Podcasts about P53

In this episode of Hema Now, Jonathan Sackier is joined by John Riches, Clinical Reader in Cancer Immunometabolism at the Barts Cancer Institute and Honorary Consultant Haemato-oncologist. They explore how metabolic shifts drive lymphoma progression, the potential of immunotherapy, and what the future holds for treating lymphoid malignancies.  Timestamps:      00:00 – Introduction  01:46 – Riches' journey into haematology  03:42 – What is T cell exhaustion?  07:06 – The key role of metabolism in lymphoma  09:33 - Richter's syndrome  13:17 – Breakthroughs in immunotherapy  20:27 – The challenges of translational research  25:39 – B cells in autoimmune diseases  28:16 – The potential of breath biopsy  32:58 – Riches' three wishes for healthcare 

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Dr. Ebony Hoskins and Dr. Andreas Obermair discuss the surgical management of gynecologic cancers, including the role of minimally invasive surgery, approaches in fertility preservation, and the nuances of surgical debulking. TRANSCRIPT Dr. Ebony Hoskins: Hello and welcome to the ASCO Daily News Podcast, I'm Dr. Ebony Hoskins. I'm a gynecologic oncologist at MedStar Washington Hospital Center in Washington, DC, and your guest host of the ASCO Daily News Podcast. Today we'll be discussing the surgical management of gynecologic cancer, including the role of minimally invasive surgery (MIS), approaches in fertility preservation, and the nuances of surgical debulking, timing, and its impact on outcomes. I am delighted to welcome Dr. Andreas Obermair for today's discussion. Dr. Obermair is an internationally renowned gynecologic oncologist, a professor of gynecologic oncology at the University of Queensland, and the head of the Queensland Center for Gynecologic Cancer Research. Our full disclosures are available in the transcript of this episode. Dr. Obermair, it's great speaking with you today. Dr. Andreas Obermair: Thank you so much for inviting me to this podcast. Dr. Ebony Hoskins: I am very excited.  I looked at your paper and I thought, gosh, is everything surgical? This is everything that I deal with daily in terms of cancer in counseling patients. What prompted this review regarding GYN cancer management? Dr. Andreas Obermair: Yes, our article was published in the ASCO Educational Book; it is volume 44 in 2024. And this article covers some key aspects of targeted precision surgical management principles in endometrial cancer, cervical cancer, and ovarian cancer. While surgery is considered the cornerstone of gynecologic cancer treatment, sometimes research doesn't necessarily reflect that. And so I think ASCO asked us to; so it was not just me, there was a team of colleagues from different parts of the United States and Australia to reflect on surgical aspects of gynecologic cancer care and I feel super passionate about that because I do believe that surgery has a lot to offer. Surgical interventions need to be defined and overall, I see the research that I'm doing as part of my daily job to go towards precision surgery. And I think that is, well, that is something that I'm increasingly passionate for. Dr. Ebony Hoskins: Well, I think we should get into it. One thing that comes to mind is the innovation of minimally invasive surgery in endometrial cancer. I always reflect on when I started my fellowship, I guess it's been about 15 years ago, all of our endometrial cancer patients had a midline vertical incision, increased risk of abscess, infections and a long hospital stay. Do you mind commenting on how you see management of endometrial cancer today? Dr. Andreas Obermair: Thank you very much for giving the historical perspective because the generation of gynecologic oncologists today, they may not even know what we dealt with, what problems we had to solve. So like you, when I was a fellow in gynecologic oncology, we did midline or lower crosswise incisions, the length of stay was, five days, seven days, but we had patients in hospital because of complications for 28 days. We took them back to the operating theaters because those are patients with a BMI of 40 plus, 45, 50 and so forth. So we really needed to solve problems. And then I was exposed to a mentor who taught minimal invasive surgery. And in Australia he was one of the first ones who embarked on that. And I can remember, I was mesmerized by this operation, like not only how logical this procedure was, but also we did rounds afterwards. And I saw these women after surgery and I saw them sitting upright, lipstick on, having had a full meal at the end of the day. And I thought, wow, this is the most rewarding experience that I have to round these patients after surgery. And so I was thinking, how could I help to establish this operation as standard? Like a standard that other people would accept this is better. And so I thought we needed to do a trial on this. And then it took a long time. It took a long time to get the support for the [LACE - Laparoscopic Approach to Cancer of the Endometrium] trial. And in this context, I just also wanted to remind us all that there were concerns about minimal invasive surgery in endometrial cancer at the time. So for example, one of the concerns was when I submitted my grant funding applications, people said, “Well, even if we fund you, wouldn't be able to do this trial because there are actually no surgeons who actually do minimally invasive surgery.” And at the time, for example, in Australia, there were maybe five people, a handful of people who were able to do this operation, right? This was about 20 years ago. The other concern people had was they were saying, could minimally invasive surgery for endometrial cancer, could that cause port side metastasis because there were case reports. So there were a lot of things that we didn't know anyway. We did this trial and I'm super happy we did this trial. We started in 2005, and it took five years to enroll. At the same time, GOG LAP2 was ramping up and the LACE trial and GOG LAP2 then got published and provided the foundations for minimally invasive surgery in endometrial cancer. I'm super happy that we have randomized data about that because now when we go back and now when people have concerns about this, should we do minimally invasive surgery in P53 mutant tumors, I'm saying, well, we actually have data on that. We could go back, we could actually do more research on that if we wanted to, but our treatment recommendations are standing on solid feet. Dr. Ebony Hoskins: Well, my patients are thankful. I see patients all the time and they have high risk and morbidly obese, lots of medical issues and actually I send them home most the same day. And I think, you know, I'm very appreciative of that research, because we obviously practice evidence-based and it's certainly a game changer. Let's go along the lines of MIS and cervical cancer. And this is going back to the LACC [Laparoscopic Approach to Cervical Cancer] trial.  I remember, again, one of these early adopters of use of robotic surgery and laparoscopic surgery for radical hysterectomy and thought it was so cool. You know, we can see all the anatomy well and then have the data to show that we actually had a decreased survival. And I even see that most recent updated data just showing it still continued. Can you talk a little bit about why you think there is a difference? I know there's ongoing trials, but still interested in kind of why do you think there's a survival difference? Dr. Andreas Obermair:  So Ebony, I hope you don't mind me going back a step. So the LACC study was developed from the LACE trial. So we thought we wanted to reproduce the LACE data/LAP2 data. We wanted to reproduce that in cervix cancer. And people were saying, why do you do that? Like, why would that be different in any way? We recognize that minimally invasive radical hysterectomy is not a standard. We're not going to enroll patients in a randomized trial where we open and do a laparotomy on half the patients. So I think the lesson that really needs to be learned here is that any surgical intervention that we do, we should put on good evidence footing because otherwise we're really running the risk of jeopardizing patients' outcomes. So, that was number one and LACC started two years after LACE started. So LACC started in 2007, and I just wanted to acknowledge the LACC principal investigator, Dr. Pedro Ramirez, who at the time worked at MD Anderson. And we incidentally realized that we had a common interest. The findings came totally unexpected and came as an utter shock to both of us. We did not expect this. We expected to see very similar disease-free and overall survival data as we saw in the endometrial cancer cohort. Now LACC was not designed to check why there was a difference in disease-free survival. So this is very important to understand. We did not expect it. Like, so there was no point checking why that is the case. My personal idea, and I think it is fair enough if we share personal ideas, and this is not even a hypothesis I want to say, this is just a personal idea is that in endometrial cancer, we're dealing with a tumor where most of the time the cancer is surrounded by a myometrial shell. And most of the time the cancer would not get into outside contact with the peritoneal cavity. Whereas in cervix cancer, this is very different because in cervix cancer, we need to manipulate the cervix and the tumor is right at the outside there. So I personally don't use a uterine manipulator. I believe in the United States, uterine manipulators are used all the time. My experience is not in this area, so I can't comment on that. But I would think that the manipulation of the cervix and the contact of the cervix to the free peritoneal cavity could be one of the reasons. But again, this is simply a personal opinion. Dr. Ebony Hoskins: Well, I appreciate it. Dr. Andreas Obermair: Ebony at the end of the day, right, medicine is empirical science, and empirical science means that we just make observations, we make observations, we measure them, and we pass them on. And we made an observation. And, and while we're saying that, and yes, you're absolutely right, the final [LACC] reports were published in JCO recently. And I'm very grateful to the JCO editorial team that they accepted the paper, and they communicated the results because this is obviously very important. At the same time, I would like to say that there are now three or four RCTs that challenge the LACC data. These RCTs are ongoing, and a lot of people will be looking forward to having these results available. Dr. Ebony Hoskins: Very good. In early-stage cervical cancer, the SHAPE trial looked at simple versus radical hysterectomy in low-risk cervical cancer patients. And as well all know, simple hysterectomy was not inferior to radical hysterectomy with respect to the pelvic recurrence rate and any complications related to surgery such as urinary incontinence and retention. My question for you is have you changed your practice in early-stage cervical cancer, say a patient with stage 1B1 adenocarcinoma with a positive margin on conization, would you still offer this patient a radical hysterectomy or would you consider a simple hysterectomy? Dr. Andreas Obermair:  I think this is a very important topic, right? Because I think the challenge of SHAPE is to understand the inclusion criteria. That's the main challenge. And most people simplify it to 2 cm, which is one of the inclusion criteria but there are two others and that includes the depth of invasion. Dr. Marie Plante has been very clear. Marie Plante is the first author of the SHAPE trial that's been published in the New England Journal of Medicine only recently and Marie has been very clear upfront that we need to consider all three inclusion criteria and only then the inclusion criteria of SHAPE apply. So at the end of the day, I think what the SHAPE trial is telling us that small tumors that would strictly fulfill the criteria of a 1B or 1B1 cancer of the cervix can be considered for a standard type 1 or PIVA type 1 or whatever classification we're trying to use will be eligible. And that makes a lot of sense. I personally not only look at the size, I also look at the location of the tumor. I would be very keen that I avoid going through tumor tissue because for example, if you have a tumor that is, you know, located very much in one corner of the cervix and then you do a standard hysterectomy and then you have a positive tumor margin that would be obviously, most people would agree it would be an unwanted outcome. So I'd be very keen checking the location, the size of the tumor, the depths of invasion and maybe then if the tumor for example is on one side of the cervix you can do a standard approach on the contralateral side but maybe do a little bit more of a margin, a parametrial margin on the other side. Or if a tumor is maybe on the posterior cervical lip, then you don't need to worry so much about the anterior cervical margin, maybe take the rectum down and maybe try to get a little bit of a vaginal margin and the margin on the uterus saccals. Just really to make sure that you do have margins because typically if we get it right, survival outcomes of clinical stage 1 early cervix cancer 1B1 1B 2 are actually really good. It is a very important thing that we get the treatment right. In my practice, I use a software to record my treatment outcomes and my margins. And I would encourage all colleagues to be cognizant and to be responsible and accountable to introduce accountable clinical practice, to check on the margins and check on the number on the percentage of patients who require postoperative radiation treatment or chemo radiation. Dr. Ebony Hoskins: Very good. I have so many questions for you. I don't know the statistics in Australia, but here, there's increased rising of endometrial cancer and certainly we're seeing it in younger women. And fertility always comes up in terms of kind of what to do. And I look at the guidelines and, see if I can help some of the women if they have early-stage endometrial cancer. Your thoughts on what your practice is on use of someone who may meet criteria, if you will. The criteria I use is grade 1 endometrioid adenocarcinoma. No myometria invasion. I try to get MRI'd and make sure that there's no disease outside the endometrium. And then if they make criteria, I typically would do an IUD. Can you tell me what your practice is and where you've had success? Dr. Andreas Obermair: So, we initiated the feMMe clinical trial that was published in 2021 and it was presented in a Plenary at one of the SGO meetings. I think it was in 2021, and we've shown complete pathological response rates after levonorgestrel intrauterine device treatment. And so in brief, we enrolled patients with endometrial hyperplasia with atypia, but also patients with grade 1 endometrial adenocarcinoma. Patients with endometrial hyperplasia with atypia had, in our series, had an 85 % chance of developing a complete pathological response. And that was defined as the complete absence of any atypia or cancer. So endometrial hyperplasia with atypia responded in about 85%. In endometrial cancer, it was about half, it was about 45, 50%. In my clinical practice, like as you, I see patients, you know, five days a week. So I'm looking after many patients who are now five years down from conservative treatment of endometrial cancer. There are a lot of young women who want to get pregnant, and we had babies, and we celebrate the babies obviously because as gynecologist obstetricians it couldn't get better than that, right, if our cancer patients have babies afterwards. But we're also treating women who are really unfit for surgery and who are frail and where a laparoscopic hysterectomy would be unsafe. So this phase is concluded, and I think that was very successful. At least we're looking to validate our data. So we're having collaborations, we're having collaborations in the United States and outside the United States to validate these data. And the next phase is obviously to identify predictive factors, to identify predictors of response. Because as you can imagine, there is no point treating patients with a levonorgestrel intrauterine joint device where we know in advance that she's not going to respond. So this is a very, very fascinating story and we got our first set of data already, but now we just really need to validate this data. And then once the validation is done, my unit is keen to do a prospective validation trial. And that also needs to involve international collaborators. Dr. Ebony Hoskins: Very good. Moving on to ovarian cancer, we see patients with ovarian cancer with, say, at least stage 3C or higher who started neoadjuvant chemotherapy. Now, some of these patients are hearing different things from their medical oncologist versus their gynecologic oncologist regarding the number of cycles of neoadjuvant chemotherapy after getting diagnosed with ovarian cancer. I know that this can be confusing for our patients coming from a medical oncologist versus a gynecologic oncologist. What do you say to a patient who is asking about the ideal number of chemotherapy cycles prior to surgery? Dr. Andreas Obermair: So this is obviously a very, very important topic to talk about. We won't be able to provide a simple off the shelf answer for that, but I think data are emerging.  The ASCO guidelines should also be worthwhile considering because there are actually new ASCO Guidelines [on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer] that just came out a few weeks ago and they would suggest that we should be aiming for R0 in surgery. If we can maybe take that as the pivot point and then go back and say, okay, so what do need to do to get the patient to zero?  I'm not an ovarian cancer researcher; I'm obviously a practicing gynecologic oncologist. I think about things a lot and things like that. In my practice, I would want a patient to develop a response after neoadjuvant chemotherapy. So, if a patient doesn't have a response after two or three cycles, then I don't see the point for me to offer her an operation. In my circle with the medical oncologists that I work with, I have a very, very good understanding. So, they send the patient to me, I take them to the theater. I take a good chunk of tissue from the peritoneum. We have a histopathologic diagnosis, we have a genomic diagnosis, they go home the same day. So obviously there is no hospital stay involved with that. They can start the chemotherapy after a few days. There is no hold up because the chances of surgical complication in a setting like this is very, very low. So I use laparoscopy to determine whether the patient responds or not. And for many of my patients, it seems to work. It's obviously a bit of an effort and it takes operating time. But I think I'm increasing my chances to make the right decision. So, coming back to your question about whether we should give three or six cycles, I think the current recommendations are three cycles pending the patient's response to neoadjuvant chemotherapy because my aim is to get a patient to R0 or at least minimal residual disease. Surgery is really, in this case, I think surgery is the adjunct to systemic treatment. Dr. Ebony Hoskins: Definitely. I think you make a great point, and I think the guideline just came out, like you mentioned, regarding neoadjuvant. And I think the biggest thing that we need to come across is the involvement of a gynecologic oncologist in patients with ovarian cancer. And we know that that survival increases with that involvement. And I think the involvement is the surgery, right? So, maybe we've gotten away from the primary tumor debulking and now using more neoadjuvant, but surgery is still needed. And so, I definitely want to have a take home that GYN oncology is involved in the care of these patients upfront. Dr. Andreas Obermair: I totally support that. This is a very important statement. So when I'm saying surgery is the adjunct to medical treatment, I don't mean that surgery is not important. Surgery is very important. And the timing is important. And that means that the surgeons and the med oncs need to be pulling on the same string. The med oncs just want to get the cytotoxic into the patients, but that's not the point, right? We want to get the cytotoxic into the patients at the right time because if we are working under this precision surgery, precision treatment mantra, it's not only important what we do, but also doing it at the right time. And ideally, I I would like to give surgery after three cycles of neoadjuvant chemotherapy, if that makes sense. But sometimes for me as a surgeon, I talk to my med onc colleagues and I say, “Look, she doesn't have a good enough response to her treatment and I want her to receive six cycles and then we re-evaluate or change medical treatment,” because that's an alternative that we can swap out drugs and treat upfront with a different drug and then sometimes they do respond. Dr. Ebony Hoskins:  I have maybe one more topic. In the area I'm in, in the Washington D.C. area, we see lots of endometrial cancer and they're not grade 1, right? They're high-risk endometrial cancer and advanced. So a number of patients with stage 3 disease, some just kind of based off staging and then some who come in with disease based off of the CT scan, sometimes omental caking, ascites. And the real question is we have extrapolated the use of neoadjuvant chemotherapy to endometrial cancer. It's similar, but not the same. So my question is in an advanced endometrial cancer, do you think there's still a role, when I say advanced, I mean, maybe stage 4, a role for surgery? Dr. Andreas Obermair: Most definitely. But the question is when do you want to give this surgery? Similar to ovarian cancer, in my experience, I want to get to R0. What am I trying to achieve here? So, I reckon we should do a trial on this. And I reckon we have, as you say, the number of patients in this setting is increasing, we could do a trial. I think if we collaborate, we would have enough patients to do a proper trial. Obviously, we would start maybe with a feasibility trial and things like that. But I reckon a trial would be needed in this setting because I find that the incidence that you described, that other people would come across, they're becoming more and more common. I totally agree with you, and we have very little data on that. Dr. Ebony Hoskins: Very little and we're doing what we can. Dr. Obermair, thank you for sharing your fantastic insights with us today on the ASCO Daily News Podcast and for all the work you do to advance care for patients with gynecologic cancer. Dr. Andreas Obermair: Thank you, Dr. Hoskins, for hosting this and it's been an absolute pleasure speaking with you today. Dr. Ebony Hoskins: Definitely a pleasure and thank you to our listeners for your time today. Again, Dr. Obermair's article is titled, “Controversies in the Surgical Management of Gynecologic Cancer: Balancing the Decision to Operate or Hesitate,” and was published in the 2024 ASCO Educational Book. And you'll find a link to the article 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. Ebony Hoskins @drebonyhoskins Dr. Andreas Obermair @andreasobermair Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Ebony Hoskins: No relationships to disclose. Dr. Andreas Obermair: Leadership: SurgicalPerformance Pty Ltd. Stock and Ownership Interests: SurgicalPerformance Pty Ltd. Honoraria: Baxter Healthcare Consulting or Advisory Role: Stryker/Novadaq Patents, Royalties, and Other Intellectual Property: Shares in SurgicalPerformance Pty Ltd. Travel, Accommodation, Expenses: Stryker    

