respond to these drugs in the way they did, and seemingly not relapsing, made you wonder whether or not, in time-- when I went back to the NIH, I came back to the MGH to be a senior medical resident. I can tell you what was interesting, because there was no oncology Fellow, per se. They would ask me to see a patient if the patient had a malignancy. And I remember going in and seeing a patient with ovarian cancer. She had a huge belly full of ascites, malignant ascites, and I said that the drug for this disease is thiotepa, an alkylating agent. I wrote out the recipe, if you will, how many milligrams, et cetera. And I wrote in the note, and I will give the first dose, which I did. The intern covering the service, a surgical intern covering the GYN service, obviously read part of my note but not all of it, or decided he was going to give another dose as well, but somehow the woman was double-dosed. And there was a certain panic by the nursing staff, et cetera. She tolerated the drug surprisingly well. But more surprising, everything went away. She had this dramatic response to therapy. The ascites went away. The abdominal masses went away. And she was discharged. And I said to myself, at that time, this is a precedent for something, and that era will arrive once-- if it's not the right drug, we'll find the right drug for the disease. But I can tell you, it was very uplifting to me. I had already been to NIH. That's a great story. When you guys were at the NCI, a similar question is, when did the light bulb come on that it looked like you were actually curing Hodgkin's disease? Well, you're talking about a two-year appointment. At the end of the two years there, the remissions were already clear. That is to say, the disease had not come back, and the people were being followed. But two years is just two years. I mean, it's not a long time. And when I went back on the faculty-- see, I went for a year in England to become a hematologist because everybody had to be a hematologist in those days if you were interested in cancer. Anyway, that's what I did. And when I got back, they recruited me to the faculty, and the patients were still in remission, and that was great. And then we put our attention to the non-Hodgkin's lymphomas and modified the MOP regimen by putting cyclophosphamide instead of nitrogen mustard, which was a horrific drug by the way, nitrogen mustard in the doses that we gave. But like it or not, we put Cytoxan into it and we called it CMOP. It was like MOP but it was with C instead of the M. So we called it CMOP. And early in the 1970s, we did a randomized trial with the radiotherapists who were throwing radiation at everything that walked in with a non-Hodgkin's lymphomas, and we did a prospective randomized trial stage by stage, histology by histology. And I remember looking at the data for the large cell lymphomas with the CMOP and I said, Vince, you know, if we judged everything by median, the median survival of our patients was what you'd expect historically. But just below the median, the line straightened up, flattened out, and was going out now several years, at least four or five years, flat in a disease that usually recurred very quickly and killed everybody who was affected by it. And I remember when the Board of Internal Medicine decided to create a specialty called Medical Oncology and have an exam, et cetera, Vince thought it was because of Hodgkin's. And I'm sure it contributed, but I said it must be also the non-Hodgkin's because it's far more common. It's far more common. We helped far more people. And indeed, it probably is. Can I interrupt you for a moment? I interviewed Saul Rosenberg for this series, and he told me just [INAUDIBLE] the radiation psychologist. So Dr. Kaplan had referred to him from Memorial to come to Stanford and do radiation, and Dr. Rosenberg told Dr. Kaplan, I think we need to give these people chemotherapy, and Kaplan agree. But the Chair of Medicine did not and would not let Rosenberg see patients in his own clinic and give chemotherapy. So he wrangled a room from a hematologist, and he told me he would see patients in the room. He had a chair in the hallway. If the patient needed chemotherapy, he'd have the patient go sit in the chair in the hallway. Get an IV pole. He'd start the IV himself and then mix up the chemotherapy himself, hang it up. While the patient was getting chemotherapy in the hallway, he'd see the next patient in the room. Those are the kinds of obstacles he had to do. And the other thing I have to say, I didn't get to interview Dr. Holland before he passed away, but relative to your looking at the Kaplan-Meier curves, I'll never forget his yelling at me one time that, if you need a statistician to see what you've done, you probably haven't done much. I said that, 'cause I remember saying that as well, but anyway. Let me ask you another question. Yeah. You're know for lymphoma and chronic leukemias but also for breast cancer, and generally you're credited for coming up with the so-called CMF regimen. Vince and I were called into the director's office. At that time, the director of NCI was [INAUDIBLE]. And they said, all this lymphoma stuff is wonderful, but we want you to do solids. Now, we didn't have a referral pattern for solids at all. The only breast patients we saw were relatives of employees of the NCI. So Vince wanted to do ovarian, and I said ovarian is a good disease because they have malignant cells floating around, and we can do stuff on those. And Vince really wanted to do ovarian. I chose breast. And, again, we had no mastectomy surgical group or anything. And so what we did was make deals with medical oncologists in the community, two of them who actually trained-- one of them trained at the Brigham Hospital, actually, and they lived in the area. And they liked to come to our conferences and things. They would refer patients. And what we specified, initially, was that we have patients without isolated bone lesions only, that they had to have measurable lumpy, bumpy disease. And so to design a therapeutic treatment for them, we had to use the principles that we learned from the lymphoma experience. And that's where CMF came. CMFP, we used to have prednisone in some circumstance. And so that was the regimen that-- if you notice, the design of it would be like the MOP program. Anyway, so we started treating people like that. Suddenly, they did respond and some responded quite well. They had some toxicity, of course. And the very first paper we wrote was on the toxicity of CMFP. It was hard to get things published in medical oncology areas, and the Lancet was wonderful for us. The Lancet was very helpful, and we published a lot of stuff in the Lancet. But the first one was in the British Medical Journal, the toxicity of CMF program in patients, and we especially cautioned patients who had compromised liver function because they seemed to get worse toxicity at that time in our imagination. But it worked. It did work. We published it in the Annals of Internal Medicine eventually. But the important thing was, our friend Johnny Bonadonna would come over periodically to find out what we were doing. And he came over with an offer. He said he had all these patients who would get mastectomies and then nothing. Let me interrupt you for a moment 'cause I was going to ask you about Dr. Bonadonna. Yeah. Would you, just for the audience, a lot of them may not know who he is. Oh. Well, Johnny Bona-- Do you want me to describe him? Well, at that time, he was a young investigator working in Milan at the major hospital there in oncology, and he trained at Memorial before and then went but back to Italy. So he came and he wanted to know what we were doing. We showed him the protocol that we were doing for breast, and he was interested. And what he offered was the opportunity of doing a randomized trial on patients with a higher risk, if you will, breast cancer, node-positive patients. And he said that in Italy that nothing was done for them and that he could randomize them nothing to chemotherapy, and we offered him a contract. He required money. We gave him a contract. We gave him our protocol, at least the chemotherapy protocol. He went back to Italy and did that trial. And he left the prednisone out. He made sure it was of just CMF. And the patients, apparently, I guess, knew what they were getting, but I don't know whether they had strict requirements or informed consent and things like that. We didn't ask. We didn't ask. All we wanted was randomized data, and he certainly had it. And I remember being at the ASCO meeting in 1976, I think it was, '75 or '76, in Toronto when the first data was presented by Bonadonna. And the media people were there. People were barely hanging from the rafters to hear. The room wasn't big enough, really. None of the rooms were big enough because they never expected the attendance, that there were that many young oncologists around or people interested in oncology. And so he gave that first data, and that was a shot in the arm for adjuvant therapy, certainly for breast cancer, but for other things as well. I think, in general, he and Dr. Fisher, who sadly passed away before I had a chance to interview him, are responsible for thousands and thousands of people. Yeah. Absolutely. Absolutely. Absolutely. But I'm giving you the NCI side, my personal side of it, and you're right. Bernie was a real pioneer because he had so much opposition from the surgical establishment at the time. I can tell you that. From a surgeon's point of view, they really thought he was the Antichrist. I mean, it was terrible. I saw him and Jerry Urban get into a verbal argument at a meeting. I thought it was going to be a fistfight, actually, over-- Really? Yes, yes. Yes, they're