JCO PO author Dr. David R. Gandara at UC Davis Comprehensive Cancer Center, shares insights into his JCO PO article, “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer,” one of the Top Articles of 2024. Host Dr. Rafeh Naqash and Dr. Gandara discuss how the PROphet® blood test supports first-line immunotherapy treatment decisions for metastatic NSCLC patients. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today, we are absolutely thrilled to be joined by Dr. David R. Gandara, Professor of Medicine Emeritus, Co-Director of the Center for Experimental Therapeutics and Cancer and Senior Advisor to the Director at UC Davis Comprehensive Cancer Center and also the senior author of the JCO Precision Oncology article entitled “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer.” This was one of the top performing articles of 2024, which is one of the reasons why we wanted to bring it in for a podcast discussion. At the time of this recording, our guest's disclosures will be linked in the transcript.  David, it is an absolute pleasure to have you today. For somebody like you who's led the field of lung cancer over the years, I'm really excited that you are going to be talking to us about this very interesting article, especially given that I think you're one of the big proponents of liquid biopsies and plasma-based testing. So, for the sake of our listeners - which comprises of academic oncologists, community oncologists, trainees - could you tell us where the biomarker landscape for non-small cell lung cancer is currently, and then we can try to take a deeper dive into this article. Dr. David Gandar: Okay. Well, thank you, Rafeh. It's a pleasure to be with you here today. And I think the current landscape for biomarkers for immunotherapy in non-small cell lung cancer is a mess. There's no better way to describe it. That makes this paper describing a new plasma proteomic assay even more important. So I'll just give you a perspective. There are 14 trials, phase three trials, that were done in first line non-small cell lung cancer advanced stage of immunotherapy versus chemotherapy and some other aspects, although they vary tremendously. Some of them were checkpoint monotherapy, some combined with chemotherapy, some combined with CTLA-4 inhibitors and so forth. 12 out of the 14 were positive, 12 got FDA approval. So there are 12 different options that an oncologist could use. Some of them were squamous cell only, some non-squamous, some used PD-L1 as a biomarker driven part of the study. Some used TMB, tumor mutational burden, some were agnostic. So when you put all of this together, an oncologist can pick and choose among all these various regimens. And by and large, it's PD-L1 that is the therapeutic decision maker.  ASCO actually, I think, has done the very best job of making a guideline, and it's, as you well know, called a living guideline, it's dynamic. And it is much easier to interpret, for me and I think for oncologists, than some of the other guidelines. It's got a green light and a red light, it may be kind of orange. And so the green light means this is a strong recommendation by the guideline committee. The orange means it's weak. For this purpose, non-small cell lung cancer, advanced stage, only a very few of the recommendations were green. It's mainly monotherapy and patients with cancers with a PD-L1 over 50%. In our surveys, at our meetings, less than 50% of oncologists in the United States are following these guidelines. Why? Because they don't trust the biomarker. And TMB has the same sort of limitations. They're not bad biomarkers, they're incomplete. They're only looking at a part of the story. So that means we need a new biomarker. And this is one that, I think, the data are quite impressive and we'll discuss it more. Dr. Rafeh Naqash: Absolutely. Like you said, abundance of many therapy options, but not necessarily everything works the same in different subsets of PD-L1 positivity or different subsets of patients with different levels of tumor burden. And like you said, again, difficulty in trying to identify the right biomarker. And that's a nice segue to this PROphet test that you guys ran. So can you tell us a little bit about the plasma proteomic assay? Because to the best of my knowledge, there's not a lot of validated plasma proteomic assays. A lot has been done on the tumor tissue side as far as biomarkers are concerned, but not much on the blood side, except for maybe ctDNA MRD testing. So what was the background for trying to develop a plasma-based proteomic test? And then how did this idea of testing it in the lung cancer setting come into play? And then we can go into the patient population specifics, the cohort that you guys have. Dr. David Gandara: Okay. Well, of course there's a company behind this assay, it's called OncoHost, and I'm a consultant for them. And they came to me two years ago and they said, “We have something different from anyone else.” And they explained the science to me, as well as some other lung cancer experts here in the United States. I'm not a proteomic expert, of course, but they developed an AI machine learning platform to assess plasma proteins in normal people and in people with cancer, and specifically then in people with non-small cell lung cancer. They identified over 7,000 proteins that had cancer implications for therapy, for resistance, for prognosis, etc., and they categorized them based on the literature, TCGA data, etc., and used this machine learning process to figure out which proteins might be most specific for non-small cell lung cancer. And that's where they started. And so out of that 7,000 proteins, where they've identified which ones are angiogenic, which ones are involved with EMT or cell cycle or whatever it might be, they distilled it down to 388 proteins which they thought were worth testing in non-small cell lung cancer. And that's when I became involved.  They had a retrospective cohort of patients that had been treated with various immunotherapies. They looked at the analytic validation first, then applied it to this cohort. It looked good. Then they had a very large cohort, which they split, as you usually do with an assay, into a test set and then a validation set. For the test set, they wanted something more than a response. They wanted some indicator of long term benefit because that's where immunotherapy differentiates itself from chemotherapy and even targeted therapy. And so they picked PFS at 12 months. And I became involved at that point and it looked really good. I mean, if you look at the figures in the manuscript, the AUC is superb about their prediction and then what actually happened in the patient. And then in this paper, we applied it to a validation set of over 500 patients in a prospective trial, not randomized, it's called an observational trial. The investigator got to pick what they thought was the best therapy for that patient. And then in a blinded fashion, the proteomic assay experts did the analysis and applied it to the group.  And so what that means is some of the patients got chemotherapy alone, some got checkpoint immunotherapy monotherapy, some got in combination with chemotherapy. None of the patients in this study got a CTLA-4 inhibitor. That work is ongoing now. But what the study showed was that this assay can be used together with PD-L1 as what I would call a composite biomarker. You take the two together and it informs the oncologist about the meaning of that PD-L1. I'll give you an example. If that patient has a PD-L1 over 50% in their cancer and yet the PROphet test is negative, meaning less than 5 - it's a 0 to 10 scale - that patient for survival is better served by getting chemotherapy and immunotherapy. However, if the PROphet test is positive and the PD-L1 is over 50%, then the survival curves really look equivalent. As I said earlier, even in that group of patients, a lot of oncologists are reluctant to give them monotherapy. So if you have a test and the same sort of example is true for PD-L1 0, that you can differentiate. So this can really help inform the oncologist about what direction to go. And of course then you use your clinical judgment, you look at what you think of as the aggressiveness of the tumor or their liver metastases, etc. So again, that's how this test is being used for non-small cell lung cancer. And maybe I'll stop there and then I'll come back and add some other points. Dr. Rafeh Naqash: I definitely like your analogy of this therapy de-escalation strategy. Like you mentioned for PD-L1 high where the PROphet test is negative, then perhaps you could just go with immunotherapy alone. In fact, interestingly enough, I was invited to a talk at SITC a couple of weeks back and this exact figure that you're referring to was one of the figures in my slide deck. And it happened by chance that I realized that we were doing a podcast on the same paper today.  So I guess from a provocative question standpoint, when you look at the PD-L1 high cohort in the subset where you didn't see a survival difference for chemo plus immunotherapy versus immunotherapy alone, do you think any element of that could have been influenced by the degree of PD-L1 positivity above 50%? Meaning could there have been a cohort that is, let's say PD-L1 75 and above, and that kind of skews the data because I know you've published on this yourself also where the higher the PD-L1 above 50%, like 90% PD-L1 positivity survival curves are much better than 50% to 89%. So could that have somehow played a role? Dr. David Gandara: The first thing to say is that PD-L1 and the PROphet score, there's very little overlap. I know that sounds surprising, but it's also true for tumor mutational burden. There's very little overlap. They're measuring different things. The PD-L1 is measuring a specific regulatory protein that is applicable to some patients, but not all. That's why even in almost all of the studies, people with PD-L1 0 could still have some survival benefit. But in this case they're independent. And not in this paper, but in other work done by this group, the PROphet group, they've shown that the PROphet score does not seem to correlate with super high PD-L1. So it's not like the cemiplimab data where if you have a PD-L1 of greater than 90%, then of course the patient does spectacularly with monotherapy. The other thing that's important here is they had a group of around a little less than 100 patients that got chemotherapy alone. The PROphet score is agnostic to chemotherapy. And so that means that you're not just looking at some prognostic factor. It's actually clinical utility on a predictive basis. Dr. Rafeh Naqash: I think those are very important points. I was on a podcast a couple of days back. I think there's a theme these days we're trying to do for JCO Precision Oncology, we're trying to do a few biomarker based podcasts, and the most recent one that we did was using a tissue transcriptome with ctDNA MRD and you mentioned the composite of the PD-L1 and the PROphet test and they use a composite of the tissue transcriptome. I believe they called it the VIGex test as well as MRD ctDNA. And when your ctDNA was negative at, I believe, the three month mark, those individuals had the highest inflamed VIGex test or highest infiltration of T cells, STING pathway, etc. So are there any thoughts of trying to add or correlate tissue based biomarkers or ctDNA based correlations as a further validation in this research with the company? Dr. David Gandara: Right. So there are many things that are being looked at, various composites looking at the commutations that might affect the efficacy of immunotherapy and how they correlate with profit positivity or negativity. And I'll just give the examples of STK11 and KEAP1. As you know, there's some controversy about whether these are for immunotherapy, whether they're more prognostic or predictive. I'm one of the co-authors among many in the recently published Nature paper by Dr. Skoulidis and the group at MD Anderson which report that for KEAP1 positive especially, but also SDK11 mutated getting immunotherapy, that that's where the CTLA-4 inhibitors actually play the greatest role. So realizing that this is still controversial, there are preliminary data, not published yet, that'll be presented at an upcoming meeting, looking at many of these other aspects, P53, SCK11, KEAP1, other aspects, TMB, that's actually already published, I think in one of their papers. So yes, there's lots of opportunities.  The other cool thing is that this isn't a test, it's a platform. And so that means that the OncoHost scientists have already said, “What if we look at this test, the assay in a group of patients with small cell lung cancer?” And so I just presented this as a poster at the world conference in San Diego. And it turns out if you look at the biology of small cell, where neither PD-L1 nor TMB seem to be very important, if you look at the biology of small cell and you form an assay, it only shares 44 proteins out of the 388 with non-small cell. It's a different biology. And when we applied that to a group of patients with small cell lung cancer, again it had really pretty impressive results, although still a fairly small number of patients. So we have a big phase three study that we're doing with a pharmaceutical company developing immunotherapy where we are prospectively placing the PROphet test in a small cell trial.  The platform can also be altered for other cancer types. And at AACR, Dr. Jarushka Naidoo presented really impressive data that you can modify the proteins and you can predict immunotherapy side effects. So this is not like a company that says, “We have one test that's great for everything.” You know how some companies say, “Our test, you can use it for everything.” This company is saying we can alter the protein structures using AI machine learning assisted process to do it and we can have a very informed assay in different tumor types and different situations. So to me, it's really exciting. Dr. Rafeh Naqash: Definitely to me, I think, combining the AI machine learning aspect with the possibility of finding or trying to find a composite biomarker using less invasive approaches such as plasma or blood, definitely checks a lot of boxes. And as you mentioned, trying to get it to prospective trials as an integral biomarker perhaps would be likely the next step. And hopefully we see some interesting, exciting results where we can try to match or stratify patients into optimal combination therapies based on this test.  So now to the next aspect of this discussion, David, which I'm really excited about. You've been a leader and a mentor to many. You've led ISLC and several other corporate group organizations, et cetera. Can you tell us, for the sake of all the listeners, junior investigators, trainees, what being a mentor has meant for you? How your career has started many years back and how it's evolved? And what are some of the things that you want to tell people for a successful and a more exciting career as you've led over the years? Dr. David Gandara: Well, thank you for the question. Mentoring is a very important part of my own career. I didn't have an institutional mentor when I was a junior investigator, but I had a lot of senior collaborators, very famous people that kind of took me under their wing and guided me. And I thought when I basically establish myself, I want to give back by being a mentor to other people. And you wouldn't believe the number of people that I'm even mentoring today. And some of them are not medical oncologists, they're surgeons, they're radiation oncologists, they're basic scientists. Because you don't have to be an expert in that person's field to be a mentor. It helps, but in other words, you can guide somebody in what are the decision making processes in your career. When is it time to move from this institution onward because you can't grow in the institution you're in, either because it's too big or it's too small? So I established a leadership academy in the Southwest Oncology Group, SWOG. I've led many mentoring courses, for instance, for ISLC, now for International Society Liquid Biopsy, where I'm the executive committee liaison for what's called The Young Committee. So ISLB Society, totally devoted to liquid biopsy, six years old now, we have a Young Committee that has a budget. They develop projects, they publish articles on their own, they do podcasts. So what I'm saying is those are all things that I think opens up opportunities. They're not waiting behind senior people, they are leading themselves.  We just, at our International Lung Cancer Congress, reestablished a fellows program where a group of fellows are invited to that Huntington beach meeting. It's now in its 25th year and we spend a day and a half with them, mentoring them on career building. I'll just give you my first, I have the “Letterman Top 10”. So my first recommendation is if all you have is lemons, make lemonade. And what I'm meaning is find what you can do at your institution if you're a junior person, what you can claim to be your own and make the very best of it. But then as you get further along in my recommendations, one of them is learn when to say ‘no'. Because as a junior investigator the biggest threat to your career is saying ‘yes' to everybody and then you become overwhelmed and you can't concentrate. So I'll stop there. But anyway, yes, mentoring is a big part of my life. Dr. Rafeh Naqash: Well, thank you, David. This is definitely something that I'm going to try to apply to my career as well. And this has been an absolute pleasure, especially with all the insights that you provided, not just on the scientific side but also on the personal career side and the mentorship side. And hopefully we'll see more of this work that you and other investigators have led and collaborated on. perhaps more interesting plasma based biomarkers. And hopefully some of that work will find its home in JCO Precision Oncology. Thank you again for joining us today. Dr. David Gandara: My pleasure. Dr. Rafeh Naqash: And thank you for listening to JCO Precision Oncology Conversations. 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 ASCO shows at 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.   Dr. David Gandara Disclosures: Consulting or Advisory Role Company: Henlius USA, Foundation Medicine, Janssen Pharma, Merck & Co, Mirati Therapeutics, Regeneron, AstraZeneca, Guardant Health, Genentech, Exact Sciences  Research Funding Company: Amgen, Genentech, Astex Pharma  

De'Ann Richter is a renowned coach at Breast Cancer Conqueror who works closely with Veronique Desaulniers. Their mission is to provide women and men with a variety of options when it comes to cancer, specifically breast cancer. Learn the many options available to combat breast cancer, both conventional medicine and alternative approaches to empower you to live your best life through healing body, mind, and soul. Look for special supplements marked with an asterisk* New episodes of Welcome to Wellness released every Friday! Not listening on Spotify? Show notes at: https://www.ashleydeeley.com/w2w/breastcancerconqueror Episode brought to you by: Dry Farm Wines Episode brought to you by: ⁠⁠⁠⁠⁠Thyroid Fixxr⁠⁠⁠⁠⁠ (Code: WELCOMEWELLNESS) Episode brought to you by: ⁠⁠VieLight⁠⁠ (Code: DEELEY10) Episode brought to you by: ⁠⁠⁠⁠⁠Methylene Blue⁠⁠⁠⁠⁠ (Code: ASHLEY15) 3:23: Has been a coach for over 10 years 4:23: The Seven Essentials Let Food Be Your Medicine Reduce Your Toxic Exposure Balance Your Energy Heal Your Emotional Wounds Embrace Biological Dentistry Repair Your Body with Therapeutic Plants Adopt Very Early Detection 8:15: Dr Veronique Desaulniers, two-time breast cancer survivor 10:29: How to heal 12:16: * Broccoli Sprouts * Sulforaphane supplement 12:42: * Vitamin D 12:54: *Curcumin 13:05: *Modified Citrus Pectin / or, Econugenics brand of Modified Citrus Pectin powder 13:35: Modified citrus pectin can up regulate the P53 gene which helps kill tumors 14:40: Exposing your breasts to sunlight 15:19: Stop wearing underwire bras 16:33: Reduce your EMF exposure (Visit Tech Wellness to learn more!) 17:40: Gia for EMF protection (or BluShield is one of my favorites!) 18:48: My free Clean Beauty Guide 21:35: Thermography 22:37: Inflammatory markers (ask for these on your blood test): CRP LDH ESR Homocysteine 23:58: BRCA gene 25:19: Difference between mammography and thermography 28:04: Ultrasounds 29:00: Diagnostic sample 31:48: Coffee enemas (MUST use organic coffee) (blog post) 34:03: You don't get glutathione from food 36:46: Wine during cancer (low alcohol is OK! Dry Farm wine ONLY makes low alcohol wine!) 38:26: Anatomy of an Illness 38:44: Stimulating the vagal nerve 42:31: How to mitigate damage from chemo 42:41: Dr. Valter Longo: Fasting Cancer 43:39: Mistletoe & breast cancer 44:19: Sex, Lies, & Menopause 45:27:* Morning Glory tincture 45:44: *Dandelion tincture 46:12: Bioidentical Hormone Replacement Therapy (hormone solutions) 50:23: * DIM 50:52: Soy & breast cancer (YES to Haelen, fermented soy beverage) 56:05: Top book recommendations: Heal Breast Cancer Naturally The Metabolic Approach to Cancer How to Starve Cancer You Are the Placebo Getting Well Again The Success Principles Limitless by Jim Kwik Where to find De'Ann: Website Instagram Where to find Ashley Deeley: ⁠⁠⁠Website⁠⁠⁠ ⁠⁠⁠Instagram⁠⁠⁠ hello@ashleydeeley.com

In this episode, Dr. Jessica Steier and Dr. Sarah Scheinman discuss the complexities of cancer with Dr. Joe Zundell, a cancer biologist. They explore the definition of cancer, its prevalence, and the hallmarks that characterize cancer cells. The conversation delves into the mechanisms of cancer growth, including sustaining proliferative signaling, evading growth suppression through the P53 gene, and the process of apoptosis. The discussion aims to make these complex topics accessible to a broader audience while highlighting the importance of understanding cancer biology. In this conversation, Dr. Joe Zundell discusses the complexities of cancer biology, focusing on key hallmarks such as immune response, replicative immortality, angiogenesis, and metastasis. He emphasizes the importance of early detection and the challenges of targeting cancer cells without affecting healthy cells. The discussion highlights the need for careful consideration of information regarding cancer treatment and the significance of working with healthcare professionals. All our sources from this episode are available at: https://www.unbiasedscipod.com/episodes/ (00:00) Introduction  (05:28) Understanding Cancer: Definitions and Statistics (10:15) The Hallmarks of Cancer: An Overview (15:14) Sustaining Proliferative Signaling in Cancer (20:07) Evading Growth Suppression: The Role of P53 (25:17) Apoptosis: The Controlled Cell Death Mechanism (30:21) Understanding Cancer: Immune Response and Cell Death (33:31) Replicative Immortality: The Hayflick Limit (38:27) Angiogenesis: Blood Vessel Formation in Tumors (46:32) Invasion and Metastasis: The Spread of Cancer (54:22) Final Thoughts: The Complexity of Cancer Treatment and Early Detection Interested in advertising with us? Please reach out to advertising@airwavemedia.com, with “Unbiased Science” in the subject line. PLEASE NOTE: The discussion and information provided in this podcast are for general educational, scientific, and informational purposes only and are not intended as, and should not be treated as, medical or other professional advice for any particular individual or individuals. Every person and medical issue is different, and diagnosis and treatment requires consideration of specific facts often unique to the individual. As such, the information contained in this podcast should not be used as a substitute for consultation with and/or treatment by a doctor or other medical professional. If you are experiencing any medical issue or have any medical concern, you should consult with a doctor or other medical professional. Further, due to the inherent limitations of a podcast such as this as well as ongoing scientific developments, we do not guarantee the completeness or accuracy of the information or analysis provided in this podcast, although, of course we always endeavor to provide comprehensive information and analysis. In no event may Unbiased Science or any of the participants in this podcast be held liable to the listener or anyone else for any decision allegedly made or action allegedly taken or not taken allegedly in reliance on the discussion or information in this podcast or for any damages allegedly resulting from such reliance. The information provided herein do not represent the views of our employers. Learn more about your ad choices. Visit megaphone.fm/adchoices

Dr. Shannon Westin and her guest, Dr. Brian  Slomovitz discuss the article “Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors” recently published in the JCO and presented at the 2024 International Gynecologic Cancer Society. TRANSCRIPT The guest's disclosures can be found in the transcript.  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist and JCO Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology and presented at the Annual Meeting of the International Gynecologic Cancer Society on October 16, 2024. And this is “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors.” This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial. And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation. Welcome, Brian. Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial. Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease? Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality. Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer? Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an indication in the PMR population saying that immunotherapy works in all women with endometrial cancer at some point, then we really had the groundbreaking trials. And Shannon, thank you. You are the leader on one of the four trials that happened, to DUO-E, AtTEnd, GY018 and RUBY trial, all very similar studies showing that the combination of immunotherapy with chemotherapy in the first line, metastatic or recurrent setting had a better outcome for patients than if given chemotherapy alone. That actually led to amazing things. We had three of those drugs have FDA approvals, pembrolizumab for all comers, dMMR and PMMR in the first line metastatic setting with chemotherapy; Dostarlimab, PMR, dMMR in the first line or metastatic with chemotherapy. And Shannon, in your study, I think we still have to learn a lot from your study. DUO-E, chemotherapy plus minus dostarlimab. And you also added a PARP inhib, and those patients with a PARP did better. So I'm really looking forward to your data, to the subgroup analysis to figure out which of those patients, depending on the biomarker, do better with PARP therapy. And right now, you have a dMMR FDA indication. But who knows? The future is really exciting to see- to be splitters, not lumpers. And I really want to see how that data pans out. And so that's how it came into the first and second line setting and that led us really to come up with the idea for this trial to put it into the adjuvant setting. Dr. Shannon Westin: Right. And so, I think this would be really important because we're so ingrained in this. We see this on the day to day. Can you kind of tease out a little bit what's different about those patients that would be treated in that advanced recurrent setting versus the patients that would be potentially treated in this B21 study? Dr. Brian Slomovitz: Yeah, so the first step, we demonstrated the efficacy in patients that really the treatment options were an unmet need. In the second line setting, we didn't have good treatment options. Those are the patients with measurable disease, with symptomatic disease giving immunotherapy. And not only did we see the efficacy, which was better, but we also were able to give it with limiting the side effects as seen with chemotherapy, which is nice. And then we know that the first line therapy, traditionally for endometrial cancer with carboplatin paclitaxel, response rates about 50%, progression free survival about a year, really something that we needed to improve upon. So, adding immunotherapy to the platinum backbone therapy really demonstrated an advantage. But now what we want to do is we want to see if we could prevent, in the high-risk patients, those without disease, what can we do to help prevent the disease from recurring and help patients live longer without really the need for really lifesaving types of treatments? We want to prevent it from recurring. Dr. Shannon Westin: Yeah, I think that's essential. We know that if we can sit on that prevention side and kind of invest all the time and effort that we need to upfront, that really does yield the longer survival. So why don't you just walk through the overall design of this trial, please? Dr. Brian Slomovitz: Yeah. So, this was an all-comers trial, meaning in individuals that had high risk endometrial cancer, high risk for recurrence, that included, in endometrial cancer, we have aggressive histologic subtypes, serous histologies, clear cell histologies, any stage, as long as there was some myometrial invasion. We also, for the first time, included patients looking at the molecular subclassifications. So, if there was a P53 mutation and they were stage 1 with myometrial invasion, they were included. And then in all comers, any patients with stage 3 or up to 4a disease, as long as the surgery was for a curative intent, and they had no residual disease after surgery, then they were allowed to enroll into this trial. One of the things is that this is the first time we've done an adjuvant trial this large. I think one of the reasons that helped us succeed in doing a trial like this is that we left radiation as investigator's choice, because a lot of times going into a trial like this, people feel strongly, we know our radiation oncology colleagues, rightfully so, feel that radiation could help prevent disease from coming back. And we also have the camp that says they don't need radiation. We took that question out of this study. We let investigators decide whether or not they're going to get radiation. It was for patients to get chemotherapy, who are going to normally get chemotherapy for their high-risk disease and randomize them to chemotherapy plus placebo or chemotherapy plus pembrolizumab, a PD-1 inhibitor, in order to see if we could prevent the disease from coming back. Dr. Shannon Westin: And the primary results of this study were just presented at ESMO and published in the Annals of Oncology. Can you give us just a quick overview of what that was, what they found? Dr. Brian Slomovitz: Yep. So, we enrolled 1100 patients. The primary objective of the study was to look at the ITT population, progression free survival and overall survival. And the overall study was negative. Okay, so the hazard ratio in the ITT population was 1.02, not demonstrating a benefit of adding pembrolizumab in this population. I would say disappointing, but at the same point, something that we could really learn a lot from and somewhere that we know that in the whole population, we need to come up with better strategies to help prevent recurrence of disease, better adjuvant treatment strategies. But there's also information that we learned from this trial and that we're reporting on that we're actually super excited about and we feel may be game changing. Dr. Shannon Westin: Yeah. So, let's go to that. This is the good news. Your manuscript in the JCO, thank goodness you published it here, was focused on that subset of mismatch repair deficient. So, tell us what you found. Dr. Brian Slomovitz: So, in this study, we found that the first stratification factor was dMMR versus pMMR. Now, in the pMMR group, those patients had further stratification factors, but dMMR by itself was a stratification factor. Amongst those patients that had dMMR tumors, we found the hazard ratio to be 0.31 benefiting those patients who received pembrolizumab in the adjuvant setting. Really something that when we look at the treatment studies, the GY018s, the RUBYs, the atTEnds, the DUO-Es, in a dMMR setting, we see a similar hazard ratio of 0.3, 0.4. But to get that hazard ratio, which was statistically significant, obviously, is something that we were quite pleased with and something that we felt was worthy of reporting further. I will say it was a pre-specified endpoint. We didn't allocate alpha to it. So, at the beginning, it was a pre-specified endpoint, but at the same time even though we didn't specify alpha towards that outcome, it still, we feel is clinically meaningful and can definitely add to affect the standard of care and the management of these patients. Dr. Shannon Westin: Yeah. I'm very intrigued to see what kind of people do with this. It makes sense, mechanistically, it makes sense if there was a population that was going to benefit, if not everybody does, this is the group that will. I mean, do you feel like there's enough data? What are you going to do? FDA approval aside, obviously, those kinds of things. But how do you feel about this? Is this something you're going to offer to your patients? Dr. Brian Slomovitz: The first answer is yes. I think it's something that I would like to offer my patients. As you know, we need one of two things: we either need an FDA approval or for a lot of our payers required to be in the NCCN listings. I don't serve on the committee. I have no influence on NCCN. I'm excited to see how they'll respond to not only the Annals article, but obviously in today's release of the JCO article, I hope that they'll look upon it favorably. It's a drug that we're used to giving. Pembrolizumab, we have a lot of experience with it. It's interesting. We didn't see any new safety signals, Shannon. Dr. Shannon Westin: Yeah, I was going to ask - that's great. Dr. Brian Slomovitz: There was nothing, nothing additional that we found in this trial. So, I feel that it can definitely improve the outcome of those patients, in my view, with high risk for recurrence, treating pembrolizumab in this setting. Dr. Shannon Westin: Yeah, I think it's important, of course, to look at the safety. What about quality of life? Any new findings there? Dr. Brian Slomovitz: Yeah, we did that quality of life as part of the phase 3 trial. No difference between the two arms. No difference between the two arms. When we looked at a couple of the other analyses, we found that the benefit is the same on stage 3, 4 tumors. We saw that the benefit was there as well. So, there were less patients in the stage 1, 2 group. But I think really, for all comers, for the patient population, I would definitely consider giving pembrolizumab, again, for those patients with a deficient mismatch repair. Dr. Shannon Westin: It's really exciting, and I think you mentioned some of the statistical limitations. Anything else that gives you pause about the study or things you wish you did better? I know we always like to armchair quarterback ourselves after we do these kinds of studies. Dr. Brian Slomovitz: Yeah, it's interesting. When we designed the study years ago, we used the best information we had at that time to come up with the study design, and we're happy with it, and we really don't think that we could have done it much better. I should say, this was a great partnership that we had here between the GOG, ENGOT and with sponsor Merck, Toon Van Gorp was the lead PI of the global trial. When he gave me the good opportunity to present it at the IGCS and to be the lead author on this, it was really a great partnership. And when we came up with a trial years ago, it was the best trial that we thought at that time. And based on the information now, I think it's really something that we're excited about these results, even though the overall trial was negative. Dr. Shannon Westin: Yeah, I agree with you. I think it's interesting, it's informative to think about, “Well, what would we do now or then if we knew what we knew now?” But still, you design the trial the best way you can. I think the results are super intriguing. I'm hopeful at the way they'll be reviewed. I agree I don't have any inside information about the NCCN committee, but I do hope that they'll consider the overarching data to support immunotherapy and mismatch repair deficiency and the findings of this study. And then I guess the last question I would just ask, as you're an expert here, what are you looking forward to seeing coming next in this space? What's the stuff you're intrigued about in endometrial cancer? Dr. Brian Slomovitz: I think, Shannon, you and I have talked about this for a while. I think we're getting really close to eliminating chemotherapy for some of the patients who suffer from this disease. So, I'm not sure if we'll do a follow up to this trial, but I think a logical type of follow up would be to see: what if we just took away chemotherapy altogether and we did pembro in the adjuvant setting, pembrolizumab versus chemotherapy? We don't have that trial in the adjuvant setting, but actually, we completed accrual of that trial in the recurrent setting and we're anxiously awaiting those results. That's KEYNOTE-C93, where in the dMMR population we studied pembrolizumab versus carboplatin paclitaxel. How those results may translate into this setting, I'm not sure. Right now, it's exciting what we have, but yeah. And I think future is bright for this. Just to highlight, in the two arms, there's 140 patients approximately in each arm; there were 25 recurrences in those patients who received placebo. Only eight recurrences in those that received pembrolizumab. Really, when we talk about numbers, it's really remarkable and it shows you the benefit it really had on the patients. Dr. Shannon Westin: Well, this was great. It flew by, as it always does when I'm having conversations with you. I just really want to thank you again for taking the time to share your knowledge with our listeners. Dr. Brian Slomovitz: Thanks, Shannon. Dr. Shannon Westin: And listeners. Thank you all for taking the time to hear about endometrial cancer. Again, this was “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer Results in Mismatch Repair Deficient Tumors.” And this was the JCO After Hours. If you loved what you heard, please check out wherever you get your podcast to see what else we have to offer. Have an awesome day.   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.        

It's very rare that elephants get cancer, thanks to an abundance of cancer protection genes called P53. Humans have two copies of these genes, but elephants have about 40. Our experts discuss how we can utilize this information to create cancer-fighting medications. Learn More: https://radiohealthjournal.org/do-elephants-hold-the-key-to-curing-cancer Learn more about your ad choices. Visit megaphone.fm/adchoices

Lawrence Ingrassia, author and journalist, joins Vineeta Agarwala, general partner, and Kris Tatiossian, editorial lead at a16z Bio + Health. Together, they discuss Larry's recently published book, A Fatal Inheritance: How A Family Misfortune Revealed A Deadly Medical Mystery. In the book, Larry recounts the story of the p53 cancer suppressor gene, also known as the “guardian of the genome.” Mutations in this gene, which can be inherited, remove a natural tumor defense, making it more likely for an individual to get cancer during their lifetime.He tells the story of the search for this gene and the scientists who unlocked the mystery of high familial incidences of cancer, Drs. Li and Fraumeni. He also shares a more personal aspect of the story: many members of his family inherited Li-Fraumeni Syndrome and suffered from multiple cancers themselves.

Drs. John Sweetenham and Marc Braunstein discuss practice-changing studies in hematologic malignancies that were featured at the 2024 ASCO Annual Meeting, including the ASC4FIRST trial in chronic myeloid leukemia and IMROZ and CARTITUDE-4 in multiple myeloma.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. On today's episode, we'll be discussing practice-changing abstracts and other key advances in hematological malignancies that were featured at the 2024 ASCO Annual Meeting. Joining me for this discussion is an old friend, Dr. Marc Braunstein, a hematologist and oncologist from the NYU Langone Perlmutter Cancer Center.  Our full disclosures are available in the transcript of this episode. Marc, it's great to have you back on the podcast again. There were some important studies in the heme space at the Annual Meeting this year, and we're very pleased that you're able to share your takeaways.  Dr. Marc Braunstein: Thank you, John. It's great to be back again. Dr. John Sweetenham: Let's start out, Marc, with LBA6500. This abstract reports the primary results of the ASC4FIRST trial, and this was a trial comparing asciminib with investigator selected tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia. Could you tell us a little about the trial and how you think it's going to impact clinical practice? Dr. Marc Braunstein: Absolutely. So, asciminib is an oral tyrosine kinase of the ABL kinase domain. As we know in CML, the BCR-ABL translocation is characteristic of the disease, and asciminib is approved for chronic phase CML with a T315I resistance mutation or for patients who have received 2 or more prior lines of therapy. So the ASC4FIRST trial was a randomized trial of 405 patients with newly diagnosed chronic phase CML who are randomized one to one to receive either asciminib at 80 milligrams once daily, or investigator's choice of a first generation TKI imatinib or one of three second generation TKIs nilotinib, dasatinib, or bosutinib. The primary endpoint of the study was the major molecular response, or MMR, at 48 weeks. Pretty much, the study met its primary endpoint with a 67% rate of MMR at 48 weeks, with asciminib versus 49% in patients treated with the investigator's choice of TKI. And in addition, the major molecular remission or MMR of 4.5, which is a deep remission, those rates were higher as well, with asciminib versus investigator's choice at a rate of 39% versus 21% when comparing the groups. Furthermore, when we looked at toxicity, there were fewer grade 3 or higher adverse events, with the asciminib at 38% versus either 44% with the first generation, or 55% with the second generation TKI, and fewer discontinuations as well with asciminib.  So I think this abstract is practice-changing. I think it offers compelling data to use asciminib upfront for chronic phase CML. Those who don't agree with that sentiment might argue that we want to see longer term follow up. There's a planned follow-up at 96 weeks. We would want to see the rate of progression to acute myeloid leukemia and of course overall survival as well. But I think the abstract certainly shows an improvement in outcomes with asciminib versus our current array of TKIs. Dr. John Sweetenham: Yeah, I think it certainly is, at least at minimum, potentially practice changing. I agree with you. Just one question, and this may be a little bit speculative, but do you have any thoughts about treatment free survival with asciminib and how that might line up against some of the other TKIs? Dr. Marc Braunstein: Yeah, that's a great question. The abstract did not necessarily address that, patients were treated until progression, but we know that with the current landscape of TKIs, that in patients who have achieved a deep MR of 4 or 4.5 for at least 2 years who discontinue their TKI, the rate of relapse is about 50%. The current study, the ASC4FIRST, doesn't address that, but I think it's a really good question about whether, for those patients who have achieved a deep remission, whether they can eventually stop asciminib down the line. Dr. John Sweetenham: Yeah, I guess it's one of those ‘watch this space' things.  So we'll see how the data mature out. And let's move on to what I think is another potentially practice-changing study, at least in certain parts of the world. And that's [the] LBA7000 study in classical Hodgkin lymphoma. As you remember, this was a German Hodgkin lymphoma study group trial which looked at the tolerability and efficacy of a novel regimen, BrECADD versus eBEACOPP for patients with advanced stage classical Hodgkin lymphoma in their study, which is known as GHSG HD21. Can you give us your thoughts and take home messages from this trial? Dr. Marc Braunstein: Yeah, John, absolutely. So the German HD21 study is a phase 3 study of 1,500 patients with classical Hodgkin lymphoma. The majority were stage 3 or 4, 84%, that compared two regimens BEACOPP to BrECADD. The major difference between these 2 groups being that the newer BrECADD regimen swaps out bleomycin for brentuximab vedotin, which is an anti-CD30 antibody drug conjugate. Also, in the BrECADD regimen they eliminate vincristine that's incorporated into BEACOPP. Those are kind of the global differences between these 2 regimens. And when comparing these, they looked at the primary endpoint of progression-free survival. Of note, in this study there was a PET adjusted approach where if patients achieved interim PET negativity after 2 cycles, that was followed by an additional 2 cycles of their treatment as opposed to 4 cycles if they were PET positive after the initial 2 cycles of their respective treatment. And of note, there were similar rates of PET2 negativity between both arms, about 58% in both arms.  So at a median follow-up of 48 months, the 4-year progression-free survival was significantly better with the brentuximab containing BrECADD regimen at 94% versus 91% with a hazard ratio of 0.66. And the overall survival of the BrECADD arm was 98.6%, which is very high and impressive. The 4-year overall survival was similar between the arms at around 98%, but of note, there were fewer severe adverse events with BrECADD, the brentuximab containing arm versus BEACOPP at about 42% versus 59% and interestingly less peripheral neuropathy with the brentuximab containing BrECADD. So we're doing extremely well in treating advanced stage classical Hodgkin lymphoma. So the bar is set very high. But in this study, the rates of progression-free survival and overall survival are very impressive.  While these intensive regimens tend to be used outside of the U.S., there are several notable benefits of the study, including greater than 50% PET2 negativity and high rates of progression-free survival at 4 years. In discussing this abstract, it's worth noting that there are other competing regimens, if you want to call it that, that are more commonly used in the U.S. So the ECHELON-1 study looked at brentuximab AVD compared with ABVD with bleomycin and it was a 94% versus 89% 6-year overall survival rate favoring the brentuximab containing A+AVD regimen. And lastly, more recently, the SWOG S1826 study that hasn't been published but was presented in abstract form looked at nivolumab AVD versus brentuximab AVD at a median follow up of 12 months showed a progression-free survival of 94% versus 86%. And that study still has yet to be published and needs to mature. But both of those regimens are in the NCCN guidelines. So, we're definitely pushing the bar higher in terms of improving responses in treating advanced classical Hodgkin lymphoma. Dr. John Sweetenham: I think that there's no question that these results from BrECADD are very impressive. But I'm taken back to what I think has been a kind of philosophic discussion in Hodgkin lymphoma now for a number of years about balancing disease control and efficacy against the potential short-term and long-term toxicity of the regimens, particularly when you have very effective salvage therapies for those patients who may suffer a relapse. So I think that this is a discussion over whether you take a very intensive, upfront approach to Hodgkin lymphoma versus something that may be less and slightly less intensive. I suspect that's a discussion that's going to continue for a long time. I don't know what you feel, but my own feeling about this is that this study will likely have a major influence over treatment of Hodgkin lymphoma, particularly in western Europe. Less likely in the US.., I would think. I don't know what your thoughts about that are. Dr. Marc Braunstein: Well, it's a great question. In SWOG S1826, that study did include pediatric patients. In HD21, the median age was 31 and did not include pediatric patients. So I think we have to be selective in terms of fitness and which patients may be better suited for different regimens. But I think what all these studies show is certainly when we incorporate novel immunotherapies, whether it's brentuximab vedotin, nivolumab, we improve progression-free survival and even overall survival. Dr. John Sweetenham: Absolutely.  So let's shift gears now and take a look at Abstract 7500, the IMROZ study. This was the study of isatuximab, bortezomib, lenalidomide and dexamethasone versus VRD alone for transplant ineligible patients with newly diagnosed multiple myeloma. I know we discussed this in our preview podcast a few weeks back, Marc, but I just wonder now, having seen the data in more detail, what do you think of the important takeaways? And again, are we looking at a new standard of care? Dr. Marc Braunstein: You know, there are many standards of care in multiple myeloma, but we're always looking to make improvements on the regimens we have at our disposal. So, just to recap, IMROZ is a phase 3 randomized study of the anti-CD38 monoclonal antibody isatuximab with the backbone of bortezomib, lenalidomide, dexamethasone or VRD versus VRD alone, specifically, in transplant ineligible newly diagnosed multiple myeloma patients age less than 80. They studied 446 patients in this study, randomized 3 to 2 to Isa-VRD versus VRD alone, with the primary endpoint of progression free survival. Now, similar to other studies where they included a monoclonal antibody up front, the study met its primary endpoint of improving progression-free survival with the quad regimen containing the monoclonal antibody isatuximab versus VRD alone.  So what was interesting about the study, it's really the first of its kind to be presented that specifically looked at transplant ineligible patients, which is presumably a less fit or perhaps more frail population that wouldn't go on to consolidation with stem cell transplant. And in this study, the progression-free survival at 5 years was 63% versus 45%, clearly superior when you included isatuximab. And the rates of complete remission and MRD negativity were all significantly improved, too. However, that was also met with slightly more grade 3 or higher treatment emergent adverse events, 92% versus 84% in the control arm. There are also 11% grade 5 treatment emergent adverse events with the isatuximab group versus 5.5% with VRD alone. Although there was no major difference in treatment discontinuation. One small caveat worth noting, too, is that high-risk patients in this study, when presented at ASCO, did not necessarily show a difference in benefit, although there wasn't necessarily a detriment either.  So, John, I think that clearly quadruplet regimens are superior in outcomes of efficacy to triplets, even in transplant-ineligible patients. But I think we have to tailor these treatments to individual patients because I think when it comes to transplant-ineligible patients, it's a spectrum of patients who may be more or less fit for quad regimens versus triplet regimens. It's also worth noting, though, that in this study, the patients are really only getting a quad regimen for 4 cycles. They get their Isa-VRD, and then you drop the bortezomib.  So when we think about quads, it's not that they're getting the quad regimen indefinitely, it's really for the induction cycles. But still, I think we have to be aware of potential safety issues. Dr. John Sweetenham: Okay, great. And let's stay on the theme of multiple myeloma, Marc, and talk a little bit about Abstract 7504, which was a subgroup analysis of the CARTITUDE-4 study. This is a report on the use of ciltacabtagene autoleucel versus standard of care in patients with functional high risk multiple myeloma. Can you give us your thoughts on this and maybe put it into a bit of context for us?  Dr. Marc Braunstein: Absolutely, John. It's really a great time to be in the field of multiple myeloma. We're making tremendous progress, but when we think about one of the unmet needs, it's just consistently the high-risk patients who have shorter responses and are at higher risk for poorer outcomes. Just to review, cilta-cel is one of the 2 available anti-BCMA CAR T-cell products available for the treatment of relapsed or refractory multiple myeloma. Very recently, the FDA approved cilta-cel for lenalidomide refractory patients after 2 or more prior lines of therapy based on the CARTITUDE-4 study, which was published by San-Miguel and colleagues in New England Journal of Medicine in July 2023. And that study randomized 419 patients with multiple myeloma with 1 to 3 prior lines of therapy to receive either cilta-cel or physician's choice of standard of care, which was either 1 of 2 triplet regimens, a pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide and dexamethasone. It's worth noting that about 25% of the patients in the CARTITUDE-4 study had prior anti-CD38 antibody treatment previously and the carfilzomib was not included in one of the standard-of-care arms, and we know that those regimens containing carfilzomib do increase survival in relapsed myeloma.  Nevertheless, the primary outcome of progression-free survival was not reached in the CAR T-cell arm versus 11.8 months in the standard-of-care arm, with a significant reduction in progression of 74%. So clearly a positive study and CAR T-cell therapy is included in the NCCN guidelines for patients who have an early relapse from their myeloma. The current abstract by Costa et al focused specifically on a subgroup of 79 patients from CARTITUDE-4 in second line of treatment and looked at what they called functional high-risk myeloma, defined as progression of disease within 18 months of initial treatment or after stem cell transplant. Again, the study showed a retained benefit of cilta-cel with significant improvement in progression-free survival either not reached or 12 months with the control standard of care arm, as well as complete remission rate and rates of MRD negativity of 65% versus 10% in the control.  The overall survival outcome was still immature and not presented. Nevertheless, cilta-cel is clearly superior to standard-of-care triplet regimens. I think that for patients with high risk, they clearly derive a benefit from CAR T-cell therapy if they have short progression-free survival after initial therapy.  Dr. John Sweetenham: Thanks, Marc. So let's round this out by talking about another area of unmet need, I guess in a way in a difficult to treat patient group. And that's Abstract 7007, the SYMPATICO study. This is a study which looks at the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who had a mutated TP53. Can you just briefly review this for us and tell us what you think we should be taking away from this studys? Dr. Marc Braunstein: So, mantle cell lymphoma typically has an aggressive behavior, but the subgroup of patients with a P53 mutation tend to have the poorest outcomes and do represent an area of unmet need. Although BTK inhibitors are making important improvements in mantle cell lymphoma, they have yet to be approved in newly diagnosed mantle cell lymphoma. Acalibutinib and zanubrutinib are FDA-approved BTK inhibitors for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market in the U.S. for mantle cell lymphoma. Dr. Michael Wang's group presented late-breaking data from the phase 3 SYMPATICO trial at ASH 2023, in which 267 patients with relapsed refractory mantle cell lymphoma were randomized to receive either ibrutinib plus the BCL2 inhibitor venetoclax or ibrutinib plus placebo after 1 to 5 prior lines of therapy. And that study showed a 32 versus 22 months progression-free survival at a median follow up of 51 months. The current abstract, also by Dr. Wang and colleagues, looked at the subgroup of patients who had a P53 mutation and included an open label cohort of 44 patients in the first line of treatment and a relapse refractory cohort of 75 patients, and compared this subgroup of patients with P53 mutation to those without. When we look at the outcomes, the patients who did not have a P53 mutation clearly did better in terms of progression-free survival being not reached in first-line treatment compared to 22 months progression-free survival in those patients with first-line [treatment] with a P53 mutation. As well as in the relapsed refractory setting, the PFS without the P53 mutation was 47 months versus 21 months with the mutation. However, when you look at these patients treated with ibrutinib and venetoclax comparing whether they got treated in first line or the relapse refractory setting, the overall response rates are very similar at about 80% to 90% and the CR rates were very similar at about 55% to 58%, which to me suggests that although patients with P53 mutation do worse than those without it, whether they're treated in the first-line or the relapse setting with this combination of venetoclax, they tend to do somewhat similar, suggesting that you can overcome resistance to prior therapy in the relapse setting. So I think further data are certainly warranted to explore the role of combination therapies that include novel agents such as BTK inhibitors in the first line setting.  It's worth noting that the TRIANGLE study was recently published, and this study looked at including ibrutinib at various phases, including at induction in combination with intensive chemotherapy and during the maintenance phase. And that study showed encouraging outcomes in patients who received ibrutinib even without stem cell transplant compared to those who received stem cell transplant. So the role of BTKIs in mantle cell lymphoma is certainly evolving, and I think it offers a very effective intervention without the same kind of toxicities we see with cytotoxic chemotherapy that's traditionally used in mantle cell lymphoma. But I think the subgroup of patients with P53 mutation in this disease still represent an area of unmet need that unfortunately have worse outcomes. But novel agents may be able to overcome some of those adverse outcomes. Dr. John Sweetenham: Yeah, I agree. I think these are intriguing data, and obviously it needs more follow-up and probably more prospective studies. But nevertheless, I think there are some signals there for sure that need to be followed up on.  Marc, as always, it's great to have your insights on key advances in the heme space from ASCO. An important year this year, and we really appreciate your time and effort in sharing with us your thoughts on what we've learned this year. So thank you as always. Dr. Marc Braunstein: My pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract 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 guest:  Dr. Marc Braunstein  @docbraunstein    Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Marc Braunstein:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp  Speakers' Bureau: Janssen Oncology  Research Funding (Institution): Janssen, Celgene/BMS   