severe. But anyway, let me go-- let me go to my next question, which has tended to change gears for a moment. You may or may not remember this, but when you were ASCO President, in your presidential address, I was in the audience and you said something to the effect that the greatest clinical experiment you have conducted are the Fellows you have trained, or something like that. Yes. Yeah. And I was in tears, of course. But you certainly can claim success on that. The division chiefs, department chairs, cancer center directors, most recently a Nobel Laureate, [INAUDIBLE], all of them came out of the program. But when you returned to Boston, you could not have envisioned all of this. What was the atmosphere, and what was Dr. Farber's vision? Well, Dr. Farber had died by the time I got there. Oh, he was already gone? OK. He was already gone. And when I was leaving, when Tom Frei recruited me, Vince thought I was mad because they made me Clinical Director. At least have a go at acting job as clinical director of the NCI. But really, down the line, it was a bureaucratic evolution. And I said, I don't really want to be an oncocrat at this age, anyway. What I said was, Vince, I said, the doctor draft is over. The best and the brightest and the youngest and the cheapest are all going to be in these hospitals, and there are a lot of them in Boston because I happen to know Boston, including house staff at the Brigham, house staff at the BI and Mass General. And I said, that's the future, or at least the future challenge. And I think he accepted it, but he didn't like it. I mean, he thought-- well, we were great buddies and we worked well together, and that goes for Bob Young and Bruce Chabner too. They thought I was very-- Where else-- at that time, there must have only been two or three places to train in oncology in the whole country, I would imagine. Yes, yes, yes. And people were just starting to set up cancer centers, sometimes without funding. And then there were all these, not many, but job requests for me to go and look at the job at Wisconsin or you name it, but I didn't want to do that. I really wanted to do medical oncology and not be a bureaucrat in any way. And many of the places, Dan, would say come and be a head of our cancer program, and it was also translated in parentheses, come and write a CORE grant. A lot of places who didn't deserve a CORE grant were asking me for people to come and write a CORE grant. You knew forever they would never get one because they really didn't have the makeup for it, yet. So what were the hurdles in Boston when you got there? Well, the hurdles in Boston were twofold. One is the fact that oncology had a very slow start in Boston, and that goes at the Brigham and at the MGH. The MGH was even disinterested in oncology at that time, actively disinterested. They didn't think it had any academic merit and therefore didn't put any effort into it. I have to say that Gene Braunwald, who was Chief of Medicine at the Brigham at the time, was interested because he had been at NIH at the Heart Institute, he knew Tom Frei, and he wasn't sure about it yet because he couldn't swallow it, I guess. And the fact was that it was growing a bit, and one of his very close associates developed large cell lymphoma and he got chemotherapy, he got to see MOP. And he was long-term remission. And I remember telling Braunwald, he was shocked that it was so successful. And I kept telling him, I said, this is not a rare event. This is happening. But the big challenge, Dan, at Dana Farber was that there was no oncology known, and we had to build the program from the bottom up. We hospitalized our patients at the Brigham before we opened the beds at the Dana Farber, but we needed the volume of patients. And we had all these beds, I think 59 beds, licensed beds, open. And I kept saying, we don't have the patients. But Tom Frei opened the beds. The next thing you know, I was talking to trustees because Tom said, we'll bring George up and we'll grow. The clinical program will grow. So the trustees thought the program would probably grow the next day. It didn't. It took a lot of effort without the [? scare ?] and myself going around giving talks in every little hospital that existed. And one of the big things I had my mind, because the house staff looked after our patients as well, was to show them what we could do. Now, in those days, other than the large cell lymphomas, of which we did not have many because they were in the hands of hematologists, was testes cancer. And the head of urology at the Brigham Hospital used to have these Saturday morning urology rounds inviting all of the practicing urologists around to come and they'd present their problem cases, et cetera. But he asked me to come along and give a talk about this new drug called cisplatin, which was having a big effect in testes cancer in other places. And I did. And I would come and talk about the early results in other places in testes cancer and that we were interested in actually starting a program. Then, they would-- of course, urologists are anything but chemotherapists, and so they would refer the patients in because, A, they couldn't give any chemotherapy. There was nothing oral that would work. What we would do is, if they sent patients in, we would do an early trial and we would publish the series in a, let's say, not spectacular journal and get reprints. We would send them reprints. And in some instances, I put the name of the referring doctor, if he'd sent us more than one patient, on the paper for, let's say, testing some antineoplastic thing. And we would put their names on the papers and send them reprints. And there's nothing a urologist loves more than to see his name on a scientific paper, a medical paper. And we started getting a ton of testes cases eventually and did trials and wrote papers about them. And I remember, when we recruited Phil Kantoff, a Fellow of mine, and I thought he was going to go back to the NIH and do gene therapy. And he walked in one day and he said, I'd like to apply for the GU job, and I said, it's yours. And he wrote quite a few papers based on the accumulated testicular data and the [INAUDIBLE]. Oh yeah. Yeah. And he was wonderful. He's Chief of Medicine now at Memorial. He's Chief of Medicine at Memorial, yes. I want to bring up one more thing that this segues into, though, and I believe now almost every medical oncologist who has trained in the last 10 years thinks that multispecialty tumor boards have always existed. But I believe that another of your trainees, Dr. Craig Henderson, who was my mentor, frankly, and you really started the first multispecialty clinic perhaps in all of oncology in this country. Do you agree with that? We called it the BEC, the Breast Evaluation Center. Yes, and we got cooperation but from surgeons. There were surgeons around, more nihilistic surgeons, if you will, not wanting to do radical surgery and radiotherapists, like Sam Hillman. And they were all around and doing those things. And we brought them into this BEC, the Breast Evaluation Center, and your mentor, Craig, was a little rough on the Fellows, I can tell you, in those days. Just his demands. Anyway, whatever it was. And so I would go to that clinic as well and see breast patients just to calm things down a bit at times. Anyway, it worked. And I know that the breast people elsewhere were recognizing that Craig had a nice thing going there with the multidisciplinary aspects. You know, it was so awful that breast cancer was treated so badly. I mean, they'd have a radical operation. And God knows, if there was some disease, that they would then get radical radiotherapy to their chest. And they were walking around sort of mutilated. And we had a part-time psychiatrist when I first arrived to see these patients because many of them had body image problems. So the idea of not doing radical mastectomy was revolutionary at that time. And I remember being called by the local Blue Cross to serve on a committee to decide whether or not Blue Cross should pay for breast reconstruction on these poor patients, and we voted. There was a committee of medical oncologists from MGH, me, and a plastic surgeon, and we voted 3 to 3 to they should pay, and they didn't. Then they said, thank you for serving on this advisory committee, but we're not paying. We've decided not to pay. Then, I can tell you, a women's agitation group got a hold of the facts. And one of them called me up and she said, I heard you were on this committee that voted not to pay. And I said, absolutely we voted to pay. They told us, thanks very much but we're not going to pay. So within two weeks then the insurance company changed its opinion because they went bananas at the insurance company. Yeah. The strength of advocacy, that's been something. Anyway, we're running out of time. I'd like to thank you for taking your time with us. Not at all, Dan. Not at all. It's a pleasure. And as I have done for every other interview in this series, I want to thank you not just for taking time with us but for all you've done for the field, for those of us who trained with you or are in the field, and most importantly for all the patients who have benefited. You look back over the-- Yeah, I know. I still follow them. My clinic has follow-ups of cured patients. You become the primary care doc for cured patients. Well, you think of the 60 years of your career and other fine folks that you were with at the NCI and then beyond, and the thousands or millions of people who have benefited, it's pretty remarkable. Yeah, well. Thanks again. I appreciate you being on. Not at all. And enjoy the rest of the day. Thank you very much, Dan. Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