Drs. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.   TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting. You'll find our full disclosures in the transcript of the episode. Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer. Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast. Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages? Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.  The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program. Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results. Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter's theme this year of bringing care to patients incorporating supportive care. So I agree with you.  Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?  Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.  So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.  So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation. Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.  The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach. Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.  Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting. Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.  In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.  There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.  So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that? Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.  Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?  Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.  I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the  lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don't happen as frequently as we see with the earlier generation ALK inhibitors.  So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes', but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we've got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients. Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.  That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting. Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.  Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?  Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C  inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.   And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.  So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.  Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.  Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along. And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study? Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.  In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.  So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.  So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.  Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.  It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted. Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.  And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.  Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients. Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from 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.   Find out more about today's speakers:    Dr. Vamsi Velcheti  @VamsiVelcheti    Dr. Nathan Pennell  @n8pennell    Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:  Dr. Vamsi Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus  Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Nathan Pennell:    Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron   Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it's great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction < 1% regardless of the treatment arm. Furthermore, ctDNA fraction >1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, 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. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:     Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Dr. John Sweetenham and Dr. Marc Braunstein look ahead at key abstracts across the spectrum of hematologic malignancies that will be presented at the 2024 ASCO Annual Meeting, including the OPTIC trial in chronic myeloid leukemia, treatment options for transplant-ineligible patients with multiple myeloma, and the 7-year analysis of the ECHELON-1 trial in classical Hodgkin lymphoma. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast. I'm delighted to be joined again this year by Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center in New York. We're going to be discussing some of the key abstracts in hematologic malignancies that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Marc, it's great to have you back on the podcast. Dr. Marc Braunstein: It's a pleasure to be back, John.  Dr. John Sweetenham: There are some exciting abstracts to be presented at this year's meeting, and I would like to begin, if we can, with Abstract 6501. As you know, this reports the four-year results from the OPTIC trial of ponatinib in patients with chronic-phase CML and the T315I mutation. Can you tell us about the trial and about these latest follow-up results? Dr. Marc Braunstein: Sure. Well, we've made tremendous progress in managing patients with CML in the past two decades using these oral tyrosine kinase inhibitors such as ponatinib. Ponatinib is a third-generation TKI that has activity in both Philadelphia-positive ALL as well as CML, and can overcome the resistance mutation you mentioned, called the T315I mutation, which is sometimes found following prior TKI therapy. The OPTIC study is a multicenter phase 2 randomized study of various doses of ponatinib in 283 chronic phase CML patients who had received 2 or more prior lines of therapy or those who had the presence of a T315I mutation, with the current analysis examining the major remission at 48 months, PFS, as well as OS. Of note, in this study, after patients have achieved a major remission with a transcript level of 1% or less, the study allowed for dose reduction of ponatinib from the original dose of either 45 milligrams or 30 milligrams to a reduced dose of 15 milligrams.  So, when we look at the results, we find that the patients who had the highest overall response rates and higher rates of molecular remission were those who received the 45-milligram dose. And remember, these patients were allowed to be dose-reduced to the 15-milligram dose once they achieved a molecular remission of 1% or less. In addition, the rates of overall survival were highest in the 45-milligram dose as well. When looking at the T315I subgroup, the rates of molecular remission, the depth of remission, and the rates of progression-free survival, in general, were lower in that subgroup, but still higher in the 45-milligram dose than the 35- milligram dose.  Furthermore, when looking at the rates of treatment-emergent adverse events leading to discontinuation, they were 8% in the 45-milligram dose compared to 14% in the 30-milligram dose and 5% in the patients who only received the 15-milligram dose. The authors have concluded that the 45-milligram dose, with the potential to be reduced to 15 milligrams after achieving 1% or less of the BCR-ABL transcript level, seems to be the right balance between efficacy and safety.  Dr. John Sweetenham: Thanks, Marc. In the longer term, do you think that this study will, in any way, affect the position of ponatinib in the treatment algorithm for CML? Is it going to remain as a second or third-line option, or do you think there's any chance it will be moved up? Dr. Marc Braunstein: Well, that's a great question. There are other TKIs, such as asciminib, that also target the T315I mutation, and that mutation tends to develop after prior first-line or second-line TKI therapy. But given its activity in both ALL and CML, I think it's certainly reasonable to expect that ponatinib will be used in earlier lines of therapy given its efficacy in later lines. Dr. John Sweetenham: Let's change gears and move the focus to acute myeloid leukemia. There has been a lot of discussion around frailty in many different malignancies, but the impact of frailty on outcomes in AML is maybe something that hasn't been quite so well studied. In Abstract 6506, investigators did a population-based study in Ontario, Canada, that assessed the patient's frailty risk and the impact that might have on outcomes. What are your takeaways from this study, and how do you think these data will help optimize treatment decisions?  Dr. Marc Braunstein: Yeah, I'm glad we're talking about this abstract John, because frailty scores are increasingly being used in hematologic malignancies to help guide goals and intensity of care. And as opposed to using age or performance status alone, these composite frailty assessment tools, such as the MFI tool that they used in this particular study, take into account multiple variables that are both physiologic, such as the patient's comorbidities, as well as social, and what kind of support system do they have, and things of that nature. And that accounts for their overall fitness. So, in this retrospective cohort study that was a population-based study in Ontario between 2006 and 2021, they looked at 5,450 patients retrospectively with acute leukemia and grouped those patients into 3 categories based on this frailty index. Patients who are either fit, somewhere in the middle between fit or frail, which they call pre-frail, or frail. And they looked at outcomes such as overall survival, comparing patients who got intensive chemotherapy regimens for induction or those who got non-intensive therapy for induction. Patients in either group could have been assigned to either fit, pre-frail, or frail although there are much more fit patients than those who got intensive induction.  And so, looking at their findings, it was noted that patients who were in the frail category, not entirely unexpectedly, had lower overall survival when compared to those who were fit or pre-frail. I think the value of a study like this is not just to highlight the benefit of frailty scores to help predict which patients may ultimately have a shorter survival, but also to help potentially guide which patients may be more suitable for intensive versus less intensive induction. I will note that this study was conducted in an era where we didn't have the same sorts of less intensive induction that are very effective in less fit patients, such as the combination of azacytidine and venetoclax, which is commonly used in less fit patients nowadays. So, the study may encompass patients who didn't have access to that therapy because it wasn't available during that time. But I think it still, overall, does highlight the fact that assessing fitness or frailty in acute myeloid leukemia is important for predictive value. Dr. John Sweetenham: I agree. Marc, I don't know what your thoughts are on this, but it goes either way. I mean, I think that, if I remember the numbers correctly, 25% of fit patients received non-intensive therapy. So, is there a missed opportunity there for that group of patients who actually may have tolerated the intensive therapy but it was never offered? Dr. Marc Braunstein: That's an excellent point, John, and I think that highlights the importance of frailty indices because they take into account much more than one particular factor, or even just a subjective assessment of the patient in real time when they're first presenting. And they may have disease-specific features that are decreasing, say one element of their assessment such as their performance status. So, really taking these composite fitness scores into account may actually allow you to escalate therapy in a patient who may actually be fit but maybe perceived as less fit when they present. Dr. John Sweetenham: Yeah. So, I think, as you mentioned, there are better treatment options out there now maybe than there were at the time this study was conducted. Nevertheless, there may still be that opportunity for more intensive therapy for some of these patients when they are more holistically assessed.  Let's move on and switch gears once again and talk about a study in multiple myeloma, the so-called IMROZ study, which is Abstract 7500. So, this is a study looking at treatment options for transplant-ineligible patients with newly diagnosed multiple myeloma. Some of these patients may not have a chance for subsequent therapy if they are not eligible for transplant. What are your thoughts on this study? Do you think we're closer to a new standard of care for patients who are not going to proceed to an autologous stem cell transplant?  Dr. Marc Braunstein: It seems like every year there's a new standard of care for newly diagnosed multiple myeloma because there's so much data emerging, which is just wonderful. So, I think as background, at the 2023 ASH meeting, the IsKia study was presented, which is a randomized phase 3 study in newly diagnosed transplant-eligible patients. And that was using isatuximab with carfilzomib, lenalidomide, and dexamethasone upfront and that study did show a benefit in terms of reducing minimal residual disease compared to carfilzomib, lenalidomide, and dexamethasone alone. But that study was looking at fit newly diagnosed patients who were going on to stem cell transplant. Right now, the standard of care for patients who are not eligible for transplant is generally to use a 2 or 3-drug regimen, such as daratumumab, lenalidomide, and dexamethasone, based on the phase 3 MAYA study. But this study is really unique in that it looks at using a quadruplet regimen in patients who are transplant ineligible or not intended to go for transplant.  So, the phase 3 IMROZ study was a randomized study of 446 patients that compared isatuximab, bortezomib, lenalidomide, and dexamethasone to bortezomib, lenalidomide, and dexamethasone alone. So, a quad versus a triplet regimen. The primary endpoint in this study was progression-free survival, but they also looked at secondary endpoints, such as complete response rate and minimal residual disease negativity.   Just to quickly highlight the results and then discuss the standard of care, the median duration of treatment in this study was 53 months in the quad regimen and 31 months in the control arm. At a median follow-up of about 60 months, the progression-free survival was not reached with the quad regimen versus 54 months in the triplet, and that was a significant difference. In addition, the safety profile was pretty much consistent with the class, there were a bit more grade three or higher treatment-emergent adverse events with the ESA-containing regimen, 92% versus 84%, but no difference in adverse events leading to discontinuation in either arm.   So, this study is certainly compelling in terms of using quadruplet-based regimens that contain an anti-CD38 monoclonal antibody for newly diagnosed patients who are not intended to undergo transplant. I think at the meeting, I will be interested to see the patient population that was included. Patients who are over the age of 80, for example, are excluded. So, I would like to know more about their fitness level and performance status. But I think it's clear, John, that using quad regimens over triplet regimens is just consistently superior in terms of efficacy outcomes. Dr. John Sweetenham: Right. I guess that, even though maybe we can't focus on the specific agents right now, it looks as if quad regimens are going to be the standard of care regimens for the future in this group. Do you think that is fair?  Dr. Marc Braunstein: Very likely. Dr. John Sweetenham: Absolutely. Well, that's a pretty challenging group of patients.   And so to move on again, let's talk about another, perhaps equally challenging group - patients with mantle cell lymphoma, particularly those who carry certain mutations. The so-called SYMPATICO study, which is reported in Abstract 7007, presents data on the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who carry a TP53 mutation. We know that this mutation confers a high risk of early progressive disease and poorer outcomes when these patients are treated with standard chemoimmunotherapy for mantle cell. Trials to date have been limited to small single-arm studies. Can you tell us a little bit about this study and the outcomes and what you think it means for the future?  Dr. Marc Braunstein: As a background, although BTK inhibitors such as ibrutinib have yet to be approved for newly diagnosed mantle cell lymphoma, acalabrutinib and zanubrutinib, which are second-generation BTK inhibitors, are FDA-approved for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market. The lead author of this abstract, Dr. Michael Wang, had presented a late-breaking data from the phase 3 SYMPATICO trial at ASH last year, in which 267 patients with relapsed or refractory mantle cell lymphoma after one to five prior lines of therapy were randomized to receive the combination of ibrutinib plus the BCL-2 inhibitor venetoclax or ibrutinib plus placebo. That study showed there was a 32 versus 22-month progression-free survival with a hazard ratio of 0.65 at a median follow-up of 51 months, indicating the PFS benefit of the combination of ibrutinib and venetoclax compared to ibrutinib with placebo.   So that leads us to this subgroup analysis in the current study being presented at ASCO, in which they looked at a subgroup of patients with mantle cell lymphoma who are at very high risk for treatment failure and early relapse - those are patients who have a mutation in TP53, which again is high risk for treatment failure. This abstract examined an open-label cohort of 44 first-line patients, as well as 75 patients who were in the relapse/refractory cohort, and compared to patients who either did or did not have the P53 mutation. When we look at the progression-free survival outcomes, the median progression-free survival in the first-line cohort of patients who did not have a P53 mutation was not reached, whereas those with the P53 mutation had a median progression-free survival of 22 months, which is still meaningful but still less than those who did not have a P53 mutation. Which again is not entirely unexpected. But the overall response rate of the combination of ibrutinib and venetoclax was very high at 90%, and the median duration of response was about 21 months.  Now comparing this to the relapse/refractory cohort, in those without a P53 mutation, the progression-free survival of the combination of ibrutinib and venetoclax was about 47 months versus those who don't have the P53 mutation was about 21 months with an overall response rate of 80%. I think one takeaway looking at this comparison of the first-line and relapse/refractory setting is that patients seem to do very similar in terms of overall response rate and progression-free survival, whether they were in the first line or in the later lines of treatment if they had the P53 mutation, which says that the combination of ibrutinib and venetoclax is effective no matter which phase of the disease the patient might be in, indicating its overall activity and being strong.    Dr. John Sweetenham: Yeah, I thought that was an interesting observation, actually, how similar the outcomes were in those two groups.  Dr. Marc Braunstein: No, I agree. And I think although patients with TP53 mutations did comparatively worse than those without the mutation according to progression-free survival, overall response rate, or complete remission rates, they did seem to be similar whether a patient was in first-line or relapsed refractory if they were P53 mutant and were treated with this combination. So, I think we need further data in the first line, such as the data that's awaiting publication from the TRIANGLE study, which is examining upfront ibrutinib. But certainly, BTK inhibitors have significant activity in either the first line or the relapse setting of mantle cell lymphoma.  Dr. John Sweetenham: Great. Thanks, Marc.  Let's wind up with one more abstract, and this is Abstract 7053. It's a 7-year analysis of the so-called ECHELON-1 study. This was a study comparing the standard of care, ABVD, with the same regimen with bleomycin substituted by brentuximab vedotin for patients with previously untreated advanced-stage classical Hodgkin lymphoma. The study at the time it was originally reported, resulted in a significant practice change in the first-line therapy of Hodgkin's lymphoma. We now have mature follow-up. What are your take-homes from this study? Dr. Marc Braunstein: The ECHELON-1 study has certainly been a practice-changing clinical trial where, as you said, brentuximab with the backbone of AVD was compared to ABVD, which was the prior standard. And this was examined in newly diagnosed patients with classical Hodgkin lymphoma who were at advanced-stage, stage 3 or 4. The publication, first of the progression-free survival, and more recently, in the New England Journal of Medicine in 2022, where we saw the 6-year overall survival was 94% with the brentuximab-containing arm versus 89% in the control arm, established the brentuximab AVD, or otherwise called AAVD, as the standard of care in advanced stage newly diagnosed classical Hodgkin lymphoma. The current study is now reporting 7-year follow-up on about 1,300 randomized patients who were enrolled in this impressive study.   Though at a median follow-up of 89 months now, the 7-year overall survival was quite similar, 94% versus 89%, again favoring the brentuximab-containing arm. In particular, this was driven by patients who had stage 4 disease or those patients who were aged less than 60 in subgroup analyses. So, what I take away from this abstract in the 7-year follow-up of the ECHELON-1 is that brentuximab with AVD remains the standard of care for previously untreated advanced-stage classical Hodgkin lymphoma. It is worth noting that the SWOG S1826 study that was presented at ASCO last year compared nivolumab with AVD compared to brentuximab AVD and did show a slight PFS advantage of 94% versus 86% with nivolumab AVD. Obviously, these were different studies with different patient populations enrolled, so we're really just cross-comparing different studies. But I think brentuximab AVD, given the survival benefit that is retained now at seven years in the current abstract, still remains the standard of care for advanced-stage classical Hodgkin lymphoma. The role of immune checkpoint inhibitors like nivolumab is making headway in terms of treating newly diagnosed patients as well. Dr. John Sweetenham: Yeah, thanks, Marc. I mean, one of the observations that I thought was of interest in this study was the outcome for patients who were PET-2 positive, when you compare AAVD and ABVD. It does seem as if even in those patients who are PET-2 positive, having had AAVD, they still apparently have a better outcome than those who received ABVD in that situation who were PET-2 positive. So, I think that's another interesting observation. I'm not quite sure what it means, except speaking to the overall superior efficacy of that regimen. Dr. Marc Braunstein: You make a great point, John, because it's worth noting that in ECHELON-1, a PET scan was done after cycle 2, but the study was not PET-adapted. So even if you had a positive PET, you continued for the full six cycles of treatment. But PET-2 status is often used in various studies of Hodgkin lymphoma to guide whether to give additional cycles or escalate therapy. So, I think the benefit of presenting those subgroups is that even if you were PET-2 positive, you still did better by continuing on the brentuximab-containing regimen. Dr. John Sweetenham: Yeah, exactly. I mean, the other important takeaway message, I think, is that the outcome for patients with advanced Hodgkin lymphoma seems to continue to steadily improve, which is great news and also really remarkable. And I'm excited to see there may be some additional data presented at one of the late-breaking abstracts in this year's meeting, so it will truly be interesting to see what that shows us as well.  Dr. Marc Braunstein: Incredible. Dr. John Sweetenham: Well, Marc, as always, thank you for sharing your insights with us today on the ASCO Daily News Podcast. We look forward very much to hearing the updated data from these abstracts at the meeting.  Dr. Marc Braunstein: As do I and thank you so much for inviting me again.  Dr. John Sweetenham: And thank you to our listeners for joining us 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 guest: Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers' Bureau: Janssen Oncology Research Funding (Institution): Janssen, Celgene/BMS

Intoxicação alimentar na P53 e falta de sanitário na P25,Troca de comando na Petrobras, causa e reflexos na Bacia de Campos,PT de Campos com três prefeitáveis e novidade na nominata a vereador ,

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Ana Luzarraga to discuss molecular profiles as predictors of endometrial recurrence. Dr. Luzarraga is a Gynecologic Oncologist currently working in the Vall d'Hebron University Hospital in Barcelona, Spain. She has completed her two years ESGO fellowship in 2023 and is currently finishing her PhD programme about molecular profile in endometrial cancer.   Highlights: Molecular subgroups of endometrial cancer present distinctive recurrence patterns: p53-abn tumors relapse mostly with peritoneal and distant disease and NSMP tumors at distance. Molecular profile is a stronger independent predictor for vaginal, peritoneal, and distant recurrence than classic histologic factors. P53-abn is the sole independent predictor of peritoneal relapse. P53-abn and NSMP are independent predictors of distant recurrence.

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.   I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.   While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted.  The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and  chemo-only arm, respectively. The majority of the patients were EGFR at  90%.  The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation.  In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.   In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.  Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration.  There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.   Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen.  The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.  This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you. 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 ofASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

BUFFALO, NY- March 25, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.” ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. In this new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta demonstrate the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. “The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.” Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. “The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.” DOI - https://doi.org/10.18632/oncotarget.28563 Correspondence to - Benigno C. Valdez - mbalasik@yahoo.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28563 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, acute myeloid leukemia, aml, pre-transplant regimens, venetoclax, thiotepa, busulfan About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Is Sugar Feeding Your Cancer?Discover how a simple shift in your diet and metabolism could render cancer and chronic disease powerless. In this episode Dr. Katie Deming brings an intriguing conversation with Dr. Thomas Seyfried, a renowned biology professor at Boston College and author of "Cancer as a Metabolic Disease." Dr. Seyfried challenges the traditional view of cancer as a genetic disease. His insights into the Warburg Effect, the role of mitochondria in cancer cells, and the impact of diet are eye-opening.Discover how dietary interventions play a crucial role in metabolic therapy. Chapters:07:41 - Weight Loss Led To Tumor Reduction, Not Drug.15:40 - The Argument That Cancer Is A Metabolic, Not Genetic 21:04 - Incentives Against Systemic Change In Cancer Treatment22:18 - How To Maintain Healthy Mitochondria30:30 - Why Monitor Glucose Ketone Index In Cancer Patients46:49 - The Key To Aging And Death01:03:55 - ATP is Life's EnergyDr. Deming helps bridge the gap between conventional cancer treatments and metabolic therapy.  You learn about the importance of personalized treatment plans based on individual metabolic profiles and the latest research in the field.Join this enlightening conversation that could change the way you think about cancer and chronic disease management.Listen, learn, and prepare to challenge your understanding of chronic illnesses and explore a transformative perspective on cancer treatment.This episode promises to provide insights into the future approach of cancer treatment and how it could revolutionize patient care.GLOSSARY:Mitochondria's primary function is to produce energy in the form of adenosine triphosphate (ATP).Metabolic Therapy for cancer treatment  involves a combination of dietary changes, possibly supplements, and in some cases, specific medications. The Glucose Ketone Index (GKI) as a way to monitor how your body is fueling itself – whether it's mainly using sugars (glucose) or burning fats (ketones). Grab Your Spot for the Free Radiant Health Online Workshop on March 5th: Sign Me Up!MORE FROM KATIE DEMING M.D. Take a Deeper Dive into Your Healing JourneyFollow Dr. Katie Deming's Substack HereWork with Dr. Katie:www.katiedeming.comFollow Dr. Katie Deming on Instagram:The.Conscious.OncologistPlease Support the Show Share this episode with a friend or family member Give a Review on Spotify Give a Review on Apple Podcast DISCLAIMER:The Born to Heal Podcast is intended for informational purposes only and is not a substitute for seeking professional medical advice, diagnosis, or treatment. Individual medical histories are unique; therefore, this episode should not be used to diagnose, treat, cure, or prevent any disease without consulting your healthcare provider.

When Peter Brodhead, a beacon of knowledge in the world of nutrition and herbalism, crosses your path, you know you're in for an extraordinary conversation. His tale of resilience as a cancer survivor and the wisdom he's distilled from his roles as a health food store owner, certified nutritionist, and homeopath, are nothing short of inspiring. In this episode, we unpack the symbiotic relationship between cancer and natural remedies, and Peter's invaluable insights underscore just how powerful the right food, supplements, and lifestyle adjustments can be for those navigating the complexities of this illness. Understandably, the prospect of maintaining optimal health in the face of cancer can seem daunting. Yet, as we traverse topics like the life-preserving functions of the P53 gene and the detoxifying prowess of heat shock proteins, it becomes clear that we hold more power over our well-being than we might imagine. From the immune-boosting properties of vitamin A to the mood-lifting and cardiovascular benefits of regular sauna use, this episode is a treasure trove of actionable strategies. Moreover, we delve into how everyday decisions, such as the spices we cook with or the companies we trust for our supplements, can significantly tilt the scales in our favor when it comes to preventing and battling cancer. Connect with Julie Stevens and the Mojo Movement:  Instagram: https://instagram.com/mojohealthorg  TikTok: https://tiktok.com/@mojohealthorg  YouTube: https://www.youtube.com/@mojohealth  Facebook: https://facebook.com/mojohealthorg  Website: https://www.mojohealth.org/ DISCLAIMER: The views, thoughts, and opinions expressed on this podcast are the speaker's own and do not represent the views, thoughts, and opinions of MOJO Health Cooperative LLC, a Georgia Limited Liability Company, its respective officers, directors, employees, agents, or representatives. This podcast is presented by MOJO Health Cooperative, and cannot be copied or rebroadcast without consent. The material and information presented here is for general information purposes only, and not intended to supplant the expert advice and/or consultation of a medical doctor and/or a licensed physician, and/or an attorney. In short, this podcast is not intended to replace professional medical advice, nor legal advice. The "MOJO Health" name and all forms and abbreviations are the property of its owner and its use does not imply endorsement of or opposition to any specific organization, product, or service. Again, none of the content of this podcast should be considered legal advice, nor medical advice. As always, consult a lawyer and/or a licensed physician in lieu of relying upon the advice of any of the participants of this podcast. The host(s) of this podcast are not licensed lawyers, physicians, doctors of osteopath, nor medical doctors in any jurisdiction anywhere. The host(s) of this podcast do not practice medicine and do NOT profess to be able to do any of the following: (1) diagnose, heal, treat, prevent, prescribe for, or removing any physical, mental, or emotional ailment or supposed ailment of an individual; (2) engage in the end of human pregnancy; (3) treat human ailments; nor (4) perform acupuncture. MOJO Health Cooperative LLC is not responsible for any losses, damages, or liabilities that may arise from the use of this podcast.

Giovanni tem um diagnóstico de vitiligo e recebe constantemente conselhos diversos nas ruas para tratar o seu quadro; Maria Alice, a avó do Porchat, acreditou que a lama do Mar Morto pudesse curar uma micose no seu dedão. A doutora Aline Bressan, especialista em dermatologia, elucida as principais crenças infundadas sobre os quadros que afetam a nossa pele. Confira o terceiro episódio da nossa "Edição especial sobre fake news em saúde". Referências: 1. Antoniou C, Schulpis H, Michas T, Katsambas A, Frajis N, Tsagaraki S, Stratigos J. Vitiligo therapy with oral and topical phenylalanine with UVA exposure. Int J Dermatol. 1989 Oct;28(8):545-7. doi: 10.1111/j.1365-4362.1989.tb04613.x. PMID: 2583897. 2. Sociedade Brasileira de Dermatologia. Vitiligo. Disponível em: Vitiligo - SBD. Acessado em: 30/11/2023 3. Hospital Israelita Albert Einstein: Vida Saudável. Vitiligo: o que é, quais são as causas e como identificá-lo?. Disponível em: Vitiligo: o que é, quais são as causas e como identificá-lo? | Vida Saudável | Conteúdos produzidos pelo Hospital Israelita Albert Einstein. Acessado em: 30/11/2023 4. Ministério da Saúde. Portadores de Vitiligo podem desenvolver sintomas emocionais em decorrência da doença, alerta especialista da Rede Ebserh. Disponível em: Portadores de Vitiligo podem desenvolver sintomas emocionais em decorrência da doença, alerta especialista da Rede Ebserh — Empresa Brasileira de Serviços Hospitalares (www.gov.br). Acessado em: 30/11/2023 5. Bakry OA, Hammam MA, Wahed MM. Immunohistochemical detection of P53 and Mdm2 in vitiligo. Indian Dermatol Online J. 2012 Sep;3(3):171-6. doi: 10.4103/2229-5178.101812. PMID: 23189248; PMCID: PMC3505423. 6. Sociedade Brasileira de Dermatologia. Micose. Disponível em: Micose - SBD. Acessado em: 30/11/2023 7. Ministério da Saúde. Micoses endêmicas. Disponível em: Micoses Endêmicas — Ministério da Saúde (www.gov.br). Acessado em: 30/11/2023. PP-CMR-BRA-0662

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we're discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who's going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he's the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it's been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we're seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that's really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we've really gone away from that, and now we understand that we're seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it's created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that's important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that's changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it's important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that's even evolved; some people term it TP53 wild type. That's a bit of even a heterogeneous cohort amongst itself. So we're going to take these subsets, independent of POLE and an MSI-high, and we're going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it's really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we're really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we're going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we're still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it's going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. 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.      

Postdoc Mathias Heltberg har sammen med Professor Mogens Høgh Jensen forsket i komplekse systemer i biologiske organismer. Ved at kombinere viden om rytmer og svingninger fra fysikkens verden har de udviklet en forklaringsmodel for, hvordan kroppens celler kan udnytte deres naturlige reparationsmekanismer optimalt. Ved at koncentrere proteinet P53 på de steder i cellen hvor DNA skaderne er opstået kan kan forskerne få cellerne til at lave en dråbe-struktur, der kan samle de proteiner som er nødvendige for at reparere DNA reparationen bedst muligt. På denne måde kan cellen mindske sandsynligheden for at nogle mindre genfejl i en kropscelle udvikler sig til cancer. Det er videnskabsjournalist Jens Degett, som interviewer Mathias Heltberg. Foto kredit: Jens Degett, © Science Stories ApS. Læs mere på Niels Bohr Institutets hjemmeside: https://nbi.ku.dk/Nyheder/nyheder_2023/ny-forstaaelse-af-kroppens-celler-slaar-i-takt-som-bornholmerure/

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.08.548192v1?rss=1 Authors: Aguilan, J., Pedrosa, E., Dolstra, H., Nur Baykara, R., Barnes, J., Zhang, J., Sidoli, S., Lachman, H. Abstract: Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Javier Orozco-Mera, MD, FACS, MSc, a neurosurgeon in the Department of Neurosurgery at Hospital Universitario del Valle “Evaristo García,” University of Valle, spoke with CancerNetwork® about his study titled, Signaling Pathways in the Relapse of Glioblastoma, which was published in the journal ONCOLOGY®. In his study, Orozco-Mera and his colleagues identified a several signaling pathways and molecular processes that are involved in glioblastoma relapse, including markers such as O-6-methylguanine-DNA methyltransferase, micro-RNA, EGFR, and P53. Don't forget to subscribe to the “Oncology On-The-Go” podcast on Apple Podcasts, Spotify, or anywhere podcasts are available.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.10.536321v1?rss=1 Authors: Hu, Y., Cheng, B., Zhang, J., Shen, Q., Sun, Z., Luo, Y. Abstract: Ferroptosis contribute to temporomandibular joint osteoarthritis (TMJOA) lesion development is still poorly understood. In this study, we used different TMJOA animal models to detect whether ferroptosis is related to onset of TMJOA which modelling by monosodium iodoacetate (MIA), IL-1{beta}, occlusion disorder (OD) and unilateral anterior crossbite (UAC). Immunohistochemical staining and Western blot analysis were used to detect ferroptosis proteins and cartilage degradation related protein expression. Our results revealed that lower level of ferroptosis-related proteins GPX4 in cartilage layer, but the level of ACSL4 and P53 increase in that of condyle. Injection of ferroptosis inhibitor liproxstatin-1 (Lip-1) effectively decrease ACSL4, P53 and TRF expression. In vitro, IL-1{beta} induced the reduction of cartilage extracellular matrix expression in mandibular condylar chondrocytes (MCCs). Lip-1 maintain the morphology and function of mitochondria, and inhibited the aggravation of lipid peroxidation and reactive oxygen species (ROS) production which induced by IL-1{beta}. These results suggested that chondrocytes ferroptosis play an important role in the development and progression of TMJOA. Inhibition of condylar chondrocyte ferroptosis could be a promising therapeutic strategy for TMJOA. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week I discuss a new study in which twenty-five healthy young males were recruited and performed 17–19 h/day fasting for 30 days. In this explanatory study, Ramadan fasting (RF) was used to investigate the effects of prolonged IF on autophagy, inflammasome, and senescence activity in mRNA levels. Main conclusions from the study were the following:Fasting 17 to 19 hours per day for 30 days increased autophagy and increased tumor suppressor P53.Autophagy increased, favorable changes were made in the inflammasome hub, and there was a decrease in senescence-associated-signaling molecules.P53 helps repair DNA damage, prevents senescence, and contributes to reduced atherogenic risk.One downside of the study was the fact that none of the participants' sleeping, eating, and exercise habits were recorded which might influence autophagy, inflammasome, and senescence mRNA expression.Either way, I thought this would be an interesting study to share and if you have any questions feel free to email me at brian@briangryn.com. Have a great week!Episode Resources:https://www.sciencedirect.com/science/article/pii/S2666149723000063If you love the Get Lean Eat Clean Podcast, we'd love for you to subscribe, rate, and give a review on Apple Podcasts and Spotify! Until next time!Links:Watch Get Lean Eat Clean podcast video episodes on YouTube!LMNT: A tasty electrolyte drink mix that is formulated to help anyone with their electrolyte needs and is perfectly suited to folks fasting or following low-carb, whole food diets. Free gift with purchase:DrinkLMNT.com/getleaneatcleanhttps://www.21dayfastingchallenge.com/Upgraded Formulas hair mineral test (Coupon Code: GETLEAN10) :https://www.upgradedformulas.com/pages/kit?rfsn=6677062.f87541&utm_source=refersion&utm_medium=affiliate&utm_campaign=6677062.f87541X3 Bar: Variable Resistance Technology allows for a full body workout in only 10 minutes! Use discount code "Save50" for $50 off your purchase! https://www.anrdoezrs.net/click-100286468-13650338| Listen to the Get Lean Eat Clean Podcast |►Apple Podcasts | https://podcasts.apple.com/us/podcast/get-lean-eat-clean/id1540391210►Spotify | https://open.spotify.com/show/0QmJzYZsdV6tUNbDxaPJjS| Connect with Brian |►Website | https://www.briangryn.com►Instagram | https://www.instagram.com/bdgryn►Facebook | https://www.facebook.com/getleanandeatclean►Twitter | https://twitter.com/grynnerwinner

A new study found daily intermittent fasting for ~ 17-19 hours was sufficient to enhance fat loss, metabolic health and bio-markers linked longevity as well as cancer prevention.  Support your Intermittent Fasting lifestyle with the updated Berberine HCl Fasting Accelerator by MYOXCIENCE: Use code podcast to save 12% Link to study, show notes: https://bit.ly/3JqFft4 Time Stamps:   00:00 Fasting 17 to 19 hours per day for 30 days increased autophagy and increased tumor suppressor P53. 02:10 Autophagy increased, favorable changes were made in the inflammasome hub, and there was a decrease in senescence-associated-signaling molecules. 03:00 P53 helps repair DNA damage, prevents senescence, and contributes to reduced atherogenic risk. 06:05 Autophagy has tissue-specific benefits, especially in the liver and brain. 07:35 Regular exercisers have a great increase in fasted-associated autophagy initiation proteins. 08:35 Long duration fasts can catabolize lean mass, possibly increasing risk for cardiovascular disease.

⚡ Cryo-EM is a powerful tool that helps look at cancer molecules differently. Penn State University uses the cryo-EM technique to understand and outsmart cancer. Professor Kelly explains, "Our lab uses a very high-tech imaging approach. It's called cryo-electron microscopy or cryo-EM, which pioneers in our field actually won the Nobel Prize for just a few years ago. And what we'd like to do is dive deep into cancer cells, understand what molecules look like using these instruments, take pictures and snapshots of them — what you would do with your iPhone but in portrait mode — so we can really focus very deeply on the nuances of these molecules. Then we use these molecules to try and better understand what goes wrong in cancer, how these molecules are to cancer, and what we might do to better inform treatments based on differences in molecules from cancer cells versus normal cells."⚡ Cryo-electron microscopy allows us to image things at the level of atoms. So what makes cryo-EM technology so useful in cancer research? Professor Kelly says, "What cryo-EM does is it allows us to see all the molecules that constitute cells, their different placements within cells, as well as their over architecture down at the level of atoms. So going even deeper beyond just the level of cells, we can get down and understand the level of which proteins are with DNA, how these proteins don't interact with DNA properly to protect cells from diseases, or how things might work against us when cells become cancerous and how molecules go awry and don't perform their job properly."⚡ What makes Penn State unique in cryo-EM? Professor Kelly explains what makes her lab's cryo-EM one of a kind. She says, "Cryo-electron microscopes that are installed and operational at Penn State are uniquely built to service the life science community as well as the material science community. And some of these instruments have different analytical tools and cameras integrated in them that you wouldn't find in any other cryo-EM instrument. We're looking to screen and look at proteins differently."

In this week's episode, Jonathan Sackier, surgeon, innovator, and entrepreneur, explores the history and uses of regenerative medicine while highlighting its different to transplantation. Comparing the protein P53 to Kim Kardashian, Jonathan contemplates the uses of other proteins as well as the different types of regenerative medicine, including gene therapies and the use of petroleum-based prosthetics. He even provides hints to his latest project in the field and elaborates on the use of scaffolding in regenerative medicine.

David Mack, co-founder and CEO of PMV Pharma, gives us an in-depth look at the cancer-stopping power of P53. We discuss emerging cancer therapies, small-molecule chemistry, and future drug targets. Plus, fun stories from the invention of PCR.

Dr. John Sweetenham, of the UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and Dr. Marc Braunstein, of NYU Langone Health, discuss key data from the CAPTIVATE and GRIFFIN trials and other compelling studies in hematologic malignancies featured at the 2022 ASCO Annual Meeting.  Dr. John Sweetenham: Hello. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast.  For my guest today, I'm pleased to introduce Dr. Marc Braunstein, a hematologist, and oncologist at NYU Perlmutter Cancer Center. We'll be discussing key posters on advances in hematologic malignancies that will be featured at the 2022 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Marc, it's great to have you on the podcast today.  Dr. Marc Braunstein: Thank you, John. It's a pleasure to be here.  Dr. John Sweetenham: So, Marc, there are going to be some very interesting abstracts with some provocative results presented at the ASCO Annual Meeting this year. I know we've selected a number of these to speak about today, beginning with Abstract 8027 on the subject of multiple myeloma. And this I think is a long-term follow-up study for long-term survivors of multiple myeloma more than 12 years out now. Can you comment on this and let us know what you believe the key takehomes from this study are?  Dr. Marc Braunstein: Sure. Absolutely, John. So, this was a prospective registry that has been in place since 2009, and it's composed of various practice settings, but primarily community practices where most patients get their myeloma care. And what they did was they looked at about 1,400 patients with newly diagnosed multiple myeloma across 250 sites in the U.S. between 2009 and 2011 who were included in the registry. The participants also filled out the quality-of-life surveys, and they compared a group of long-term survivors who had more than 8 years of follow-up to patients who were not long-term survivors below that 8-year threshold.  So, about 20% were in the long-term survival group and 80% in the non-long term survival group. And they basically characterized those 2 groups. What they found was that the individuals who did have long-term survival were generally younger—median age of 62 versus 68, and had better performance status, were more likely to receive stem cell transplants, about 66 versus 60%.  And therefore, the implication of this is that patients who fit those criteria may have a better prognosis in addition to the other cytogenetics and other factors we use as prognostic indicators. And what was also interesting was that the 8-year overall survival of the overall group was about 36%.  So, we still have room to go in terms of bringing new therapies to extend survival in this condition. And only 20% of the total population were long-term survivors at that 8-year threshold. So, those were the general findings of the abstract.  Dr. John Sweetenham: Do you think it gives us new information on patient selection for more intensive therapies upfront?  Dr. Marc Braunstein: Well, I think it certainly tells us which patients are more likely to have longer-term survival. I think we know in multiple myeloma that it's essential to really use the patient's presenting features, their disease features, their comorbidities, and their degree of fitness or frailty to guide how intensive a therapy or regimen we can devise for that individual patient. But I think it certainly says that if you have a patient who is on the younger side of the spectrum, who is eligible for stem cell transplant, who has a better performance status, those are the patients that are more likely to have the long-term survival. It doesn't necessarily say that if you're not in that category, you won't have long-term survival, but on average, those were the patients who fared better in the long term.  Dr. John Sweetenham: Okay. So, staying for a little while on the subject of multiple myeloma, Abstract 8037 is really addressing a very different question. It's the application of circulating tumor DNA analysis and its association with relapse in patients with refractory myeloma. Would you comment a little on this and maybe let us know what you think the significance of this will be for the future?  Dr. Marc Braunstein: Sure. My colleagues in the solid tumor space are using circulating tumor DNA regularly and in the myeloma field, we're a little bit jealous of them.  So, it's helpful to have a study like this that's looking at circulating peripheral blood markers, in this case circulating tumor DNA, to help guide various prognostic or predictive indices that will help us guide therapeutic decisions.  So, this was a study where they looked at patients who were enrolled in a phase 2 study of a free-drug regimen of carfilzomib-thalidomide-dexamethasone the MM17 study, and they took 50 transplant eligible multiple myeloma patients who were refractory to their first line of therapy, and they collected bone marrow samples and peripheral blood at 3 time points at the third cycle of treatment and at the end of the study or at the point of refractoriness to that regimen.  They collected about 187 samples in total. They used a sequencing technique to determine the variance of 22 gene signatures known to be mutated in multiple myeloma. And what they found was a particular gene signature that was associated with shorter progression-free and overall survival in that phase 2 study. And those genes included known oncogenic drivers, including BRAF genes, ATM, and P53.  What was particularly interesting among the circulating tumor DNA mutations was that they were found in about 88% of patients at the start of the study. So, what that tells us is, number 1, circulating tumor DNA offers a wealth of information that can be highly valuable in multiple myeloma, which is a disease where we typically rely on the bone marrow to assess the status of the plasma cells and status of the mutation profile.  And number 2, that many of these mutations may be present earlier on in a disease that we know evolves in a clonal way that leads to disease progression. So, I think there's still a lot of information we have to learn about the utility of circulating tumor DNA in myeloma, but this study certainly shows that there's a lot to be explored in terms of the mutational profile and peripheral blood in myeloma.  Dr. John Sweetenham: A couple of questions that arise for me out of this study. First of all, do you think this is going to have any implications for future study design and patient selection?  Dr. Marc Braunstein: Definitely. I think the whole field in multiple myeloma is progressing quickly in terms of how we assess response, how we use minimal residual disease, and moving more towards using novel markers in peripheral blood, including mass spectrometry, and now perhaps circulating tumor DNA to look at surrogate markers for survival.  And so, what this abstract is showing is that we could potentially use circulating tumor DNA both as prognostic markers, potentially as disease response markers, and prognostic markers to guide which patients may be more likely to have shorter survival. So, I think this has a lot of implications for how we design future studies.  Dr. John Sweetenham: Yeah. And the second question, do you think this is the beginning of the end of bone marrow analysis in multiple myeloma?  Dr. Marc Braunstein: So, I can tell you if it is, patients I think will be very happy and so will clinicians because we really want to know at the core what the degree of residual disease is in a patient. And right now, the only way to do that is through a bone marrow biopsy.  And so, I think that this is the beginning of the use of peripheral blood studies with higher resolution to allow us to gain more information on patients that hopefully will allow us to obviate the need for more invasive testing like bone marrow biopsies.  Dr. John Sweetenham: Yeah, absolutely. Thanks. Just changing gears now, moving on to Abstract 7050. This is an abstract that addresses what I think we'd all agree is becoming an increasingly important question in the management of chronic myeloid leukemia (CML), and that is number 1, is it safe to discontinue therapy in responding patients? And number 2, when is it safe to discontinue that therapy?  Dr. Marc Braunstein: So, this is an abstract that is looking primarily at CML. You know that we're making a lot of progress when we can begin to talk about discontinuation and de-escalation of therapy.  And so, in the field of CML, the use of tyrosine kinase inhibitors (TKIs) and the targeting of the BCR-ABL mutation has brought about tremendous progress in patients in the chronic phase.  So, there have been several retrospective studies that have looked at the role of discontinuing one of the TKIs. Most of the studies have focused on imatinib since that was the first one that was discovered, but they've looked at others in the class as well.  What struck me the most is that there's a remarkable consistency between these studies. So, when you discontinue one of these TKIs, the percentage of patients who remain in remission is somewhere between 40 to 50%. And what this abstract looked at was a single institution retrospective assessment of 284 patients with CML, between 1999 and 2017, who were treated with a TKI for their CML and then subsequently discontinued the therapy.  Now, what's worth noting in the various studies that have looked at discontinuation therapy is that patients who were taken off of the TKI generally were in a good molecular remission, MR 4 or 4.5, for at least 2 or 3 years. And in this study, about 70% of patients had electively discontinued and 24% of patients stopped due to adverse events.  So, it wasn't necessarily guided by their response to treatment at the time of discontinuation. What they found actually was fairly consistent with the literature that at a median follow-up of 36 months after TKI discontinuation, about 19% lost their molecular remission and 88% had achieved a molecular remission after resuming therapy. And that is consistent with the literature that fortunately, even if a patient loses their molecular remission off of the TKI therapy, the majority of patients will go back into molecular remission when you re-challenge them.  Dr. John Sweetenham: Important data, indeed. And you know, on something of a similar theme, the next abstract that we're going to look at is the Abstract 7519. In this case, in chronic lymphocytic leukemia (CLL), and certainly, those of us who remember when ibrutinib was initially introduced into the second-line treatment of CLL, didn't really know whether discontinuation or fixed duration treatment with agents like this was going to be something that we could pursue or whether treatment with these drugs was going to be indefinite. This abstract certainly addresses that specific question, and again, I'm interested in your insights into this.  Dr. Marc Braunstein: Sure. So, this is an abstract looking at CLL, where we've really begun to move away from chemotherapy, and we have a variety of targeted oral therapies that target the underlying pathology of this leukemia.  And so, as you mentioned, ibrutinib is approved both in the relapsed and more recently in the frontline setting, wherein the RESONATE-2 study that was published in the New England Journal of Medicine in 2015, there was actually an overall survival benefit of ibrutinib even in higher-risk patients.  So, the CAPTIVATE study is an ongoing phase 2 study that is looking at whether we can improve the efficacy of single-agent ibrutinib in the first-line setting when combined with venetoclax.  Ibrutinib targets protein tyrosine kinase and venetoclax targets Bcl-2, and that combination is hypothesized to further weaken the resistance of CLL and lead to better outcomes.  So, this was a multicenter phase 2 study. And in this abstract, they looked at the 3-year follow-up of patients who were actually able to discontinue therapy on this regimen. So, just as a bit of background, ibrutinib is typically continued until progression, and venetoclax as it's been studied in the first-line setting with obinutuzumab is given for about 12 months.  So, in this study, at 3-year follow-up, they looked at the patients in the cohort who were off therapy and looked at the percentage of patients who maintained a complete remission at 3 years. And that complete remission rate was about 57%.  The majority of patients, greater than 95% of patients, were alive at 3 years even in the high-risk cohort. So, I think the implications of the study is that upfront or oral targeted therapies when you combine ibrutinib and venetoclax really produce tremendous responses that are durable, and it's found even in the high-risk patients who are expected not to do quite as well at 3 years.  Dr. John Sweetenham: Yeah, I agree. I think it's very reassuring actually to see these durable responses with this fixed duration regimen. And to conclude, Abstract 8011 was an abstract which addressed treatment in the first-line setting for multiple myeloma. And again, I wonder if you could comment on this study.  Dr. Marc Braunstein: Sure! So, this is a study looking at the GRIFFIN regimen, which was a phase 2 randomized study of daratumumab (DARA), plus lenalidomide, bortezomib, and dexamethasone.  So, DARA RVd versus RVd alone. In that study, the primary endpoint was stringent, complete remission, and it has been previously presented and published that the stringent complete remission (CR) rate was significantly improved, 42% versus 32%, when you include daratumumab upfront.  In this abstract, they looked at the sustained rate of minimal residual disease negativity, which is basically the deepest possible remission you can achieve in upfront therapy and in myeloma.  What they found was that, again, when you looked at the quadruplet regimen versus the triplet regimen, the rates of minimum residual disease (MRD) negativity were just improved with the quad regimen.  So, at a median follow-up of 38.6 months, there were about 54 versus 20% of patients who were MRD negative at 12 months amongst the patients who had achieved a CR, and 59 versus 17% MRD negative among the patients who achieved a stringent CR favoring the daratumumab arm.  So, I think this abstract shows the benefit of including a monoclonal antibody upfront in newly diagnosed patients with myeloma combined with stem cell transplant and maintenance, allowing for sustained MRD negativity.  Dr. John Sweetenham: Do you think this represents a new standard of care?  Dr. Marc Braunstein: I do. At our institution, we've adopted this regimen for most newly diagnosed transplant-eligible patients. I think the data clearly show an improved depth of response and MRD negativity rates, and I think that there are a number of ongoing studies looking at the role of monoclonal antibodies in the maintenance phase as well.  I'm especially excited this year, at ASCO Annual Meeting there's a plenary session involving myeloma looking at patients who received RVd upfront and then went for transplant. But I think we can improve on that regimen by including monoclonal antibodies and immunotherapies upfront, and I do think it represents a new era of immunotherapies in multiple myeloma.  Dr. John Sweetenham: Well, thanks, Marc. I mean, to your last point, it sounds as if there is a lot, including these abstracts, to look forward to at the upcoming ASCO meeting. So, we really appreciate you sharing your insights into these abstracts with us today.  Dr. Marc Braunstein: Sure. My pleasure. Thank you for having me, John.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.      Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Marc Braunstein:  Consulting or Advisory Role: Celgene, Janssen, AstraZeneca, Amgen, Takeda, Verastem, Celgene, Janssen, Karyopharm Therapeutics, Epizyme, Morphosys, Takeda, Pfizer  Research Funding (Inst): Janssen, Celgene/BMS  Travel, Accommodations, Expenses: Takeda  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. 

A new MP3 sermon from Antioch Presbyterian Church (PCA) is now available on SermonAudio with the following details: Title: "The Urgent Gospel, P53, The Abomination of Desolation" Subtitle: Mark: The Urgent Gospel Speaker: Kelley Buffaloe Broadcaster: Antioch Presbyterian Church (PCA) Event: Sunday Service Date: 4/24/2022 Bible: Mark 13:9-23 Length: 28 min.

Dr. Jeffery Gladden and Dr. Navarro talk about Covid. They talk about people still suffering symptoms after taking the vaccine. You will learn how Covid accelerates aging and shortens telomeres. You also learn about the importance of time, supplements, and more extensive procedures in the recovery journey. Get the knowledge and insights you need to stay ahead of the curve. Dr. Gladden introduces the show and mentions how exposure to Covid is actually aging us. (1:25) Dr. Gladden talks about how mitochondria function is knocked down for most people who have suffered from Covid and how they don't seem to be making much ATP. (3:45) Dr. Navarro talks about the additional resources he uses to help patients suffering from Covid and their recorded improvements. (4:59) Dr. Gladden talks about the importance of improving the NAD to NDH ratio. (6:59) Dr. Gladden mentions that from measurements done, there seems to be immuno-senescence when telomeres are short. (8:00) Dr. Gladden mentions that when the telomeres are shorter, they release a molecule called P53, which signals to the mitochondria to shut down energy production. (8:35) Dr. Gladden reminds us that Covid is not just an infection but can also be accelerating some of the drivers of aging. (9:14) Dr. Navarro mentions how helpful the sauna can be a helpful detox in dealing with any build-ups in the system. (10:52) Dr. Gladden talks about things that can be done at the office that clients may not be able to do at home to help them recover faster. (13:33) Dr. Gladden mentions how sometimes recovery from Covid takes time, supplements, and some more extensive procedures. (14:05) Dr. Gladden talks about how dealing with the aftermath of Covid in a systematic way yields better results. (15:18) Dr. Navarro discusses how hormones affect recovery from Covid and how hormone optimization helps. (15:56) Dr. Gladden thanks Dr. Navarro for taking out time for this discussion. (16:54)   Visit our website, www.gladdenlongevitypodcast.com, for more information on this episode and other episodes as well. Follow us on social media! Instagram: @gladdenlongevitypodcast Twitter: @GLPodcast_ Facebook: @GladdenLongevityPodcast   To learn more about Gladden Longevity and how you can become a client, visit www.gladdenlongevity.com today!

传说，关于巨人的秘密，就写在我们的17号染色体上，这里有一个基因，叫P53。本来，科学家们想用这个基因来解释佩托悖论。结果却发现，这里面残留着有关巨人的秘密。

Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review." 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 at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%? Dr. Greg Hundley: All right, Carolyn, I'm going to guess here. I'm going to go 10%. Dr. Carolyn Lam: Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days. Dr. Carolyn Lam: Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use. Dr. Carolyn Lam: Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern. Dr. Greg Hundley: Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Dr. Greg Hundley: While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells. Dr. Carolyn Lam: Interesting. So what did Dr. Loscalzo and colleagues find? Dr. Greg Hundley: Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance. Dr. Greg Hundley: Whoa. Okay, Carolyn. Now what is filamin-C? Dr. Carolyn Lam: I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found. Dr. Carolyn Lam: First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms. Dr. Carolyn Lam: Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy. Dr. Carolyn Lam: And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy. Dr. Greg Hundley: Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease. Dr. Carolyn Lam: Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please? Dr. Greg Hundley: Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease. Dr. Carolyn Lam: Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study. Dr. Greg Hundley: And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy? Dr. Carolyn Lam: Yay. All right, let's go, Greg. Dr. Greg Hundley: Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease? Dr. Babken Asatryan: Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease. Dr. Babken Asatryan: The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease. Dr. Babken Asatryan: Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy. Dr. Babken Asatryan: Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease. Dr. Babken Asatryan: The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: And patients present generally when, in terms of lifespan? Dr. Babken Asatryan: So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria. Dr. Greg Hundley: And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family? Dr. Babken Asatryan: Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging. Dr. Greg Hundley: Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking?   Dr. Anwar Chahal: Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us. Dr. Anwar Chahal: Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging. Dr. Anwar Chahal: So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this. Dr. Anwar Chahal: As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens. Dr. Anwar Chahal: That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this. Dr. Anwar Chahal: Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies. Dr. Anwar Chahal: It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury. Dr. Anwar Chahal: There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link. Dr. Greg Hundley: Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article? Dr. Ntobeko Ntusi: Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM. Dr. Ntobeko Ntusi: The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see. Dr. Ntobeko Ntusi: The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two. Dr. Ntobeko Ntusi: The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events. Dr. Ntobeko Ntusi: Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD. Dr. Ntobeko Ntusi: Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed. Dr. Ntobeko Ntusi: So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg. Dr. Greg Hundley: Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space? Dr. Babken Asatryan: I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well. Dr. Greg Hundley: Very nice. And Anwar, do you have anything to add? Dr. Anwar Chahal: Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques. Dr. Anwar Chahal: The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. Well, on behalf of 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, 2021. 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 visit ahajournals.org.

Avanish Vellanki, Cofounder and CEO at Rain Therapeutics, discusses the role of p53 and MDM2 in cancers like liposarcoma, the mechanism of action of milademetan, and the positive pre-clinical data presented at the 2021 World Conference of Lung Cancer. As Mr. Vellanki explains, p53 regulates the cell cycle and is essential for tumor suppression. MDM2 is a crucial regulator of p53. If MDM2 is overexpressed, p53 can be inactivated, leading to tumor growth and cancer progression. Milademetan, Rain Therapeutics' lead product candidate, inhibits MDM2, and, in doing so, is hypothesized to reactivate p53 and thus control cancer growth in approximately 50% of cancers without a p53 mutation. Mr. Vellanki notes that MDM2 inhibition has been studied for a number of years. However, in the past, blood toxicity has been an issue. One reason for that is previous treatment regimens would allow the drug to accumulate in the tissues of patients. Milademetan does not accumulate in tissues when patients take milademetan for 3 days and then no treatment for 11 days. This allows the drug to be effective but prevents blood toxicity. This dosing schedule, according to Mr. Vellanki, has led to triple-to-quadruple the length of progression free survival compared to standard of care in liposarcoma, milademetan's main indication. At the 2021 World Conference of Lung Cancer, pre-clinical data suggested milademetan could also be safe and effective in treating malignant pleural mesothelioma. To learn more about liposarcoma and other rare cancers, visit checkrare.com/diseases/cancers/

Learn about simple solutions for resolving human-wildlife conflict; and how exposure to sunlight can increase romance. Plus: Trivia! More from “America's funniest science writer” Mary Roach: Pick up "Fuzz: When Nature Breaks the Law" at your local bookstore to learn more about the weird world of human-wildlife conflict: https://www.indiebound.org/book/9781324001935  Mary Roach's official website: https://maryroach.net/  Follow @mary_roach on Twitter: https://twitter.com/mary_roach  Exposure to sunlight releases sexy hormones, leading to more romantic passion by Grant Currin Exposure to sunlight enhances romantic passion in humans. (2021, August 25). EurekAlert! https://www.eurekalert.org/news-releases/926348  Parikh, R., Sorek, E., Parikh, S., Michael, K., Bikovski, L., Tshori, S., Shefer, G., Mingelgreen, S., Zornitzki, T., Knobler, H., Chodick, G., Mardamshina, M., Boonman, A., Kronfeld-Schor, N., Bar-Joseph, H., Ben-Yosef, D., Amir, H., Pavlovsky, M., Matz, H., & Ben-Dov, T. (2021). Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior. Cell Reports, 36(8), 109579. https://doi.org/10.1016/j.celrep.2021.109579  Episodes referenced in Curiosity Challenge Trivia game: One purchase leads to more: https://www.curiositydaily.com/diderot-effect-animated-cave-art-running-benefits-your-knees/  Cells kill bacteria: https://www.curiositydaily.com/mapping-the-ocean-soap-making-cells-crows-comprehend-zero/  Mountains on neutron stars: https://www.curiositydaily.com/backward-letters-dogs-detect-lies-neutron-star-mountains/  Follow Curiosity Daily on your favorite podcast app to learn something new every day withCody Gough andAshley Hamer. Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers. See omnystudio.com/listener for privacy information.