Ever read through a study and wondered how to apply the hazard ratio, or if you should change your practice because of a secondary endpoint finding? In this episode, Lauren M. Catalano, MD, of the University of Pennsylvania, Philadelphia, explains all the common terms and why they matter in the context of the KEYNOTE-024 trial.  In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about how to prepare for an unexpected bad outcome. Practice points: Don’t skip over the statistical analysis portion of a paper. Use Google to find simple definitions for unfamiliar biostatistics terms. Understanding the statistical elements is essential to determining the quality of the research. * * * Understanding statistics in the context of KEYNOTE-024 Article discussed: Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-46.  Primary endpoint: The outcome that is necessary to ensure the efficacy of the trial. What is the study’s objective? The primary endpoint is defined prior to starting the study, which influences how many patients need to be enrolled to ensure statistical significance. This paper’s primary endpoint: Time since random assignment to disease progression or death. Secondary endpoint: These are interesting trends or observations that the investigators were able to determine, but for which the original study may not have been powered, meaning that they may not have enough data to determine the statistical significance. This paper’s secondary endpoints: Objective response rate (confirmed complete and partial responses) and safety. Hazard ratio: “Ratio” suggests that this is a comparison between the intervention and control arm. HR is a measure of an effect or intervention on the outcome of interest over a period of time (risk per unit of time). The outcome can be positive or negative. Confidence interval: Since it is not possible to survey the entire population, a confidence interval provides a range of values where the true value most likely falls. If the confidence interval crosses “1” then there is no difference between the arms of the study. Kaplan-Meier curve: Often used to illustrate survival. This is a graphical representation of hazard ratio, usually drawn as a step function. P value: The degree of error that we are willing to accept. Often P = .05, which means we are willing to accept a 5% risk that the hypothesis is incorrect. Crossover: Patients assigned in one arm of the study (usually the control arm) can be reassigned to the other arm (usually the intervention group). Intention to treat: A technique used in randomized, controlled trials in which patient outcomes are compared within the group the patient was originally assigned to. This may not reflect the treatment that the patient actually received. If the patient is in a group that is treated but then leaves that group, they are still counted in the original group. Show notes by Ronak Mistry, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2757311?widget=personalizedcontent&previousarticle=2757307 Prior authorization requirements increased from 8% to approximately 24% of covered drugs on Medicare Part D plans between 2007 and 2019. Solutions- First, focus prior authorization on its intended purpose. Health plans should eliminate prior authorization requirements for medications that have very low final denial rates… this should only be for people that are outliers protect continuity of patient care. For patients who are stable with chronic treatment, insurers should offer protections to minimize disruptions and inefficiencies—get a drug forever shouldn’t need to go off the drug or switch insurance than try a new drug on their formulary when you have already failed it on the other insurance Third, promote transparency, efficiency, and fairness. Technology exists to enable prescribers to view the formulary status, prior authorization requirements, and cost sharing for medications and alternatives in electronic health records (EHRs https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2757311?widget=personalizedcontent&previousarticle=2757307 FDA updated its gadolinium warning in 2010, specifying that 3 agents (gadopentetate dimeglumine, gadodiamide, and gadoversetamide)- the FDA stated that other GBCAs could be used cautiously under certain circumstances We needed a solution so BOOM newer agents, termed group II agents (gadobenate dimeglumine, gadobutrol, gadoteridol, and gadoterate meglumine), In this study – almost 5k pts. stage 4 and 5 CKD receiving group II GBCAs, including patients undergoing dialysis. They report a 0% pooled incidence of unconfounded NSF https://www.bmj.com/content/368/bmj.l6669 Sticking to a healthy lifestyle including not smoking, not being overweight, and exercising regularly, is associated with a longer life expectancy at age 50 free of major diseases such as cancer, cardiovascular diseases, and diabetes, The number of extra disease-free years is around 7.6 for men and 10 for women, compared with participants with no low risk lifestyle factors. https://jamanetwork.com/journals/jama/article-abstract/2758598 prostate cancer and diet Time to progression did not differ significantly between the groups (unadjusted hazard ratio, 0.96 [95 percent confidence interval, 0.75 to 1.24]; adjusted hazard ratio, 0.97 [95 percent confidence interval, 0.76 to 1.25]). For the intervention and control groups, the 24-month Kaplan-Meier progression-free percentages were 43.5 and 41.4 percent, respectively (difference, 2.1 percent; 95 percent confidence interval, −8.1 to 12.2 percent). https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2759737?guestAccessKey=dc41fd4e-5c0c-46bb-9353-ceca16f96b25&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamainternalmedicine&utm_content=olf&utm_term=020320 just read the summary- These findings suggest that, among US adults, higher intake of processed meat, unprocessed red meat, or poultry, but not fish, was significantly associated with a small increased risk of incident CVD, whereas higher intake of processed meat or unprocessed red meat, but not poultry or fish, was significantly associated with a small increased risk of all-cause mortality. SUMMARY This study revealed approximately 3% to 7% higher relative risks and less than 2% higher absolute risks of incident CVD and all-cause mortality over the 30 years of follow-up. People who consume more servings per week would have greater risks. Why they are wrong and the big problem Furthermore, risks of CVD and mortality are determined by a range of factors, including but not limited to genetic predisposition, demographic factors, socioeconomic status, weight, lifestyle factors (eg, smoking, sleep, physical activity, and diet), and the built environment Overall looked at 6 studies total- large heterogeneity- people could eat all sorts or amounts of meat Food preparation methods were not consistently and universally assessed across the cohorts in this study. Therefore, separating fried chicken from poultry intake was not possible They used questionnaires- we know people lie to be healthier on questionnaires Only baseline diet data was analyzed from the 6 studies in this cohort. – 19 years of follow up but only used one questionnaire for each study!!!!!!!!!!!!!!!!!!!!!! only 1 dietary measurement was used—

This week we answer a few questions: the first is from Patreon backer, Harry Hong, on Kaplan-Meier curves. The second is from a student at Mount Sinai Medical School who reached out with some ethical questions they had after the ASH annual meeting on the obligations and responsibilities of peer reviewers. Finally, we end the episode with an interview with Dr. Bishal Gyawali of Queens University in Kingston, Ontario, Canada on his new paper out today in the Journal of the National Comprehensive Cancer Network titled "Response Rates and Durations of Response for Biomarker-Based Cancer Drugs in Nonrandomized Versus Randomized Trials". Durations of Response: doi.org/10.6004/jnccn.2019.7345 Vinay's new book, Malignant: www.amazon.com/Malignant-Policy-…cer/dp/1421437635 Back us on Patreon! www.patreon.com/plenarysession

We're back in Plenary Session HQ! We have multiple topics for you this week. We cover the use of trastuzumab in later lines of therapy for HER2+ metastatic breast cancer, we take a listener question on Kaplan-Meier curves, and we talk a little about Patreon. Malignant: www.amazon.com/Malignant-Policy-Evidence-People-Cancer/dp/1421437635 Back us on Patreon! www.patreon.com/plenarysession

Treatment-free survival is a novel endpoint in immunotherapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma” by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology. Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word “cure” is not completely out of mind. Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990’s for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma. Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment. In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death.  With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity. These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health. If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of  immune suppressants. To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time following subsequent therapy. The TFS can be further subdivided into TFS with or without toxicity (≥2 or ≥3 TRAE or use of immune suppressants). These additional  measures give some granularity to the survival and let us see what exactly survival constitutes, time off treatment and toxicity or time on treatment and with side effects. These measures have several limitations: one of the important ones is introducing differences between treatment arms which by primary outcome measures have no difference by standard PFS or OS and by favoring short duration high toxicity treatments (such as ipi) over low toxicity, low intensity chronic treatments (such as nivo). These are value judgements which matter to many patients but need to be understood as such. In oncology, we need to make these value judgements explicit and make the tradeoffs clear. Ultimately though, the importance of TFS and similar outcome measures may be that they encourage this conversation and help our field open up to what matters. This concludes this JCO Podcast. Thank you for listening.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off? Dr Carolyn Lam:                I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes?                                                 Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL. Dr Greg Hundley:             So Carolyn, what did they find in this interesting study? Dr Carolyn Lam:                Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes. Dr Greg Hundley:             Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines.                                                 Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines. Dr Carolyn Lam:                Wow. So what did they find, Greg? Dr Greg Hundley:             Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention.                                                 So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR. Dr Carolyn Lam:                Wow, Greg. So what are the take home messages? That was a lot of numbers. Dr Greg Hundley:             Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly. Dr Carolyn Lam:                Great, Greg. So what are the clinical implications? Dr Greg Hundley:             Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis. Dr Carolyn Lam:                Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter.                                                 And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease. Dr Greg Hundley:             So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work? Dr Carolyn Lam:                Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five. Dr Greg Hundley:             Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue? Dr Carolyn Lam:                I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it.                                                 And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject. Dr Greg Hundley:             Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal. Dr Carolyn Lam:                Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it? Dr Greg Hundley:             Absolutely. So how about onto our feature discussion? Dr Carolyn Lam:                You bet, Greg. Dr Greg Hundley:             Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population? Dr William Gray:               The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well.                                                 The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design. Dr Greg Hundley:             So Bill, tell us now about the results. Dr William Gray:               It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone.                                                 Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out.                                                 When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects. Dr Greg Hundley:             Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease? Dr Joshua Beckman:        I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December.                                                 On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices.                                                 And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal.                                                 It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray.                                                 This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices. Dr William Gray:               Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups.                                                 So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true.                                                 I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there.                                                 And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly. Dr Joshua Beckman:        So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field. Dr Greg Hundley:             We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Neste episódio discutimos o famoso MAGIC Trial. Esse trabalho foi considerado um divisor de águas no tratamento do câncer gástrico e de JEG devendo ter a nossa atenção. David Cunningham e seus colaboradores investigaram o papel da quimioterapia perioperatória comparada com a cirurgia isolada para os pacientes. Com esse tratamento ousado, seu trabalho foi publicado no New England Journal of Medicine em 2006, tendo excelentes resultados! Não perca esse mais novo episódio e aprenda um pouco também sobre a famosa curva de sobrevida Kaplan-Meier e o método de log rank. Para saber mais sobre o estudo publicado na revista NEJM, acesse o link: https://www.nejm.org/doi/full/10.1056/nejmoa055531