Revelations in gene editing have made it possible to tinker in the vast human epigenome and to potentially alter the projection of diseases, including cancer. DNA methylation is an epigenetic mechanism that marks the regulation of gene expression. P53 is a highly-mutated gene in many patients with various cancerous tumors. The insulin-like growth factor binding protein 2 (IGFBP2) is an oncogene directly regulated through p53-mediated transcription. In tumorigenesis, this protein has both tumor-promoting and -suppressing functions. “In this study, we will focus on the insulin-like growth factor binding protein 2 (IGFBP2), a recently discovered multitasked gene regulated by DNA methylation which has also been reported to function both as a tumor-promoting and -suppressing gene.” Researchers from The Netherlands Cancer Institute in Amsterdam conducted a study using CRISPR/Cas9 technology and IGFBP2 to learn about the process of DNA methylation in various tumor settings. Their trending research paper was published in Oncotarget in 2021, and entitled, ​​“Diverse transcriptional regulation and functional effects revealed by CRISPR/Cas9-directed epigenetic editing.” “Here, we have taken advantage of CRISPR/dCas9 technology adapted for epigenetic editing through site-specific targeting of DNA methylation to characterize the transcriptional changes of the candidate gene and the functional effects on cell fate in different tumor settings.” Full blog - https://www.impactjournals.com/journals/blog/oncotarget/exploration-of-gene-editing-in-the-tumor-setting/ Press release - https://www.oncotarget.com/news/pr/crispr-cas9-directed-epigenetic-editing/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28037 DOI - https://doi.org/10.18632/oncotarget.28037 Full text - https://www.oncotarget.com/article/28037/text/ Correspondence to - Miguel Vizoso - orcid.org/0000-0002-9992-2851 and Jacco van Rheenen - j.v.rheenen@nki.nl Keywords - targeted DNA methylation, CRISPR/Cas9-based system, IGFBP2, epithelial-to-mesenchymal transition 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 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

This week Harry is joined by Kevin Davies, author of the 2020 book Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing. CRISPR—an acronym for Clustered Regularly Interspaced Short Palindromic Repeats—consists of DNA sequences that evolved to help bacteria recognize and defend against viral invaders, as a kind of primitive immune system. Thanks to its ability to precisely detect and cut other DNA sequences, CRISPR has spread to labs across the world in the nine years since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking 2012 Science paper describing how the process works. The Nobel Prize committee recognized the two scientists for the achievement in 2020, one day after Davies' book came out. The book explains how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused. Today's interview covers all of that ground and more.Davies is a PhD geneticist who has spent most of his career in life sciences publishing. After his postdoc with Harvey Lodish at the Whitehead Institute, Davies worked as an assistant editor at Nature, the founding editor of Nature Genetics (Nature's first spinoff journal), editor-in-chief at Cell Press, founding editor-in-chief of the Boston-based publication Bio-IT World, and publisher of Chemical & Engineering News. In 2018 he helped to launch The CRISPR Journal, where he is the executive editor. Davies' previous books include Breakthrough (1995) about the race to understand the BRCA1 breast cancer gene, Cracking the Genome (2001) about the Human Genome Project, The $1,000 Genome (2010) about next-generation sequencing companies, and DNA (2017), an updated version of James Watson's 2004 book, co-authored with Watson and Andrew Berry.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to the page of the MoneyBall Medicine podcast. You can find it by searching for it or selecting it from your library. Just note that you'll have to go to the series page which shows all the episodes, not just the page for a single episode.3.Scroll down to find the subhead titled "Ratings & Reviews."4.Under one of the highlighted reviews, select "Write a Review."5.Next, select a star rating at the top — you have the option of choosing between one and five stars. 6.Using the text box at the top, write a title for your review. Then, in the lower text box, write your review. Your review can be up to 300 words long.7.Once you've finished, select "Send" or "Save" in the top-right corner. 8.If you've never left a podcast review before, enter a nickname. Your nickname will be displayed next to any reviews you leave from here on out. 9.After selecting a nickname, tap OK. Your review may not be immediately visible.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: We talk a lot on the show about how computation and data are changing the way we develop new medicines and the way we deliver healthcare. Some executives in the drug discovery business speak of the computing and software side of the business as the “dry lab” —to set it apart from the “wet labs” where scientists get their hands dirty working with actual cells, tissues, and reagents.But the thing is, recent progress on the wet lab side of biotech has been just as amazing as progress in areas like machine learning. And this week, my friend Kevin Davies is here to talk about the most powerful tool to come along in the last decade, namely, precise gene editing using CRISPR.Of course, CRISPR-based gene editing has been all over the news since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking Science paper in 2012 describing how the process works in the lab. That work earned them a Nobel Prize in medicine just eight years later, in 2020.But what's not as well-known is the story of how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused.Kevin put that whole fascinating story together in his 2020 book Editing Humanity. And as the executive editor of The CRISPR Journal, the former editor-in-chief of Bio-IT World, the founding editor at Nature Genetics, and the author of several other important books about genomics, Kevin is one of the best-placed people in the world to tell that story. Here's our conversation.Harry Glorikian: Kevin, welcome to the show. Kevin Davies: Great to see you again, Harry. Thanks for having me on.Harry Glorikian: Yeah, no, I mean, I seem to be saying this a lot lately, it's been such a long time since, because of this whole pandemic, nobody's really seeing anybody on a regular basis. I want to give everybody a chance to hear about, you had written this book called Editing Humanity, which is, you know, beautifully placed behind you for, for product placement here. But I want to hear, can you give everybody sort of an overview of the book and why you feel that this fairly technical laboratory tool called CRISPR is so important that you needed to write a book about it?Kevin Davies: Thank you. Yes. As you may know, from some of my previous “bestsellers” or not, I've written about big stories in genetics because that's the only thing I'm remotely qualified to write about. I trained as a human geneticist in London and came over to do actually a pair of post-docs in the Boston area before realizing my talents, whatever they might be, certainly weren't as a bench researcher. So I had to find another way to stay in science but get away from the bench and hang up the lab coats.So moving into science publishing and getting a job with Nature and then launching Nature Genetics was the route for me. And over the last 30 years, I've written four or five books that have all been about, a) something big happening in genomics, b) something really big that will have both medical and societal significance, like the mapping and discovery of the BRCA1 breast cancer gene in the mid-90s, the Human Genome Project at the turn of the century, and then the birth and the dawn of consumer genetics and personalized medicine with The $1,000 Genome. And the third ingredient I really look for if I'm trying to reach a moderately, significantly large audience is for the human elements. Who are they, the heroes and the anti heroes to propel the story? Where is the human drama? Because, you know, we all love a good juicy, gossipy piece of story and rating the good guys and the bad guys. And CRISPR, when it first really took off in 2012, 2013 as a gene editing tool a lot of scientists knew about this. I mean, these papers are being published in Science in particular, not exactly a specialized journal, but I was off doing other things and really missed the initial excitement, I'm embarrassed to say. It was only a couple of years later, working on a sequel to Jim Watson's DNA, where I was tasked with trying to find and summarize the big advances in genomic technology over the previous decade or whatever, that I thought, well, this CRISPR thing seems to be taking off and the Doudnas and the Charpentiers are, you know, winning Breakthrough Prizes and being feted by celebrities. And it's going on 60 Minutes. They're going to make a film with the Rock, Dwayne Johnson. What the heck is going on. And it took very little time after that, for me to think, you know, this is such an exciting, game-changing disruptive technology that I've got to do two things. I've gotta, a) write a book and b) launch a journal, and that's what I did. And started planning at any rate in sort of 2016 and 17. We launched the CRISPR Journal at the beginning of 2018. And the book Editing Humanity came out towards the end of 2020. So 2020, literally one day before the Nobel Prize—how about that for timing?—for Doudna and Charpentier for chemistry last year. Harry Glorikian: When I think about it, I remember working with different companies that had different types of gene editing technology you know, working with some particularly in the sort of agriculture space, cause it a little bit easier to run faster than in the human space. And you could see what was happening, but CRISPR now is still very new. But from the news and different advances that are happening, especially here in the Boston area, you know, it's having some real world impacts. If you had to point to the best or the most exciting example of CRISPR technology helping an actual patient, would you say, and I've heard you say it, Victoria Gray, I think, would be the person that comes to mind. I've even, I think in one of your last interviews, you said something about her being, you know, her name will go down in history. Can you explain the technology that is helping her and what some of the similar uses of CRISPR might be?Kevin Davies: So the first half of Editing Humanity is about the heroes of CRISPR, how we, how scientists turned it from this bizarre under-appreciated bacterial antiviral defense system and leveraged it and got to grips with it, and then figured out ways to turn it into a programmable gene editing technology. And within a year or two of that happening that the classic Doudna-Charpentier paper came out in the summer of 2012. Of course the first wave of biotech companies were launched by some of the big names, indeed most of the big names in CRISPR gene editing hierarchies. So Emmanuel Charpentier, Nobel Laureate, launched CRISPR Therapeutics, Jennifer Doudna co-founded Editas Medicine with several other luminaries. That didn't go well for, for reasons of intellectual property. So she withdrew from Editas and became a co-founder of Intellia Therapeutics as well as her own company, Caribou, which just went public, and Feng Zhang and others launched Editas Medicine. So we had this sort of three-way race, if you will, by three CRISPR empowered gene editing companies who all went public within the next two or three years and all set their sights on various different genetic Mendelian disorders with a view to trying to produce clinical success for this very powerful gene editing tool. And so, yes, Victoria Gray is the first patient, the first American patient with sickle cell anemia in a trial that is being run by CRISPR Therapeutics in close association with Vertex Pharmaceuticals. And that breakthrough paper, as I think many of your listeners will know, came out right at the end of 2020 published in the New England Journal of Medicine. Doesn't get much more prestigious than that. And in the first handful of patients that CRISPR Therapeutics have edited with a view to raising the levels of fetal hemoglobin, fetal globin, to compensate for the defective beta globin that these patients have inherited, the results were truly spectacular.And if we fast forward now to about two years after the initial administration, the initial procedures for Victoria Gray and some of her other volunteer patients, the results still look as spectacular. Earlier this year CRISPR Therapeutics put out of sort of an update where they are saying that the first 20 or 24 patients that they have dosed with sickle cell and beta thallasemia are all doing well. There've been little or no adverse events. And the idea of this being a once and done therapy appears very well founded. Now it's not a trivial therapy. This is ex-vivo gene editing as obviously rounds of chemotherapy to provide the room for the gene edited stem cells to be reimplanted into the patient. So this is not an easily scalable or affordable or ideal system, but when did we, when will we ever able to say we've pretty much got a cure for sickle cell disease? This is an absolutely spectacular moment, not just for CRISPR, but for medicine, I think, overall. And Victoria Gray, who's been brilliantly profiled in a long running series on National Public Radio, led by the science broadcaster Rob Stein, she is, you know, we, we can call her Queen Victoria, we can call it many things, but I really hope that ,it's not just my idea, that she will be one of those names like Louise Brown and other heroes of modern medicine, that we look and celebrate for decades to come.So the sickle cell results have been great, and then much more recently, also in the New England Journal, we have work led by Intellia Therapeutics, one of the other three companies that I named, where they've been also using CRISPR gene editing, but they've been looking at a rare liver disease, a form of amyloidosis where a toxic protein builds up and looking to find ways to knock out the production of that abnormal gene.And so they've been doing in vivo gene editing, really using CRISPR for the first time. It's been attempted using other gene editing platforms like zinc fingers, but this is the first time that I think we can really say and the New England Journal results prove it. In the first six patients that have been reported remarkable reductions in the level of this toxic protein far, not far better, but certainly better than any approved drugs that are currently on the market. So again, this is a very, very exciting proof of principle for in vivo gene editing, which is important, not just for patients with this rare liver disorder, but it really gives I think the whole field and the whole industry enormous confidence that CRISPR is safe and can be used for a growing list of Mendelian disorders, it's 6,000 or 7,000 diseases about which we know the root genetic cause, and we're not going to tackle all of them anytime soon, but there's a list of ones that now are within reach. And more and more companies are being launched all the time to try and get at some of these diseases.So as we stand here in the summer of 2021, it's a really exciting time. The future looks very bright, but there's so much more to be done. Harry Glorikian: No, we're just at the beginning. I mean, I remember when I first saw this, my first question was off target effects, right? How are we going to manage that? How are they going to get it to that place that they need to get it to, to have it to that cell at that time, in the right way to get it to do what it needs to do. And you know, all these sorts of technical questions, but at the same time, I remember I'm going to, trying to explain this to my friends. I'm like, “You don't understand, this can change everything.” And now a high school student, I say this to people and they look at me strangely, a high school student can order it and it shows up at your house.Kevin Davies: Yeah, well, this is why I think, and this is why one reason why CRISPR has become such an exciting story and receives the Nobel Prize eight years after the sort of launch publication or the first demonstration of it as a gene editing tool. It is so relatively easy to get to work. It's truly become a democratized or democratizing technology. You don't need a million-dollar Illumina sequencer or anything. And so labs literally all around the world can do basic CRISPR experiments. Not everyone is going to be able to launch a clinical trial. But the technology is so universally used, and that means that advances in our understanding of the mechanisms, new tools for the CRISPR toolbox new pathways, new targets, new oftware, new programs, they're all coming from all corners of the globe to help not just medicine, but many other applications of CRISPR as well.Harry Glorikian: Yeah. I always joke about like, there, there are things going on in high school biology classes now that weren't, available, when I was in college and even when we were in industry and now what used to take an entire room, you can do on a corner of a lab bench.Kevin Davies: Yeah. Yeah. As far as the industry goes we mentioned three companies. But you know, today there's probably a dozen or more CRISPR based or gene editing based biotech companies. More undoubtedly are going to be launched before the end of this year. I'm sure we'll spend a bit of time talking about CRISPR 2.0, it seems too soon to be even thinking about a new and improved version of CRISPR, but I think there's a lot of excitement around also two other Boston-based companies, Beam Therapeutics in Cambridge and Verve Therapeutics both of which are launching or commercializing base editing. So base editing is a tool developed from the lab of David Lu of the Broad Institute [of MIT and Harvard]. And the early signs, again, this technology is only five or six years old, but the early signs of this are incredibly promising. David's team, academic team, had a paper in Nature earlier this year, really reporting successful base editing treatment of sickle cell disease in an animal model, not by raising the fetal globin levels, which was sort of a more indirect method that is working very well in the clinic, but by going right at the point mutation that results in sickle cell disease and using given the chemical repertoire of base editing.Base editing is able to make specific single base changes. It can't do the full repertoire of single base changes. So there are some limitations on researchers' flexibility. So they were unable to flip the sickle cell variant back to the quote unquote wild type variants, but the change they were able to make is one that they can live with, we can live with because it's a known benign variant, a very rare variant that has been observed in other, in rare people around the world. So that's completely fine. It's the next best thing. And so that looks very promising. Beam Therapeutics, which is the company that David founded or co-founded is trying a related approach, also going right at the sickle cell mutation. And there are other companies, including one that Matthew Porteus has recently founded and has gone public called Graphite Bio.So this is an exciting time for a disease sickle cell disease that has been woefully neglected, I think you would agree, both in terms of basic research, funding, medical prioritization, and medical education. Now we have many, many shots on goal and it doesn't really, it's not a matter of one's going to win and the others are going to fall by the wayside. Just like we have many COVID vaccines. We'll hopefully have many strategies for tackling sickle cell disease, but they are going to be expensive. And I think you know the economics better than I do. But I think that is the worry, that by analogy with gene therapies that have been recently approved, it's all, it's really exciting that we can now see the first quote, unquote cures in the clinic. That's amazingly exciting. But if the price tag is going to be $1 million or $2 million when these things are finally approved, if and when, that's going to be a rather deflating moment. But given the extraordinary research resources that the CRISPRs and Intellias and Beams and Graphites are pouring into this research, obviously they've got to get some return back on their investment so that they can plow it back into the company to develop the next wave of of gene editing therapies. So you know, it's a predicament Harry Glorikian: One of these days maybe I have to have a show based on the financial parts of it. Because there's a number of different ways to look at it. But just for the benefit of the listeners, right, who may not be experts, how would you explain CRISPR is different from say traditional gene therapies. And is CRISPR going to replace older methods of, of gene therapy or, or will they both have their place? Kevin Davies: No, I think they'll both have their place. CRISPR and, and these newer gene editing tools, base editing and another one called prime editing, which has a company behind it now called Prime Medicine, are able to affect specific DNA changes in the human genome.So if you can target CRISPR, which is an enzyme that cuts DNA together with a little program, the GPS signal is provided in the form of a short RNA molecule that tells the enzyme where to go, where to go in the genome. And then you have a couple of strategies. You can either cut the DNA at the appropriate target site, because you want to inactivate that gene, or you just want to scramble the sequence because you want to completely squash the expression of that gene. Or particularly using the newer forms of gene editing, like base editing, you can make a specific, a more nuanced, specific precision edit without, with one big potential advantage in the safety profile, which is, you're not completely cutting the DNA, you're just making a nick and then coaxing the cell's natural repair systems to make the change that you sort of you're able to prime.So there are many diseases where this is the way you want to go, but that does not in any way invalidate the great progress that we're making in traditional gene therapy. So for example today earlier today I was recording an interview or for one of my own programs with Laurence Reid, the CEO of Decibel Therapeutics, which is looking at therapies for hearing loss both genetic and other, other types of hearing disorders.And I pushed him on this. Aren't you actually joinomg with the gene editing wave? And he was very circumspect and said, no, we're very pleased, very happy with the results that we're getting using old fashioned gene replacement therapy. These are recessive loss of function disorders. And all we need to do is get the expression of some of the gene back. So you don't necessarily need the fancy gene editing tools. If you can just use a an AAV vector and put the healthy gene back into the key cells in the inner ear. So they're complimentary approaches which is great.Harry Glorikian: So, you know, in, in this podcast, I try to have a central theme when I'm talking to people. The relationships of big data, computation, advances in new drugs, and other ways to keep people healthy. So, you know, like question-wise, there's no question in my mind that the whole genomics revolution that started in the ‘90s, and I was happy to be at Applied Biosystems when we were doing that, would have been impossible in the absence of the advances in computing speed and storage in the last three decades. I think computing was the thing that held up the whole human genome, which gave us the book of life that CRISPR is now allowing us to really edit. But I wonder if you could bring us sort of up-to-date and talk about the way CRISPR and computation are intertwined. What happens when you combine precision of an editing tool like CRISPR with the power of machine learning and AI tools to find meaning and patterns in that huge genetic ball? Kevin Davies: Yeah. Well, yeah. I'm got to tread carefully here, but I think we are seeing papers from some really brilliant labs that are using some of the tools that you mentioned. AI and machine learning with a view to better understanding and characterizing some of the properties and selection criteria of some of these gene editing tools. So you mentioned earlier Harry, the need to look out for safety and minimize the concern of off-target effects. So I think by using some of these some algorithms and AI tools, researchers have made enormous strides in being able to design the programmable parts of the gene editing constructs in such a way that you increase the chances that they're going to go to the site that you want them to go to, and nnot get hung up latching onto a very similar sequence that's just randomly cropped up on the dark side of the genome, across the nucleus over there. You don't want that to happen. And I don't know that anybody would claim that they have a failsafe way to guarantee that that could never happen. But the you know, the clinical results that we've seen and all the preclinical results are showing in more and more diseases that we've got the tools and learned enough now to almost completely minimize these safety concerns. But I think everyone, I think while they're excited and they're moving as fast as they can, they're also doing this responsibly. I mean, they, they have to because no field, gene therapy or gene editing really wants to revisit the Jesse Gelsinger tragedy in 1999, when a teenage volunteer died in volunteering for a gene therapy trial at Penn of, with somebody with a rare liver disease. And of course that, that setback set back the, entire field of gene therapy for a decade. And it's really remarkable that you know, many of the sort of pioneers in the field refuse to throw in the towel, they realized that they had to kind of go back to the drawing board, look at the vectors again, and throw it out. Not completely but most, a lot of the work with adenoviruses has now gone by the wayside. AAV is the new virus that we hear about. It's got a much better safety profile. It's got a smaller cargo hold, so that's one drawback, but there are ways around that. And the, the explosion of gene therapy trials that we're seeing now largely on the back of AAV and now increasingly with, with non-viral delivery systems as well is, is very, very gratifying. And it's really delivery. I think that is now the pain point. Digressing from your question a little bit, but delivery, I think is now the big challenge. It's one thing to contemplate a gene therapy for the eye for rare hereditary form of blindness or the ear. Indeed those are very attractive sites and targets for some of these early trials because of the quantities that you need to produce. And the localization, the, the physical localization, those are good things. Those help you hit the target that you want to. But if you're contemplating trying something for Duchenne muscular dystrophy or spinal muscular atrophy, or some of the diseases of the brain, then you're going to need much higher quantities particularly for muscular disorders where, you run into now other challenges, including, production and manufacturing, challenges, and potentially safeguarding and making sure that there isn't an immune response as well. That's another, another issue that is always percolating in the background.But given where we were a few years ago and the clinical progress that we've talked about earlier on in the show it, I think you can safely assume that we've collectively made enormous progress in, in negating most, if not all of these potential safety issues.Harry Glorikian: No, you know, it's funny, I know that people will say like, you know, there was a problem in this and that. And I look at like, we're going into uncharted territories and it has to be expected that you just…you've got people that knew what they were doing. All of these people are new at what they are doing. And so you have to expect that along the way everything's not going to go perfectly. But I don't look at it as a negative. I look at it as, they're the new graduating class that's going to go on and understand what they did right. Or wrong, and then be able to modify it and make an improvement. And, you know, that's what we do in science. Kevin Davies: Well, and forget gene editing—in any area of drug development and, and pharmaceutical delivery, things don't always go according to plan. I'm sure many guests on Moneyball Medicine who have had to deal with clinical trial failures and withdrawing drugs that they had all kinds of high hopes for because we didn't understand the biology or there was some other reaction within, we didn't understand the dosing. You can't just extrapolate from an animal model to humans and on and on and on. And so gene editing, I don't think, necessarily, should be held to any higher standard. I think the CRISPR field has already in terms of the sort of market performance, some of the companies that we've mentioned, oh my God, it's been a real roller coaster surprisingly, because every time there's been a paper published in a prominent journal that says, oh my God, there's, there's a deletion pattern that we're seeing that we didn't anticipate, or we're seeing some immune responses or we're seeing unusual off target effects, or we're seeing P53 activation and you know, those are at least four off the top of my head. I'm sure there've been others. And all had big transient impact on the financial health of these companies. But I think that was to be expected. And the companies knew that this was just an overreaction. They've worked and demonstrated through peer review publications and preclinical and other reports that these challenges have been identified, when known about, pretty much completely have been overcome or are in the process of being overcome.So, you know, and we're still seeing in just traditional gene therapy technologies that have been around for 15, 20 years. We're still seeing reports of adverse events on some of those trials. So for gene editing to have come as far as it's common, to be able to look at these two big New England Journal success stories in sickle cell and ATTR amyloidosis, I don't think any very few, except the most ardent evangelists would have predicted we'd be where we are just a few years ago. [musical transition]Harry Glorikian: I want to pause the conversation for a minute to make a quick request. If you're a fan of MoneyBall Medicine, you know that we've published dozens of interviews with leading scientists and entrepreneurs exploring the boundaries of data-driven healthcare and research. And you can listen to all of those episodes for free at Apple Podcasts, or at my website glorikian.com, or wherever you get your podcasts.There's one small thing you can do in return, and that's to leave a rating and a review of the show on Apple Podcasts. It's one of the best ways to help other listeners find and follow the show.If you've never posted a review or a rating, it's easy. All you have to do is open the Apple Podcasts app on your smartphone, search for MoneyBall Medicine, and scroll down to the Ratings & Reviews section. Tap the stars to rate the show, and then tap the link that says Write a Review to leave your comments. It'll only take a minute, but it'll help us out immensely. Thank you! And now back to the show.[musical transition]Harry Glorikian:One of your previous books was called The $1,000 Genome. And when you published that back in 2010, it was still pretty much science fiction that it might be possible to sequence someone's entire genome for $1,000. But companies like Illumina blew past that barrier pretty quickly, and now people are talking about sequencing individual genome for just a few hundred dollars or less. My question is, how did computing contribute to the exponential trends here. And do you wish you'd called your book The $100 Genome?Kevin Davies: I've thought about putting out a sequel to the book, scratching out the 0's and hoping nobody would notice. Computing was yes, of course, a massive [deal] for the very first human genome. Remember the struggle to put that first assembly together. It's not just about the wet lab and pulling the DNA sequences off the machines, but then you know, the rapid growth of the data exposure and the ability to store and share and send across to collaborators and put the assemblies together has been critical, absolutely critical to the development of genomics.I remember people were expressing shock at the $1,000 genome. I called the book that because I heard Craig Venter use that phrase in public for the first time in 2002. And I had just recently published Cracking the Genome. And we were all still recoiling at the billions of dollars it took to put that first reference genome sequence together. And then here's Craig Venter, chairing a scientific conference in Boston saying what we need is the $1,000 genome. And I almost fell off my chair. “what are you? What are you must you're in, you're on Fantasy Island. This is, there's no way we're going to get, we're still doing automated Sanger sequencing. God bless Fred Sanger. But how on earth are you going to take that technology and go from billions of dollars to a couple of thousand dollars. This is insanity.” And that session we had in 2002 in Boston. He had a local, a little episode of America's Got Talent and he invited half a dozen scientists to come up and show what they had. And George Church was one of them. I think Applied Biosystems may have given some sort of talk during that session. And then a guy, a young British guy from a company we'd never heard of called Celexa showed up and showed a couple of pretty PowerPoint slides with colored beads, representing the budding DNA sequence on some sort of chip. I don't know that he showed any data. It was all very pretty and all very fanciful. Well guess what? They had the last laugh. Illumina bought that company in 2006. And as you said, Harry you know, I think when, when they first professed to have cracked the $1,000 dollar genome barrier, a few people felt they needed a pinch of salt to go along with that. But I think now, yeah, we're, we're, we're well past that. And there are definitely outfits like BGI, the Beijing Genomics Institute being one of them, that are touting new technologies that can get us down to a couple of hundred. And those were such fun times because for a while there Illumina had enormous competition from companies like 454 and Helicose and PacBio. And those were fun heady times with lots and lots of competition. And in a way, Illumina's had it a little easy, I think over the last few years, but with PacBio and Oxford Nanopore gaining maturity both, both in terms of the technology platforms and their business strategy and growth, I think Illumina' gonna start to feel a little bit more competition in the long read sequence space. And one is always hearing whispers of new companies that may potentially disrupt next-gen sequencing. And that would be exciting because then we'd have an excuse to write another book. Harry Glorikian: Well, Kevin, start writing because I actually think we're there. I think there are a number of things there and you're right, I think Illumina has not had to bring the price down as quickly because there hasn't been competition. And you know, when I think about the space is, if you could do a $60 genome, right, it starts to become a rounding error. Like what other business models and opportunities now come alive? And those are the things that excite me. All right. But so, but you have a unique position as editor of the journal of CRISPR and the former editor of a lot of prominent, you know, publications, Nature Genetics, Bio-IT World, Chemical & Engineering News. Do you think that there's adequate coverage of the biological versus the computing side of it? Because I, I have this feeling that the computing side still gets a little overlooked and underappreciated. Kevin Davies: I think you're right. I mean I think at my own company Genetic Engineering News, we still have such deep roots in the wet lab vision and version of biotechnology that it takes a conscious effort to look and say, you know, that's not where all the innovation is happening. Bio-IT World, which you mentioned is interesting because we launched that in 2002. It was launched by the publisher IDG, best-known from MacWorld and ComputerWorld and this, this whole family of high-tech publications.And we launched in 2002 was a very thick glossy print magazine. And ironically, you know, we just couldn't find the advertising to sustain that effort, at least in the way that we'd envisioned it. And in 2006 and 2007, your friend and mine Phillips Kuhl, the proprietor of Cambridge Healthtech Institute, kind of put us out of our misery and said, you know what I'll, take the franchise because IDG just didn't know what to do with it anymore. But what he really wanted was the trade show, the production. And even though at the magazine eventually we fell on our sword and eventually put it out of its misery, the trade show went from strength to strength and it'll be back in Boston very soon because he had the vision to realize there is a big need here as sort of supercomputing for life sciences.And it's not just about the raw high-performance computing, but it's about the software, the software tools and data sharing and management. And it's great to go back to that show and see the, you know, the Googles and Amazons and yeah, all the big household names. They're all looking at this because genome technology, as we've discussed earlier has been one of the big growth boom areas for, for their services and their products.Harry Glorikian: Right. I mean, well, if you look at companies like Tempus, right. When I talked to Joel Dudley over there on the show it's, they want to be the Amazon AWS piping for all things genomic analysis. Right. So instead of creating it on your own and building a, just use their platform, basically, so it's definitely a growth area. And at some point, if you have certain disease states, I don't see how you don't get you know, genomic sequencing done, how a physician even today in oncology, how anybody can truly prescribe with all the drugs that are being approved that have, you know, genomic biomarkers associated with them and not use that data.Kevin Davies: On a much lower, lo-fi scale, as I've been doing a lot of reading about sickle cell disease lately, it's clear that a lot of patients who are, of course, as you, as you know, as your listeners know, are mostly African-American because the disease arose in Africa and the carrier status gives carriers a huge health advantage in warding off malaria. So the gene continues to stay, stay high in in frequency. Many African-American patients would benefit from some generic drugs that are available in this country that provide some relief, but aren't aware of it and maybe their physicians aren't completely aware of it either. Which is very sad. And we've neglected the funding of this disease over many decades, whereas a disease like cystic fibrosis, which affects primarily white people of Northern European descent that receives far more funding per capita, per head, than than a disease like sickle cell does. But hopefully that will begin to change as we see the, the potential of some of these more advanced therapies.I think as far as your previous comment. I think one of the big challenges now is how we tackle common diseases. I think we're making so much progress in treating rare Mendelian diseases and we know thousands of them. But it's mental illness and asthma and diabetes you know, diseases that affect millions of people, which have a much more complicated genetic and in part environmental basis.And what can we learn, to your point about having a full genome sequence, what can we glean from that that will help the medical establishment diagnose and treat much more common diseases, not quite as simple as just treating a rare Mendelian version of those diseases? So that's, I think going to be an important frontier over the next decade.Harry Glorikian: Yeah. It's complicated. I think you're going to see as we get more real-world data that's organized and managed well, along with genomic data, I think you'll be able to make more sense of it. But some of these diseases are quite complicated. It's not going to be find one gene, and it's going to give you that answer.But I want to go back to, you can't really talk about CRISPR without talking about this specter of germline editing. And a big part of your book is about this firestorm of criticism and condemnation around, you know, the 2018 when the Chinese researcher He Jankui, I think I said it correctly.Yep.Kevin Davies: He Jankui is how I say it. Close. Harry Glorikian: He announced that he had created twin baby girls with edits to their genomes that were intended to make them immune to HIV, which sort of like—that already made me go, what? But the experiment was, it seems, unauthorized. It seems that, from what I remember, the edits were sloppy and the case spurred a huge global discussion about the ethics of using CRISPR to make edits that would be inherited by future generations. Now, where are we in that debate now? I mean, I know the National Academy of Sciences published a list of criteria, which said, don't do that. Kevin Davies: It was a little more nuanced than that. It wasn't don't do that. It was, there is a very small window through which we could move through if a whole raft of criteria are met. So they, they refuse to say hereditary genome editing should be banned or there should be a moratorium. But they said it should not proceed until we do many things. One was to make sure it is safe. We can't run before we can walk. And by that, I mean, we've got to first demonstrate—because shockingly, this hasn't been done yet—that genome editing can be done safely in human embryos. And in the last 18 months there've been at least three groups, arguably the three leading groups in terms of looking at genetic changes in early human embryos, Kathy Niakan in London, Shoukhrat Mitalipov in Oregon, and Dieter Egli in New York, who all at roughly the same time published and reports that said, or posted preprints at least that said, when we attempt to do CRISPR editing experiments in very early human embryos, we're seeing a mess. We're seeing a slew of off-target and even on-target undesirable edits.And I think that says to me, we don't completely understand the molecular biology of DNA repair in the early human embryo. It may be that there are other factors that are used in embryogenesis that are not used after we're born. That's speculation on my part. I may be wrong. But the point is we still have a lot to do to understand, even if we wanted to.And even if everybody said, “Here's a good case where we should pursue germline editing,” we've gotta be convinced that we can do it safely. And at the moment, I don't think anybody can say that. So that's a huge red flag.But let's assume, because I believe in the power of research, let's assume that we're going to figure out ways to do this safely, or maybe we say CRISPR isn't the right tool for human embryos, but other tools such as those that we've touched on earlier in the show base editing or prime editing, or maybe CRISPR 3.0 or whatever that is right now to be published somewhere. [Let's say ] those are more safe, more precise tools. Then we've got to figure out well, under what circumstances would we even want to go down this road? And the pushback was quite rightly that, well, we already have technologies that can safeguard against families having children with genetic diseases. It's called IVF and pre-implantation genetic diagnosis. So we can select from a pool of IVF embryos. The embryos that we can see by biopsy are safe and can therefore be transplanted back into the mother, taken to term and you know, a healthy baby will emerge.So why talk about gene editing when we have that proven technology? And I think that's a very strong case, but there are a small number of circumstances in which pre-implantation genetic diagnosis will simply not work. And those are those rare instances where a couple who want to have a biological child, but have both of them have a serious recessive genetic disease. Sickle cell would be an obvious case in point. So two sickle cell patients who by definition carry two copies of the sickle cell gene, once I have a healthy biological child preimplantation genetic diagnosis, it's not going to help them because there are no healthy embryos from whatever pool that they produce that they can select. So gene editing would be their only hope in that circumstance. Now the National Academy's report that you cited, Harry, did say for serious diseases, such as sickle cell and maybe a few others they could down the road potentially see and condone the use of germline gene editing in those rare cases.But they're going to be very rare, I think. It's not impossible that in an authorized approved setting that we will see the return of genome editing, but that's okay. Of course you can can issue no end of blue ribbon reports from all the world's experts, and that's not going to necessarily prevent some entrepreneur whose ethical values don't align with yours or mine to say, “You know what, there's big money to be made here. I'm going offshore and I'm going to launch a CRISPR clinic and you know, who's going to stop me because I'll be out of the clutches of the authorities.” And I think a lot of people are potentially worried that that scenario might happen. Although if anyone did try to do that, the scientific establishment would come down on them like a ton of bricks. And there'll be a lot of pressure brought to bear, I think, to make sure that they didn't cause any harm.Harry Glorikian: Yeah. It's funny. I would like to not call them entrepreneurs. I like entrepreneurs. I'd like to call them a rogue scientist. Kevin Davies: So as you say, there's the third section of four in Editing Humanity was all about the He Jankui debacle or saga. I had flown to Hong Kong. It's a funny story. I had a little bit of money left in my travel budget and there were two conferences, one in Hong Kong and one in China coming up in the last quarter of 2018. So I thought, well, okay, I'll go to one of them. And I just narrowed, almost a flip of a coin, I think. Okay, let's go to the Hong Kong meeting.It's a bioethics conference since I don't expect it to be wildly exciting, but there are some big speakers and this is an important field for the CRISPR Journal to monitor. So I flew there literally, you know, trying to get some sleep on the long flights from New York and then on landing, turn on the phone, wait for the new wireless signal provider to kick in. And then Twitter just explode on my feed as this very, very astute journalists at MIT Technology Review, Antonio Regalado, had really got the scoop of the century by identifying a registration on a Chinese clinical trial website that he and only he had the foresight and intelligence to sort of see. He had met He Jankui in an off the record meeting, as I described in the book, about a month earlier. A spider sense was tingling. He knew something was up and this was the final clue. He didn't know at that time that the Lulu and Nana, the CRISPR babies that you mentioned, had actually been born, but he knew that there was a pregnancy, at least one pregnancy, from some of the records that he'd seen attached to this registration document. So it was a brilliant piece of sleuthing. And what he didn't know is that the Asociated Press chief medical writer Marilynm Marchion had confidentially been alerted to the potential upcoming birth of these twins by an American PR professional who was working with He Jankui in Shenzhen. So she had been working on an embargoed big feature story that He Jankui and his associates hoped would be the definitive story that would tell the world, we did this quote unquote, “responsibly and accurately, and this is the story that you can believe.” So that story was posted within hours.And of course the famous YouTube videos that He Jankui had recorded announcing with some paternal pride that he had ushered into the world these two gene edited, children, screaming and crying into the world as beautiful babies I think was [the phrase]. And he thought that he was going to become famous and celebrated and lauded by not just the Chinese scientific community, but by the world community for having the ability and the bravery to go ahead and do this work after Chinese researchers spent the previous few years editing human embryos. And he was persuaded that he had to present his work in Hong Kong, because he'd set off such a such an extraordinary firestorm. And I think you've all seen now you're the clips of the videos of him nervously walking onto stage the muffled, the silence, or the only sound in the front row, the only sound in the big auditorium at Hong Kong university—[which] was absolutely packed to the rim, one side of the auditorium was packed with press photographers, hundreds of journalists and cameras clicking—and the shutters clattering was the only, that was the applause that he got as he walked on stage.And to his credit, he tried to answer the questions directly in the face of great skepticism from the audience. The first question, which was posed by David Liu, who had traveled all the way there, who just asked him simply, “What was the unmet medical need that you are trying to solve with this reckless experiment? There are medical steps that you can do, even if the couple that you're trying to help has HIV and you're trying to prevent this from being passed on. There are techniques that you can use sperm washing being one of them. That is a key element of the IVF process to ensure that the no HIV is transmitted.”But he was unable to answer the question in terms of I'm trying to help a family. He'd already moved out and was thinking far, far bigger. Right? And his naiveté was shown in the manuscript that he'd written up and by that point submitted to Nature, excerpts of which were leaked out sometime later.So he went back to Shenzhen and he was put under house arrest after he gave that talk in Hong Kong. And about a year later was sentenced to three years in jail. And so he's, to the best of my knowledge that's where he is. But I often get asked what about the children? As far as we know, there was a third child born about six months later, also gene-edited. We don't even know a name for that child, let alone anything about their health. So one hopes that somebody in the Chinese medical establishment is looking after these kids and monitoring them and doing appropriate tests. The editing, as you said, was very shoddily performed. He knocked out the gene in question, but he did not mimic the natural 32-base deletion in this gene CCR5 that exists in many members of the population that confers, essentially, HIV resistance. So Lulu and Nana on the third child are walking human experiments, sad to say. This should never have been done. Never should have been attempted. And so we hope that he hasn't condemned them to a life of, you know, cancer checkups and that there were no off-target effects. They'll be able to live, hopefully, with this inactivated CCR5 gene, but it's been inactivated in a way that I don't think any, no other humans have ever been recorded with such modifications. So we, we really hope and pray that no other damage has been done. Harry Glorikian: So before we end, I'd love to give you the chance to speculate on the future of medicine in light of CRISPR. Easy, fast, inexpensive genome sequencing, give us access to everybody's genetic code, if they so choose. Machine learning and other forms of AI are helping understand the code and trace interactions between our 20,000 genes. And now CRISPR gives us a way to modify it. So, you know, it feels like [we have] almost everything we need to create, you know, precise, targeted, custom cures for people with genetic conditions. What might be possible soon, in your view? What remaining problems need to be solved to get to this new area of medicine? Kevin Davies: If you know the sequence that has been mutated to give rise to a particular disease then in principle, we can devise a, some sort of gene edit to repair that sequence. It may be flipping the actual base or bases directly, or maybe as we saw with the first sickle cell trial, it's because we understand the bigger genetic pathway. We don't have to necessarily go after the gene mutation directly, but there may be other ways that we can compensate boost the level of a compensating gene.But I think we, we should be careful not to get too carried away. As excited as I am—and hopefully my excitement comes through in Editing Humanity—but for every company that we've just mentioned, you know, you can go on their website and look at their pipeline. And so Editas might have maybe 10 diseases in its cross hairs. And CRISPR [Therapeutics] might have 12 diseases. And Intellia might have 14 diseases and Graphite has got maybe a couple. And Beam Therapeutics has got maybe 10 or 12. And Prime Medicine will hasn't listed any yet, but we'll hopefully have a few announced soon. And so I just reeled off 50, 60, less than a hundred. And some of these are gonna work really, really well. And some are going to be either proven, ineffective or unviable economically because the patient pool is too small. And we've got, how many did we say, 6,000 known genetic diseases. So one of the companies that is particularly interesting, although they would admit they're in very early days yet, is Verve Therapeutics. I touched on them earlier because they're looking at to modify a gene called PCSK9 that is relevant to heart disease and could be a gene modification that many people might undergo because the PCSK9 gene may be perfectly fine and the sequence could be perfectly normal, but we know that if we re remove this gene, levels of the bad cholesterol plummet, and that's usually a good thing as far as heart management goes. So that's an interesting, very interesting study case study, I think, to monitor over the coming years, because there's a company looking at a much larger patient pool potentially than just some of these rare syndromes with unpronounceable names. So the future of CRISPR and gene editing is very bright. I think one of the lessons I took away from CRISPR in Editing Humanity is, looking at the full story, is how this technology, this game-changing gene-editing technology, developed because 25 years ago, a handful of European microbiologists got really interested in why certain microbes were thriving in a salt lake in Southeastern Spain. This is not exactly high-profile, NIH-must-fund-this research. There was a biological question that they wanted to answer. And the CRISPR repeats and the function of those repeats fell out of that pure curiosity, just science for science's sake. And so it's the value of basic investigator-driven, hypothesis-driven research that led to CRISPR being described and then the function of the repeats.And then the story shifted to a yogurt company in Europe that was able to experimentally show how having the right sequence within the CRISPR array could safeguard their cultures against viral infection. And then five years of work people in various groups started to see, were drawn to this like moths to a flame. Jennifer Doudna was intrigued by this from a tip-off from a coffee morning discussion with a Berkeley faculty colleagues, Jill Banfield, a brilliant microbiologist in her own. And then she met meets Emmanuelle Charpentier in Puerto Rico at a conference, and they struck up a friendship and collaboration over the course of an afternoon. And that, why should that have worked? Well, it did, because a year later they're publishing in Science. So it's serendipity and basic research. And if that can work for CRISPR, then I know that there's another technology beginning to emerge from somewhere that may, yet trump CRISPR.And I think the beauty of CRISPR is its universal appeal. And the fact is, it's drawn in so many people, it could be in Japan or China or South Korea or parts of Europe or Canada or the U.S. or South America. Somebody is taking the elements of CRISPR and thinking well, how can we improve it? How can we tweak it?And so this CRISPR toolbox is being expanded and modified and updated all the time. So there's a hugely exciting future for genome medicine. And you know, whether it's a new form of sequencing or a new form of synthetic biology, you know, hopefully your show is going to be filled for many years to come with cool, talented, young energetic entrepreneurs who've developed more cool gadgets to work with our genome and other genomes as well. We haven't even had time to talk about what this could do for rescuing the wooly mammoth from extinction. So fun things, but maybe, maybe another time. Harry Glorikian: Excellent. Well, great to have you on the show. Really appreciate the time. I hope everybody got a flavor for the enormous impact this technology can have. Like you said, we talked about human genome, but there's so many other genomic applications of CRISPR that we didn't even touch. Kevin Davies: Yup. Yup. So you have to read the book. Harry Glorikian: Yeah. I will look forward to the next book. So, great. Thank you so much. Kevin Davies: Thanks for having me on the show, Harry. All the best.Harry Glorikian: Take care.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.