Frequent contributor to Zoo Logic, Dr. Kelly Jaakkola, Director of Research for the Dolphin Research Center discusses the new peer-reviewed study she coauthored and published in the Journal Marine Mammal Science that compared survival rates and life expectancies for bottlenose dolphins living in zoological facilities with comparable values published for wild populations. The main takeaway from the study is dolphins living in zoological facilities today live at least as long or longer than wild populations studied to date. These results stand in stark contrast to some zoo and aquarium critics that continue to promote the false claim that dolphins do not live as long in human care.  Data analyzed in this new study come from a U.S. government source called the “Marine Mammal Inventory Report” (MMIR), which lists basic information (e.g. birth date, death date, transfers, etc.) for all dolphins in marine mammal facilities in the U.S over the past 40 years or so.  A few complications with comparing current MMIR data with previous studies of wild populations are due to the inherent limited scope of observations found in most wild studies and the different methods of statistical analysis that have been used in each previous publication. To make comparisons valid, the new study used the same analysis on the MMIR data that was used for each wild population publication. The last scientific paper to analyze survival for dolphins in facilities before this latest study used data that are now more than 25 years old. Even back then, survival rate and life expectancy for dolphins living in zoos and aquariums in the US were increasing and this study shows continuing significant increases since then. The current median life expectancy of bottlenose dolphins living in human care in the U.S. is 29.2 years. This is based on the most robust method of analysis called the Kaplan-Meier Survival Analysis. While the K-M approach is the most accurate analysis because it uses information from ALL animals in the population (both dead and living) and does not assume equal probability of dying at all ages like some of the other methods used in previous publications require, no wild study has yet used the Kaplan-Meier method to analyze the life expectancy of the respective wild populations examined due to the lack of detailed information on the age of living animals and the age-at-death for dead animals. Also of interest was the finding that a direct comparison of calf survival rate between the decades-long field study of the Sarasota population of dolphins and modern MMIR data found no significant difference between populations. In other words, while dolphin calf (age less than 1 year) mortality is higher than for adults, as is the case for many species including humans, there is no significant difference in survival rate between dolphin calves born in human care and those born in the wild.   K. Jaakkola/K. Willis: How long do dolphins live? Survival rates and life expectancies for bottlenose dolphins in zoological facilities vs. wild populations. Marine Mammal Science 2019; DOI: 10.1111/mms.12601. Available at: http://doi.wiley.com/10.1111/mms.12601 http://zoologic.libsyn.com www.facebook.com/ZooLogicpodcast/ www.iReinforce.com https://dolphins.org    

Ethan Basch, MD talks today about a randomized clinical trial where 766 patients used a web-based system to self-report symptoms, triggering alerts to clinicians. The results were impressive. There are learnings and inspiration in this episode for anyone pursuing better patient outcomes, with special relevance for organizations rolling with a value-based care model. Dr. Ethan Basch is an oncologist and Director of Cancer Outcomes Research at the University of North Carolina.  His research group established that up to half of patients' symptom side effects go undetected during cancer treatment and clinical trials, and that patient engagement and questionnaires substantially improve detection. His team determined that integrating web-based patient-reported symptoms into oncology clinical practice improves clinical outcomes and reduces health service utilization. His team created a system for the National Cancer Institute (NCI) to collect patient-reported side effects during cancer trials called the ‘PRO-CTCAE.' Dr. Basch is also involved in efforts to bring PROs into comparative effectiveness research, routine care, and quality improvement. He is a member of the U.S. National Cancer Institute's Board of Scientific Advisors, PCORI's Methodology Committee, and is an Associate Editor at JAMA.  Dr. Basch will discuss results of a widely cited randomized controlled trial testing a “PRO intervention” in routine cancer care, that was a Plenary session at the ASCO annual cancer meeting and was published in JAMA earlier this year.  In this trial, 766 patients receiving routine outpatient chemotherapy for metastatic solid tumors were randomly assigned to self-report 12 common symptoms via the web, or to usual care. Treating physicians received symptom printouts at visits and nurses received email alerts when participants reported severe or worsening symptoms. Overall survival was tabulated based on medical records and Social Security Death Index data, estimated using the Kaplan-Meier method, and compared between arms using a log-rank test and Cox proportional hazards regression adjusting for age, sex, race, education level, and cancer type.  Cancer types included genitourinary (32% of patients), gynecologic (23%), breast (19%), and lung cancer (26%).  Survival results were assessed after a median follow up of 7 years and 517/766 (67%) of participants had died.  Median overall survival in the PRO intervention arm was 5.2 months longer than the control arm (31.2 vs. 26.0 months, p=0.03).  These results demonstrate that systematic symptom monitoring during outpatient chemotherapy using web-based patient-reported outcomes confers overall survival benefits.  These results are being further explored in a U.S. national implementation trial. 00:00 Ethan talks his work on a self-reporting symptom system. 02:20 The results of the self-reporting system trial. 03:00 Does using a self-reporting symptom system improve Clinical Outcomes? 04:30 Analyzing the data from this self-reporting system. 09:45 The improvements in Quality of Life this self-reporting study found. 10:20 The decrease in ER visits with self-reporting symptoms. 10:45 The extension of chemotherapy treatments self-reporting patients were able to achieve. 12:50 What inspired Ethan to take this sort of a project on. 13:15 The opportunity to improve the ability to detect patient symptoms. 15:30 Refining study techniques and approaches for successful trials. 19:20 Onboarding patients for studies. 24:15 Implementing the study from the Clinician side. 26:20 The requirements needed for onboarding staff onto a successfully implemented study. 29:45 The relevance to Value-Based Reimbursement. 31:00 The tangible impacts of catching symptoms early that increased the survival benefit of patient-reporting. 34:00 EP131, relevant insight from Zach Silverzweig of Cipherhealth. 36:00 A better way to monitor how patients are doing and improve the quality of care. 37:20 You can learn more about the study in the Journal of the American Medical Association & the Journal of Clinical Oncology.

Dr Ahlgen speaks with ecancertv at ASCO 2016 about the results of SPCG12, a randomised phase III trial assessing patient survival following radical prostatectomy with docetaxel. Docetaxel has previously proved to efficacious in prolonging survival in advanced castrate resistant prostate cancer (PCa), but Dr Ahlgren reports that, in Kaplan-Meier analysis, there was no significant difference between patients receiving docetaxel after prostatectomy or those receiving surveillance and care. He highlights that docetaxel as a monotherapy seems to generate a more rapid biochemical progression in a subgroup of patients, and that further analysis of this subgroup is warranted.

The clinical course of renal cell carcinoma (RCC) shows a high variability. Prognostic markers are essential to enable an individualized therapeutic strategy. The objective of this study was the identification of novel independent prognostic markers and potential therapeutic targets in RCC. The focus was on genes involved in epithelial-mesenchymal transition (EMT) and cancer stem cell biology. EMT enhances tumor cell motility and hence plays a critical role in invasion and metastasis in various carcinomas. A set of transcription factors acts as master regulators of EMT. Whether EMT is important for tumor progression in clear cell renal cell carcinoma (RCC) is unknown. Therefore, EMT-related genes were selected from the literature, and their role and prognostic relevance in RCC were analyzed. The known cancer stem cell marker CXCR4 and the associated TPBG gene were also analyzed in this project. Additionally, a novel filter strategy was used to analyze RCC oligonucleotide microarray data for identification of potential prognostic markers: genes with increasing expression during tumor progression (normal kidney < primary tumor < metastases) were selected for outcome analysis because they could be crucial for RCC biology. Expression of 46 EMT-related genes was analyzed using oligonucleotide microarrays and gene set enrichment analysis (GSEA) in tissue samples from normal kidney and G1 and G3 primary RCC, 14 samples each. Expression of selected EMT genes was validated by real-time polymerase chain reaction (PCR) in normal kidney, primary RCC and metastases in an independent cohort of 112 patients and then combined with follow-up data for survival analysis. Immunohistochemistry, Western blot and flow cytometry were performed to further examine the expression of CXCR4 and co-expression of CXCR4 and TPBG on the surface of RCC cells. GSEA and dChip software were used for microarray data analysis. The EMT gene set was preferentially expressed in primary tumors compared to normal tissue (false discovery rate FDR=0.01), but no difference between G1 and G3 tumors was found. Quantitative RT-PCR showed down-regulation of critical EMT genes like CDH2 and ZEB1 in metastases which suggests reversal of EMT during metastasis. Kaplan-Meier analysis demonstrated a significant better outcome for patients with low CXCR4, vimentin, fibronectin and TWIST1 mRNA levels. Multivariate analysis revealed that CXCR4 and vimentin up-regulation represent independent prognostic markers for poor cancer-specific survival of RCC patients. The microarray approach using filtering and further RT-PCR validation of progression-associated genes revealed that ATAD2, TET3, HELLS and TOP2A are independent and previously unknown predictors of poor outcome in RCC patients. Taken together, this study provides strong evidence that EMT occurs in RCC. Modulation of EMT in RCC, therefore, might represent a future therapeutic option. Expression levels of a number of EMT-related genes (like the genes encoding the cancer stem cell marker CXCR4 and vimentin) could be identified as independent prognostic markers. Using a novel filtering approach on array data, additional novel prognostic markers could be identified. These findings contribute to a better risk stratification of RCC patients that can support an individualized and optimized therapeutic strategy.

Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A fundamental goal of current studies is to identify those somatic events arising in the variable landscape of PDA genomes that can be exploited for improved clinical outcomes. Methods: We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRAS(G12D)-driven genetically engineered mouse model of PDA were screened by RT-PCR. We then used a tissue microarray to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis were used to assess the association of STAG2 expression relative to overall survival and response to adjuvant therapy. Finally, RNAi-based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in response to 18 therapeutic agents. Results: STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon-mediated disruption of STAG2 in a KRAS(G12D) genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon-Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (> 95% of nuclei positive) was associated with a median survival benefit of 6.41 months (P = 0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; P = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally, we show that RNAi-mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy. Conclusions: Based on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA.

Background: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a well defined risk factor for subsequent bacteremia and death in various groups of patients, but its impact on outcome in patients receiving long-term hemodialysis (HD) is under debate. Methods: This prospective interventional cohort study (performed 2004 to 2010) enrolled 289 HD outpatients of an urban dialysis-unit. Nasal swab cultures for MRSA were performed in all patients upon first admission, at transfer from another dialysis facility or readmission after hospitalisation. Nasal MRSA carriers were treated in a separate ward and received mupirocin nasal ointment. Concomitant extra-nasal MRSA colonization was treated with 0.2% chlorhexidine mouth rinse (throat) or octenidine dihydrochloride containing antiseptic soaps and 2% chlorhexidine body washes (skin). Clinical data and outcome of carriers and noncarriers were systematically analyzed. Results: The screening approach identified 34 nasal MRSA carriers (11.7%). Extra-nasal MRSA colonization was observed in 11/34 (32%) nasal MRSA carriers. History of malignancy and an increased Charlson Comorbidity Index were significant predictors for nasal MRSA carriers, whereas traditional risk factors for MRSA colonization or markers of inflammation or malnutrition were not able to discriminate. Kaplan-Meier analysis demonstrated significant survival differences between MRSA carriers and noncarriers. Mupirocin ointment persistently eliminated nasal MRSA colonization in 26/34 (73.5%) patients. Persistent nasal MRSA carriers with failure of this eradication approach had an extremely poor prognosis with an all-cause mortality rate >85%. Conclusions: Nasal MRSA carriage with failure of mupirocin decolonization was associated with increased mortality despite a lack of overt clinical signs of infection. Further studies are needed to demonstrate whether nasal MRSA colonization represents a novel predictor of worse outcome or just another surrogate marker of the burden of comorbid diseases leading to fatal outcome in HD patients.

Introduction: While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations. Methods: A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. Results: The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95% CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95% CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95% CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. Conclusions: Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Background: There is partially conflicting evidence on the influence of the steroid hormones estrogen (E) and progesterone (P) on the development of ovarian cancer (OC). The aim of this study was to assess the expression of the receptor isoforms ER-alpha/-beta and PR-A/-B in OC tissue and to analyze its impact on clinical and pathological features and patient outcome. Methods: 155 OC patients were included who had been diagnosed and treated between 1990 and 2002. Patient characteristics, histology and follow-up data were available. ER-alpha/-beta and PR-A/-B expression were determined by immunohistochemistry. Results: OC tissue was positive for ER-alpha/-beta in ER-alpha/-beta and 60.1% and PR-A/-B in 36.2% and 33.8%, respectively. We identified significant differences in ER beta expression related to the histological subtype (p=0.041), stage (p=0.002) and grade (p=0.011) as well as PR-A and tumor stage (p=0.03). Interestingly, median receptor expression for ER-alpha and PR-A/-B was significantly higher in G1 vs. G2 OC. Kaplan Meier analysis revealed a good prognosis for ER-alpha positive (p=0.039) and PR-B positive (

Summary In this study, we analyzed vitamin D receptor (VDR) expression and survival in a breast cancer patient cohort of 82 breast cancer patients. Immunohistochemical analysis was possible in 91.5% of the patients (75/82). Staining was evaluated using the semi-quantitative assay according to Remmele and Stegner (immunoreactivity score [IRS]). IRS 0–1 was negative/very low, IRS 2–4 was moderate to high, and IRS 6–12 was high. Statistical analysis was performed by Spearman’s correlation test (p

Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets.