You can obtain Valter Longo's Fasting Mimicking Diet (Prolon) at: https://prevmedheartrisk.gethealthy.s... There is a lot of buzz re: curing diabetes. Valter Longo at USC Davis is one of the world's top biochemists/geneticists focused on gerontology or longevity. He's demonstrated stem cell-mediated regrowth of beta cells in the pancreas in mice. The mice were cured of their diabetes. Can we do that with men as well? Other articles by Longo are reviewed demonstrating improvement of multiple metabolic indicators, mostly driven by the glucose metabolism pathways including mTOR, AMPK, ILG-1. A final academic article demonstrates the probable mechanism. Caloric restriction or fasting clearly increases the transcription of genes that code for these proteins. P53 and FOXO appear to be acting agents in this transcription improvement - or upregulation. In the end, this all makes sense. Episodes of caloric restriction cause our bodies to transcribe more of the genes involved in energy metabolism. It makes sense after.For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·PrevMed's website·PrevMed's YouTube channel·PrevMed's Facebook page

My AP Biology Thoughts  Unit 4 Cell Communication and Cell CycleWelcome to My AP Biology Thoughts podcast, my name is Alex Jing and I am your host for episode #96 called Unit 4 Cell Communication and Cell Cycle: Regulation of Cell Cycle. Today we will be discussing How cells regulate their division Segment 1: Introduction to Cell Cycle Regulation The cell cycle includes 4 main stages: G1, S, G2, and mitosis. These phases are responsible for the division of cells. However, how do the cells determine when they can proceed to the next stage of the cell cycle? Cells regulate their advancement in the cell cycle through the use of Cyclin-dependent kinases, or CDKs, and CDK inhibitors. When CDKs are active, they phosphorylate other enzymes in the cell responsible for activating the next stage of the cell cycle. CDK inhibitors are receptors that when activated, will inhibit the CDKs, preventing the cell from going to the next stage.  Segment 2: More About the Regulation of the Cell Cycle A prominent example of why CDKs and their inhibitors are so important is the development of cancer. Cancers form when cells are growing at an rapid, unrestricted rate, and are usually caused by some mutations in the cell which results in either overactive CDKs or inactive CDK inhibitors. P53 is a CDK inhibitor which is responsible for ensuring that DNA is not damaged during the replication process. If it detects damaged DNA it will send out signals to inhibit the CDKs. If a mutation caused the P53 to not be responsive, than cells could be able to divide with damaged DNA, leading to a new cancer to form. Segment 3: Connection to the Course Regulation of the cell cycle is an essential part of all living organisms. Being able to conduct mitosis is what allows organisms to grow and replace damaged cells, and being able to regulate this process is extremely important to ensuring that division is done correctly.  Thank you for listening to this episode of My AP Biology Thoughts. For more student-ran podcasts and digital content, make sure that you visit http://www.hvspn.com (www.hvspn.com).   Music Credits: "Ice Flow" Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution 4.0 License http://creativecommons.org/licenses/by/4.0/ Subscribe to our Podcast https://podcasts.apple.com/us/podcast/my-ap-biology-thoughts/id1549942575 (Apple Podcasts) https://open.spotify.com/show/1nH8Ft9c9f6dmo75V9imCk (Spotify) https://podcasts.google.com/search/my%20ap%20biology%20thoughts (Google Podcasts )   https://www.youtube.com/channel/UC07e_nBHLyc_nyvjF6z-DVg (YouTube)  Connect with us on Social Media Twitterhttps://twitter.com/thehvspn ( @thehvspn)

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine. Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health - something that has since become known as “biohacking”. After creating the biohacker’s ultimate resource website, SelfHacked, Joe moved on to found the SelfDecode, the ultimate biotech software platform for DNA and lab-based health analysis.  Today, SelfDecode helps tens of thousands of users improve their health through highly personalized health recommendations. Listen in as Joe explains the most important genes every breast cancer patient should look out for (and it's not just BRCA).  How Selfcode can be used to determine your genetic weaknesses and what you can do to support your body and help prevent disease.  As a free gift for our listeners, Joe has included his e-book: 8 Ways to Use Your DNA, where he teaches you the secrets of how to use genetics to dramatically improve your health.

Boosting the Immune System to Protect Against Cancer, Bacteria and Viruses The immune system is our best line of defense against cancer, bacteria and víruses.  Cancer is the number two killer in the US after heart  disease. Viral and bacterial infections are also out of control. And, now the world is confronted with the COVID-19 pandemic. We need to understand that bacteria and víruses are not only air borne, but also live within our bodies, which contain over 100 trillion bacteria and microrganisms that live in synergy with us. In addition, we have over 100 million víruses in our body that remain dormant. The presence of internal and external bacteria and víruses don’t guarantee that we are going to get sick unless there is a reason. Bad food, air quality, change of weather, physical stress, pollution, and radiation are some examples of external factors that disrupt the body’s internal mileu, which can activate cancer and/or bacterial or viral infections. Observation of fresh blood through a special microscope can indicate the presence of activated viruses or bacteria. In fact, 50% of bacterial and viral infections and cancers result from a mutation of the P53 tumor suppressor gene. What’s more, pesticides, bacteria and víruses can also trigger a mutation of the P53 gene.  The best way to protect ourselves is by boosting the immune system by adopting a better diet, and adding supplements like magnesium, vitamin C, selenium, zinc, querticin, mushrooms, and arabinoxylan from rice bran. Of course, detoxification is also important to maintain a cleaner, less toxic body, which also improves immune function. Keep in mind drugs and vaccines introduced into a toxic body is like giving drugs to fish in a aquarium of dirty water, rather than changing the water.  Tune-in for a deep dive into the new book of Professor Serge Jurasunas, Cancer Breakthrough using Rice Bran Arabinozylan Compound, which offers a wide array of information on how to use natural interventions to preserve your health and prevent bacterial and viral infections and cancer. BIO: Professor Serge Jurasunas. M.D. (hc), N.D. (Hom) Dr. Jurasunas who was born in France and emigrated to the US in 1960. He is a doctor of Naturopathic and Homeopathic Medicine who initially trained in South Africa, England and North America, where he discovered the science of Iridology. (Dr. Jurasunas has done extensive research on the science and diagnosis of iridology with some of the best specialists in the world, such as Dr. Bernard Jensen of Escondido, California, and Professor J. Deck of Germany).  He has been in practice for 53 years, and became an internationally-known practitioner and researcher not only in Naturopathic Medicine, but especially in Naturopathic Oncology or Integrative Oncology. His areas of focus include Live Blood Analysis and Oxidative Dried Blood Testing.  E-mail: sergejurasunas@gmail.com Skype: Sergejurasunas Blog:  https://naturopathiconcology.blogspot.com Website: www.sergejurasunas.com Slideshare: https://www.slideshare.net/search/slideshow?searchfrom=header&q=serge+ju... Video Version:  https://youtu.be/Uh6PoiAIyNU Call in and Chat with Dr. Jamie during Live Show with Video Stream: Call 646-558-8656 ID: 8836953587 press #.  To Ask a Question press *9 to raise your hand Tune-in to “Love Never Dies” and discover for yourself why reconnecting and Dialoguing with Your Departed loved ones is the only way to dry your tears and transform your grief to joy! For more information about Dr. Turndorf follow her on Facebook: askdrlove and Twitter: @askdrlove and visit www.askdrlove.com.