In der prospektiven klinischen Studie zum Langzeitverhalten von IPS Empress I Keramikinlays konnten nach einer Liegedauer von 10 Jahren bei 31 Patienten insgesamt 62 Rekonstruktionen beurteilt werden; 51 Inlays waren noch in situ. Die 10-Jahres-Untersuchung umfasste die klinischen Parameter Ästhetik, Oberflächenqualität, Randqualität, Randverfärbung, Sekundärkaries, Mundhygieneparameter, Attachmentverlust, Vitalität, Okklusionsstellung und Abrasion. Weitere Fragen bezogen sich auf die Beschwerdeanamnese, Therapiemaßnahmen und Misserfolgsgründe. Die Auswertung erfolgte mittels der SPSS 15.0- Family Software. Die Überlebensrate nach Kaplan-Meier für 10 Jahre betrug 82,3%, die mittlere Überlebenszeit lag bei 122,9 Monaten. Misserfolgsgründe waren in 72,7% der Fälle pulpitische Beschwerden sowie Randdesintegration und Fraktur (27,3%). Von den noch in situ befindlichen Inlays wiesen weitere fünf (Rand-)frakturen auf; an vier Zähnen wurde Sekundärkaries im Randbereich diagnostiziert. Ein signifikanter Zusammenhang zwischen Randqualität und Randverfärbung, sowie Randqualität und Sekundärkariesbildung konnte nachgewiesen werden. Inlays im Prämolarenbereich wiesen signifikant bessere Randqualität und Überlebensraten auf. Die Lage der Inlays in Ober- oder Unterkiefer und die Wahl des Befestigungskomposits (Variolink bzw. Sonocem) hatten keinen signifikanten Einfluss auf die Überlebenszeit. Zweiflächige Inlays schnitten tendenziell besser ab als dreiflächige. Die gute Biokompatibilität der Keramik konnte bestätigt werden.

Background: Conventional external beam radiotherapy is a standard procedure for treatment of spinal metastases. In case of progression spinal cord tolerance limits further radiotherapy in pre-irradiated areas. Spinal stereotactic radiotherapy is a non-invasive option to re-treat pre-irradiated patients. Nevertheless, spinal radiosurgery results in relevant dose deposition within the myelon with potential toxicity. Aim of the study was to retrospectively analyse the efficacy and feasibility for salvage radiosurgery of spinal metastases. Methods: During a period of 4 years (2005-2009) 70 lesions in 54 patients were treated in 60 radiosurgery sessions and retrospectively analysed. Clinical (pain, sensory and motor deficit) and radiological (CT/MRI) follow-up data were collected prospectively after radiosurgery. Pain - as main symptom - was classified by the Visual Analogue Scale (VAS) score. Every patient received single session radiosurgery after having been treated first-line with conventionally fractionated radiotherapy. Kaplan-Meier method and life tables were used to analyse freedom from local failure and overall survival. Results: At a median follow-up of 14.5 months the actuarial rates of freedom from local failure at 6/12/18 months were 93%, 88% and 85%, respectively. The median radiosurgery dose was 1 x 18 Gy (range 10-28 Gy) to the median 70% isodose. The VAS score of patients with pain (median 6) dropped significantly (median 4, p = 0.002). In 6 out of 7 patients worse sensory or motor deficit after SRS was caused by local or distant failures (diagnosed by CT/MRI). One patient with metastatic renal cell carcinoma developed a progressive complete paraparesis one year after the last treatment at lumbar level L3. Due to multiple surgery and radiosurgery treatments at the lumbar region and further local progression, the exact reason remained unclear. Apart from that, no CTC grade III or higher toxicity has been observed. Conclusions: By applying spinal radiosurgery relevant radiation doses can be limited to small parts of the myelon. This prevents myelopathic side effects and makes it an effective and safe treatment option for well-suited patients. Especially for previously irradiated patients with local failure or pain salvage SRS represents a valuable treatment option with high local control rates, low toxicity and significant pain reduction.

Background: Since 2002 MI and stroke, not cancer, are leading causes of death in women. We studied 30-days and 1 year mortality of 3441 patients undergoing coronary artery bypass grafting (CABG) operations in our institution performed either conventionally or off pump (OPCAB). Our objective was to investigate the gender-related mortality in both groups. Patients and Methods: Between 2004 and 2008, 3441 patients (733 women, 2708 men) underwent CABG. 252 women and 854 men were operated using OPCAB, 481 women and 1854 men using extracorporeal circulation (ECC). Medical data was prospectively entered and retrospectively reviewed. 30-days and one year mortality rates were analyzed with Kaplan-Meier estimates and Cox proportional hazards models. Linear and logistic regression models were used to test gender differences. Results: a) 30-day mortality using ECC: 5.2% in women vs. 2.5% in men (p = 0.001). One year ECC mortality: 8.7% in women vs. 4.8% in men (p = 0.0008). b) OPCAB: 30-days and 1 year mortality in women measured 1.7%. Mortality in men was 2.1% after 30 days and 3.7% after one year c) gender specific mortality: 30 days mortality in women was 1.7% using OPCAB and 5.2% using ECC (p = 0.002), one year mortality in women was 1.7% using OPCAB vs. 8.7% using ECC (p = 0.0004). In men, 30-days mortality in OPCAB was 2.1%, one year mortality was 3.7%; using ECC early and late mortality was 2.5% and 4.8%. Conclusions: Female gender is a strong independent predictor and risk factor of increased early and midterm postoperative mortality rates when ECC is used. OPCAB significantly reduces early and midterm postoperative mortality in women and may therefore be proposed as the preferred revascularization technique in female patients.

Background: Sentinel lymph node biopsy (SLNB) has become the standard care for melanoma and is an important diagnostic procedure. It has been doubted whether lymphoscintigraphy detects the correct sentinel lymph node (SLN) when excision of the tumor and SLNB are not performed at the same time. This would imply that this sequential approach may have an increased risk of undetected micrometastases resulting in a worse outcome. Objective: The purpose of the present study was to compare the outcome of melanoma patients having received excision of the tumor and SLNB either at the same time or consecutively. Methods: A total of 854 patients with cutaneous melanoma were enrolled in this retrospective study between September 1996 and November 2007. Disease-free (DFS) and overall survivals (OS) were estimated using the Kaplan-Meier product limit method and were analyzed by the log rank test. Results: No statistically significant difference was found regarding DFS, progression rates and OS in patients with primary tumor excision and SLNB at the same time compared with patients with excisional biopsy of primary tumor and SLNB at different times. Conclusion: These data suggest that excisional biopsy of the primary tumor does not prevent the correct SLN mapping in melanoma patients. Copyright (C) 2010 S. Karger AG, Basel

Background: Surgery is the primary treatment of skeletal metastases from renal cell carcinoma, because radiation and chemotherapy frequently are not effecting the survival. We therefore explored factors potentially affecting the survival of patients after surgical treatment. Methods: We retrospectively reviewed 101 patients operatively treated for skeletal metastases of renal cell carcinoma between 1980 and 2005. Overall survival was calculated using the Kaplan-Meier method. The effects of different variables were evaluated using a log-rank test. Results: 27 patients had a solitary bone metastasis, 20 patients multiple bone metastases and 54 patients had concomitant visceral metastases. The overall survival was 58% at 1 year, 37% at 2 years and 12% at 5 years. Patients with solitary bone metastases had a better survival (p < 0.001) compared to patients with multiple metastases. Age younger than 65 years (p = 0.036), absence of pathologic fractures (p < 0.001) and tumor-free resection margins (p = 0.028) predicted higher survival. Gender, location of metastases, time between diagnosis of renal cell carcinoma and treatment of metastatic disease, incidence of local recurrence, radiation and chemotherapy did not influence survival. Conclusions: The data suggest that patients with a solitary metastasis or a limited number of resectable metastases are candidates for wide resections. As radiation and chemotherapy are ineffective in most patients, surgery is a better option to achieve local tumor control and increase the survival.

The evidence concerning the management of shortened dental arch (SDA) cases is sparse. This multi-center study was aimed at generating data on outcomes and survival rates for two common treatments, removable dental prostheses (RDP) for molar replacement or no replacement (SDA). The hypothesis was that the treatments lead to different incidences of tooth loss. We included 215 patients with complete molar loss in one jaw. Molars were either replaced by RDP or not replaced, according to the SDA concept. First tooth loss after treatment was the primary outcome measure. This event occurred in 13 patients in the RDP group and nine patients in the SDA group. The respective Kaplan-Meier survival rates at 38 months were 0.83 (95% CI: 0.74-0.91) in the RDP group and 0.86 (95% CI: 0.78-0.95) in the SDA group, the difference being non-significant.

Objective: The aim of the current prospective study was to analyse the validity of MRI based diagnosis of brainstem gliomas which was verified by stereotactic biopsy and follow-up evaluation as well as to assess prognostic factors and risk profile. Methods: Between 1998 and 2007, all consecutive adult patients with radiologically suspected brainstem glioma were included. The MRI based diagnosis of the lesions was made independently by an experienced neuroradiologist. Histopathological evaluation was performed in all patients from paraffin embedded specimens obtained by multimodal image guided stereotactic serial biopsy technique. Histopathological results were compared with prior radiological assessment. Length of survival was estimated with the Kaplan–Meier method and prognostic factors were calculated using the Cox model. Results: 46 adult patients were included. Histological evaluation revealed pilocytic astrocytoma (n=2), WHO grade II glioma (n=14), malignant glioma (n=12), metastasis (n=7), lymphoma (n=5), cavernoma (n=1), inflammatory disease (n=2) or no tumour/ gliosis (n=3). Perioperative morbidity was 2.5% (n=1). There was no permanent morbidity and no mortality. All patients with ‘‘no tumour’’ or ‘‘inflammatory disease’’ survived. Patients with low grade glioma and malignant glioma showed a 1 year survival rate of 75% and 25%, respectively; the 1 year survival rate for patients with lymphoma or metastasis was 30%. In the subgroup with a verified brainstem glioma, negative predictors for length of survival were higher tumour grade (p=0.002) and Karnofsky performance score (70 (p=0.004). Conclusion: Intra-axial brainstem lesions with a radiological pattern of glioma represent a very heterogeneous tumour group with completely different outcomes. Radiological features alone are not reliable for diagnostic classification. Stereotactic biopsy is a safe method to obtain a valid tissue diagnosis, which is indispensible for treatment decision.

Background: Mantle cell lymphoma (MCL) shows a particularly bad prognosis with a median survival of less than 5 years. There is no generally established prognostic classification system for patients with MCL as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) have been developed based on data of patients with diffuse large B-cell and follicular lymphoma, respectively. The data of 455 patients with advanced stage MCL treated within three randomized trials of German Low-Grade Lymphoma Study Group (GLSG) and European MCL Network were used to clarify the prognostic relevance of IPI, FLIPI and potential prognostic factors and, if needed, to develop a new prognostic index. Methods: The outcome parameter was overall survival, the time from trial registration to death from any cause. Potential prognostic factors were the clinical parameters documented after primary diagnosis before start of treatment. The prognostic relevance of IPI and FLIPI was evaluated with Kaplan-Meier estimates and the log rank test. Candidate prognostic factors were analyzed using univariate Cox regression. In multiple Cox regression, independent prognostic factors were identified with backward elimination and the prognostic score was determined. Prognostic groups were defined with optimal cutpoints for the prognostic score maximizing the log rank statistic. Internal validation was performed using the bootstrap method. Results: According to the IPI more than two thirds of patients were classified into the low intermediate or high intermediate risk groups whose survival curves were not clearly separated. According to the FLIPI, 6% of patients were classified into the low risk group, survival curves of low risk and intermediate risk patients were not separated, and the high risk group of almost two thirds of patients showed a relatively good survival. Of the candidate prognostic factors, age, ECOG performance status, B-symptoms, spleen involvement, tumor size, serum LDH activity, leukocyte, lymphocyte, granulocyte and monocyte count, hemoglobin, and beta2-microglobulin showed univariate prognostic relevance. In contrast, sex, Ann Arbor stage III vs. IV, bone marrow involvement, number of extranodal sites, number of involved nodal areas, platelet count, and albumin showed no prognostic relevance. Multiple Cox regression identified age, performance status, LDH and leukocyte count as independent prognostic factors. Using these four parameters, a new prognostic index, the mantle cell lymphoma international prognostic index (MIPI) defined three prognostic groups with significantly different overall survival. Bootstrap validation confirmed the separation of the prognostic groups and indicated superiority over IPI and FLIPI. Conclusions: In this work a new prognostic index for patients with advanced stage MCL was defined based on four easily available clinical prognostic factors. The modest prognostic relevance of IPI and FLIPI underlines the inappropriateness of transferring results from one lymphoma entity to another. The results of this work may be applied in clinical research for stratified randomization, risk-adjusted analyses, and as a reference to establish new biologic or molecular prognostic factors. Furthermore, the new prognostic index may facilitate risk-adapted treatment strategies to improve the prognosis of this severe disease.