Jeanny Aragon-Ching, MD, FACP, a medical oncologist and clinical program director of genitourinary (GU) cancers at the Inova Schar Cancer Institute, shares her concerns over the decline in the screening, diagnosis, and treatment of prostate and other GU cancers amid the COVID-19 pandemic, and highlights promising clinical trials underway to advance the fields of prostate, bladder, and kidney cancers. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Jeanny Aragon-Ching, a medical oncologist who serves as the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. She joins me to discuss the worrying decline in screenings for prostate cancer due to the COVID-19 pandemic. Dr. Aragon-Ching also highlights clinical trials underway to advance the treatment of prostate, bladder, and kidney cancers. Dr. Aragon-Ching reports no conflicts of interest relating to the issues discussed in this podcast. And full disclosure relating to old episodes of the Daily News podcast are available on our transcripts at ASCO.org/podcasts. Dr. Aragon-Ching, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Geraldine, for having me here. ASCO Daily News: Well, screening for prostate cancer is vitally important. What are your concerns about the long-term impact of delayed screenings, diagnosis, and treatment in this setting? Dr. Jeanny Aragon-Ching: Yes. So generally there have been already reports actually of observed decline in the common screening and diagnostic procedures and practices reflecting the impact of the COVID-19 pandemic on cancer prevention and early detection, signaling possible downstream effects on the timing and staging of future cancer diagnosis. Now, the issue is there has been no major guidelines or guidance regarding recommendations for screening during the pandemic. Now, one closely aligned guidance, if you will, from the NCCN, actually it's more for management, it suggests that patients with known low risk or certainly very low-risk prostate cancer may actually defer staging active surveillance or even testing for treatment until conditions are deemed safe. Therefore, determination of who really needs to be absolutely screened and certainly diagnosed, I think, is key. So especially since the subject of screening in prostate cancer has always actually been controversial even while the U.S. Preventive Services Task Force set forth the D recommendation, which is recommendation against PSA screening except for those target ages, let's say, between 55 and 69 years of age, they had a C recommendation, which involves individualized decision-making. And that means for us, we always have to have that dialogue with the patients in order to weigh the pros and cons of screening, especially during these times. So therefore, I mean, there's really no current standards that are set forth. A lot of it I think would be tailored to each individualized person and patient as well as physicians in practice during these times of pandemic. ASCO Daily News: Right. Well, COVID-19 will continue to be a threat for some time. So, how is the oncology care community to fill the gap in diagnostic services? Should cancer screenings, biopsies, and surgeries press on? If you see a patient that really needs treatment now, you, I assume, will proceed, correct? Dr. Jeanny Aragon-Ching: Correct. Yeah. Now, I do think the gaps in diagnostic services is really actually being remedied by performing other alternative services, if you will. So, for instance, remote telehealth services have gotten and gained ground since the COVID-19pandemic. And my general recommendation is, and the thinking really is minimal harm is really expected with delays in care certainly for certain types of risk of prostate cancer, or even bladder cancer or kidney cancers. If one were to delay the treatment for, let's say, 3 months, especially when we weigh the risk of mortality or morbidity from being exposed to COVID-19, I think those are the critical issues. Now, I would say that diagnosis and treatment for patients with GU cancers really require prioritization, adjustments for, let's say, screening biopsies, as well as individualized tailored approach to the diagnosis and treatment. The oncologic community, the GU community as a whole I think quickly filled that gap, as I mentioned earlier, by restricting non-urgent, in-person clinic visits, as well as adopting more remote telehealth visits to continue care that the physicians provide. So in terms of prioritization of the goals, patients, let's say, who need to undergo immediate diagnostic procedures and biopsies to make a diagnosis would be a priority. So especially for those who are deemed to have high-risk disease, for those who are likely to have high-grade disease, let's say, muscle-invasive bladder cancer, or let's say, big tumors that are seen on abdominal imaging for a renal cell cancer because we don't typically biopsy, let's say, renal masses to diagnose renal cell carcinoma. And as a general rule of thumb, procedures and treatments that are curative in intent would be considered high priority, whereas benefits of care from treatments certainly has to be weighed against a potential risk for infections and morbidity from COVID-19. Identifying the risks are important as well. So, for instance, treatment may be safely deferred for patients with low risk or certainly even intermediate-risk patients, whereas surgery may be delayed in most high-risk patients or alternative treatments, let's say, a neoadjuvant hormone therapy, coupled with external beam radiation, may be a treatment of choice with regard to the pandemic, and then may be a feasible alternative. So there's a lot of changes that are being set forth. Now with regard to radiation, there's also some concern, for instance, for lymphopenia, for those who undergo radiation. So actually identifying the patients who really would benefit from upfront treatment is key. So for patients with bladder cancer, let's say, who have muscle-invasive bladder cancer, they undergo surgery. We call it TURBT. And they undergo intravesical treatment. So a lot of it highly depends on the goal of the therapy. Is it curative in intent? Certainly if they undergo neoadjuvant chemotherapy, that adds to the layer of complexity for these patients because they are now being exposed to chemotherapy. But on the other hand, it is an important treatment with the goal of curative intent. And there's also something to be said about the varying institutional procedures. For instance, each institution has in place their own safeguards to screen, let's say, or treat patients with COVID-19. So in our institution, for instance, doing rapid COVID-19 tests to assess prior to performing these procedures, anesthesia or procedures that are high-risk for aerosolizing like respiratory secretions, would be of paramount importance. So I think there's a lot of institutional guidance also that comes into play in this day and age of COVID-19 in the treatment of our patients who have a diagnosis of GU cancers. ASCO Daily News: Absolutely. What can you tell us about new developments in diagnostics in the prostate cancer space which have truly advanced the field, resulting in fewer unnecessary biopsies and hopefully making men a little less reluctant to actually take care of their prostate health? Dr. Jeanny Aragon-Ching: Yes, that's a great question. And emerging data suggests that targeting using a combined MRI and an ultrasound fusion approach may perhaps increase the detection of significant high-risk prostate cancer, which, after all, is really the clinically significant and meaningful cancers that we need to treat, and therefore lead to perhaps lower detection of the lower risk prostate cancer that may not need to be treated. Now, it's important to recognize also that a negative MRI does not necessarily exclude the possibility of cancer. And therefore, biomarkers have been in place to be also helpful to perhaps avoid a biopsy in someone, let's say, who has a negative result. Now, there are numerous tests or biomarkers out there available. I always have said that a lot of times it is dealer's choice. It's highly dependent on what physicians are comfortable using, [and] what the availability is within their own institutions. And what the payers or insurance would pay for or cover. But there are several promising ones out there that help further predict if a patient has a high-risk of having a diagnosis of clinically significant prostate cancer. So, for instance, there was a urine base marker, it's called IntelliScore, so it looks at three different genes that would be able to discriminate a higher grade group of cancer versus a lower grade group. And that would help physicians and providers to help further define who needs to be biopsied, especially in this day and age, again, of COVID-19, so that they would be able to predict the likelihood of higher risk prostate cancer that ultimately needs to be treated. And that's not the only one out there that's currently available. There's other things like blood work or blood tests, like 4Kscore, which combines different parameters like free PSA, total PSA, intact PSA, that will help further predict high-grade prostate cancer. And the bottom line is all of these tests would help the physicians, the urologist hopefully to decide who they need to biopsy and prioritize versus those who can safely wait based on just an elevated PSA alone. ASCO Daily News: Well, African American men are at a significantly greater risk of getting prostate cancer. Can you talk about the health disparities that exist in this setting? And do you think the field is doing enough to address this? Dr. Jeanny Aragon-Ching: Mm-hmm. Yeah, so prostate cancer disparities actually constitutes one of the most complex issues in cancer today. So it is known that African American men unfortunately do have disproportionately higher incidence of prostate cancer, easily about 60% to 70% higher compared to Caucasian men counterparts. And they also have a higher 2-fold increased risk of prostate cancer death. So these are very relevant in the practice of prostate cancer in the field. African American men are also more likely to be diagnosed at a younger age. They tend to have more advanced and aggressive disease. And African genetic ancestry is really unfortunately not a modifiable risk factor, so when we talk about genetics...so there are potential reasons why this is so, why African American men may have a higher incidence or mortality. One potential explanation could be genetics. So it has been found that several genetic variants may be a little bit more common in African-American men. So, for instance, like 8q24 mutation in a tumor suppressor gene, there's differences in microRNA regulation, and they tend to, unfortunately, present with more aggressive tumors. And certain gene mutations also can lead to poor outcomes, let's say, P53 mutations, CDK M18, which is more commonly seen in African American men. Now, I would say that there are also possible issues with screening. So you may all recall that when US Preventive Services Task Force, which is felt to be the most influential in making recommendations for a PSA screening, gave a D recommendation in their most recent iteration of PSA screening, and that is that PSA screening is not recommended for the average person, especially for the older individuals, there was no real recommendation for men of African descent, or African American men. And they are really the ones who are underrepresented in these studies. So in one study, for instance, that looked at rigorous modeling, when they look at these trials, they suggested that PSA screening can actually yield greater mortality benefits for high-risk groups. And that includes men of African American descent. So one other big issue with this is probably access or utilization of health care, which would be a key factor in racial or ethnic disparities. And we know that standard prostate biopsies are still really the gold standard for diagnosis. And whenever we talk about better tools for making diagnosis, and we mentioned earlier about MRIs, for instance, MRIs may be less utilized in patients with lower, let's say, socioeconomic status. So there are a lot of reasons why we are seeing these disparities in men with African American descent. ASCO Daily News: So speaking of research, I'd love to ask you about your current research. You treat patients with bladder, kidney, prostate, and testicular cancers. Is there anything you'd like to highlight today? Dr. Jeanny Aragon-Ching: Yes. So, for instance, we are looking carefully at prostate cancer. And we are very much in tuned with the fact that a lot of men with prostate cancer have genetic variants and genetic and hereditary mutations. So we are looking carefully at the differences between men who present with de novo metastatic disease, and that means at the very first presentation to the medical or health professionals, they already have metastatic disease, versus those who were treated with curative intent treatment and then later on down the line present, unfortunately, with metastatic disease because they were not cured. We would like to further define what the differences is between these two population of patients because the former seems to, unfortunately, do worse. So those are the things that we are highlighting. In bladder cancer, we are very closely following what the outcomes would be for patients who have muscle-invasive bladder cancer. For the longest time, we've known that neoadjuvant chemotherapy followed by cystectomy is one of the gold standards of care for treatment of these patients. So the additional role of immunotherapy in addition to neoadjuvant chemotherapy, that is a key improvement perhaps in the field, especially now that we know that avelumab maintenance has been shown to improve survival for a lot of metastatic bladder cancer patients. And for kidney cancer, one of the key things that we would like to further highlight and improve upon the care is for patients who have high-risk, high-stage kidney cancers. So the standard of care remains to be surgery, but we know that a proportion of them would unfortunately recur with metastatic disease or have disease that comes back later on. So the idea is, can we improve upon these odds by giving them adjuvant therapy? So we have an adjuvant immunotherapy trial that seeks to answer this question of improvement in the [INAUDIBLE], in the metastases or recurrence for these patients who have or are deemed to have high risk disease (NCT03138512). ASCO Daily News: And what is the name of that trial? Dr. Jeanny Aragon-Ching: So this is actually CheckMate 914. This is the neoadjuvant immunotherapy nivolumab and ipilimumab versus a placebo. It's a placebo-controlled trial. ASCO Daily News: Excellent. So Dr. Aragon-Ching, is there anything else on your mind that you'd like to address today before we wrap up the podcast? Dr. Jeanny Aragon-Ching: Yeah. I really just think that the changes in practice brought on by the COVID-19 pandemic has us rethinking and reorganizing as an oncologic community the practice that we do. I believe that some are likely here to stay. So, for instance, the changes in the landscape and practices of treatment, we are really thinking about how long the duration of treatment are we providing. Even clinical trials, since the start of the pandemic, of course, the key issue here is some trials have closed their doors on enrollment. And I think we're starting to pick up on those. Some have limited its enrollment. And I think once we get institutional practices streamlined, and people are in general a little bit more comfortable about exposures because they see that everything is safe, I think we'll be getting back to our routine. But I don't think things are going to go back to the way they were. I think telehealth visits, for instance, are here to stay. We're creating a lot of guidance and guidelines on who are the patients who are best fit for these telehealth monitoring visits, or who are the patients who still need to come in person in order to get their care? ASCO Daily News: Absolutely. Well, Dr. Aragon-Ching, thank you so much for sharing your valuable insight with us today on the ASCO Daily News Podcast. Dr. Jeanny Aragon-Ching: Yeah. Thank you so much, too, Geraldine for having me and for sharing the insights with you all. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Jeanny Aragon-Ching Paid Honoraria: Bristol-Myers Squibb, EMD Serono, and Astellas Scientific and Medical Affairs Inc. Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, and Pfizer Speakers’ Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, and Astellas/Seattle Genetics Travel Paid or Reimbursed: Dendreon, Algeta/Bayer, Bristol Myers Squibb, and EMD Serono 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.

What's the big picture? Investors in the Philippines can enjoy income tax holidays of up to six years. After that, they are allowed to pay only a special 5% tax on gross income earned (GIE) indefinitely, instead of the full 30% income tax paid by everyone else. Why it matters: Income tax breaks enjoyed by investors result in billions of foregone government revenues. These funds could have been collected and better spent on health, education and poverty reduction. What are the facts? In 2018 alone, foregone revenues reached almost P70 billion due to the 5% special tax. This was more than the P53-billion budget of the Department of Agriculture for the same year. The bottomline: A new bill intends to curtail the special 5% tax on gross income earned, a move resisted by officials of investment promotion agencies including the Philippine Economic Zone Authority, who fear that it will drive away foreign investors. Dig deeper: Read the full story here. Produced by Robert JA Basilio Jr. Credits: Music featured in this podcast include “In the Hall” of the Mountain King, composed by Edward Krieg and rendered by Kevin Macleod, “Staycation” by Corbyn Kites, and “Sunshine Samba” by Chris Haugen.

修复P53抑癌基因就能攻克癌症吗？留存脐带血可以用于孩子日后患病治疗使用吗？肚脐贴有用吗？

修复P53抑癌基因就能攻克癌症吗？留存脐带血可以用于孩子日后患病治疗使用吗？肚脐贴有用吗？

修复P53抑癌基因就能攻克癌症吗？留存脐带血可以用于孩子日后患病治疗使用吗？肚脐贴有用吗？

In this eye-opening interview, Joe discusses how the veterinary product, Fenbendazole, helped him overcome terminal lung cancer and completely regain his health. This common de-wormer actually does three things. In addition to getting rid of parasites, it acts as a sugar blocker (important because cancer thrives on sugar), and also triggers an anti-aging, tumor-suppressing gene called P53. The post Could A Dog De-Wormer Be One Answer for Cancer? – Episode 37: Joe Tippens appeared first on Ann Louise Gittleman.

How The Iris Of The Eye Can Reveal Breast Cancer Risk And Of Other IllnessDid you know that through the use of cameras, flashlights, and microscopes, iridologists can examine a patient's iris in order to detect tissue change, stromal irregularities and pigment patterns that can provide early detection of diseases?Join me for a fascinating conversation with Dr. Jurasunas, one of the world's top natural medical research pioneers in the world. Dr. Jurasunas will share his cutting-edge findings on various health topics including how disease in the colon, modern ways to reverse cancer and other degenerative diseases, and much more.You won't to miss this eye-opening interview.CCV of Professor Serge Jurasunas. M.D. (hc), N.D. (Hom): Dr. Jurasunas was born in France and emigrated to the US in 1960. He is a doctor of Naturopathic and Homeopathic Medicine who initialy trained in South Africa, England and North America, where he discovered the science of Iridology. (Dr. Jurasunas has done extensive research on the science and diagosis of Iridology with some of the best specialists in the world, such as Dr. Bernard Jensen of Escondido, California, and Professor J. Deck of Germany).He has been in practice for 53 years, and became an internationally known practitioner and researcher not only in Naturopathic Medicine, but especially in Naturopathic Oncology or Integrative Oncology.His areas of focus include Live Blood Analysis and Oxidative Dried Blood Testing.The use of nutrition as part of his healing protocols began in 1962 when he met Dr. Bernard Jensen, a pioneer of nutrition and Iridology. Since that time, nutrition and detox have become an important pillar in the treatment of his patients.Since 1971, he has pioneered a field of theory and research linking mitochondria and cellular respiration as cause of disease and cancer. Today, mitochondria has become a main interest of science in treating many diseases including cancer.For the past 12 years, Serge Jurasunas has engaged in extensive research and investigation in the field of cancer biology and molecular markers testing specifically of the P53 tumor supressor gene,which is our defense against cancer. Dr. Jurasunas has applied his research in clinical applications in cancer prevention and treatment and especially breast cancer, which is one of his main clinical focuses.In 1978, he opened a large clinic in Portugal where thousands of patients have been treated. Doctors from several countries have also studied with him to learn his natural nutritional and detox therapies.Serge Jurasunas is former professor of Integrative Medicine at Capital University in Washington D.C. He now serves as Professor of Naturopathic Oncology at the PanAm Universtiy of Science and Medicine.For the past 20 years, he has been a frequent magazine article contributor in the Townsend Letter, the prominent magazine of integrative medicine. He is the author of more than 150 papers, articles and conferences (available online and through slideshare), and eight books in 3 languages focusing on the health revolution, Iridology, colon detox, and lapacho and germanium in the treatment of cancer. His most recent book, Health and Disease Begin in the Colon is an important book for doctors and laymen.His new book, Cancer Treatment Breakthrough, Immuno Oncology using Rice Bran Arabinoxylan Compound, is to be pu-blished in the US.Serge Jurasunas has also delivered lectures in over 45 countries, and at various universities. During his lifetime, he has received many awards, and gold collars from academies, including the Silver Medal of Research and Invention by the French Academy for his discoveries in the field of Iridology. More recently, he received the US Lifetime Achievement Award for his 50 years of pioneering work in the field of education, natural health and cancer.Today, Professor Serge Jurasunas maintains a part-time private practice for cancer patients. He also consults with patients from around the world via e-mail and Skype.E-mail: sergejurasunas@gmail.comVideo Version: https://youtu.be/ZOw_K6xhXGgSkype: SergejurasunasBlog: https://naturopathiconcology.blogspot.comWebsite: www.sergejurasunas.comSlideshare: https://www.slideshare.net/search/slideshow?sear-chfrom=header&q=serge+jurasu-nas&ud=any&ft=all&lang=**&sort=Call in and Chat with Dr. Jamie during Live Show with Video Stream: Call 646-558-8656 ID: 8836953587 press #.  To Ask a Question press *9 to raise your handTune-in to “Love Never Dies” and discover for yourself why reconnecting and Dialoguing with Your Departed loved ones is the only way to dry your tears and transform your grief to joy! For more information about Dr. Turndorf follow her on Facebook: askdrlove and Twitter: @askdrlove and visit www.askdrlove.com.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.256735v1?rss=1 Authors: Gu, H., Yuan, G. Abstract: There is an urgent need to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) that leads to COVID-19 and respiratory failure. Our study is to discover differentially expressed genes (DEGs) and biological signaling pathways by using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE150819 datasets were originally produced using an Illumina NextSeq 500 (Homo sapiens). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) were utilized to identify functional categories and significant pathways. KEGG and GO results suggested that the Cytokine-cytokine receptor interaction, P53 signaling pathway, and Apoptosis are the main signaling pathways in SARS-CoV-2 infected human bronchial organoids (hBOs). Furthermore, NFKBIA, C3, and CCL20 may be key genes in SARS-CoV-2 infected hBOs. Therefore, our study provides further insights into the therapy of COVID-19. Copy rights belong to original authors. Visit the link for more info

Podkasten Radium har samsendinger med DNB sin podkast Utbytte fra DNBs årlige nordiske helsekonferanse 12. desember. I denne første av 6 episoder snakker vi med Susanne Stuffers, forvalter i P53, om den nordiske og norske helsesektoren. I studio hører du Elisabeth Andersen og Jónas Einarsson fra podkasten Radium, Marius Brun Haugen fra podkasten Utbytte og Susanne Stuffers, forvalter i P53. I den neste 5 episodene skal vi snakke med noen av våre porteføljeselskaper, og disse episodene blir lagt ut fredag 13. desember om morgenen.

In this episode we talk all about sunlight and it's vital role in your health and longevity. Topics include: Our phobia of the sun and why it's completely wrong. The sun's role in our circadian rhythms and hormone cycles The sun's role in vitamin D production. Then we dive deep into what role vitamin D plays in your body, which is extensive, and how deficient we are as a society in vitamin D. I bust the persistent myths about the sun and it's role in cancer. We talk about the P53 gene and why it's so important to ensure it's doing its job to prevent cancer Then we talk about sunscreen and why it's not necessarily your ally in health.  Then we talk about how to get the proper amount of sun to ensure optimal vitamin D production. In this week's Call-to-Action we make a plan for getting the sun you need to optimize vitamin D levels, which will then optimize your health. Thanks for listening. Be sure to subscribe and leave a review and share it with someone who could benefit from this information. And be sure to follow me on Instagram @ThinkersApprentice Here's the link I promised to help understand possible toxicity and cancer risks associated with sunscreen. And here's the link to The Primal Blueprint, which was the source material for much of this podcast.

In this episode, Keith Flaherty, director of clinical research and targeted cancer therapy at Massachusetts General Hospital, shares his vast wealth of knowledge in cancer starting with the history of treatment from chemotherapy to radiation to surgical therapy and where those methodologies seemed to have leveled off. He also walks us through the timeline of advancements (and lack there of) from when the War on Cancer was declared in the 1970s, through the sequencing of the entire human genome, and all the way to today. Keith dives into the topic of immunotherapy, probably the most exciting recent development in cancer therapy, and also provides us a rundown of his notion of a different approach to cancer that attacks all the essential pillars of cancer growth and survival. Finally, we talk a little bit about liquid biopsies, we discuss the roles of CRISPR and other potentially over-hyped therapies with respect to cancer. We also touch on stem cell therapy a bit, as well as some other common cancer-related questions such as the role of vitamin D and sun exposure in melanoma, and much more. We discuss: Growing up around medicine, and finding a career that you love [7:30]; Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30]; Explaining chemotherapy, radiation, and how a cancer develops [23:45]; Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal  [33:15]; 25 years after the War on Cancer is declared, gene sequencing, and why Keith’s was fascinated by the HIV case study [37:15]; Cancer immunotherapy: History, how it works, and why some cancers respond and others don’t [46:00]; MHC complexes, and cancer cloaking mechanisms [56:00]; Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00]; What we learned from the Cancer Genome Atlas Project [1:07:00]; Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00]; Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45]; Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith’s “aha moment” [1:24:15]; Advice for starting your career as a scientist/clinician [1:37:00]; Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45]; Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00]; Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15]; The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40]; Peter’s clinical framework for thinking about cancer and how Keith might improve it, and how the biotech environment is hampering our ability to put together novel cancer treatments [2:05:00]; How useful is CRISPR in terms of tumor suppressing? [2:16:15]; Liquid biopsies as a therapeutic monitoring tool [2:18:00]; Stem cell therapy: The efficacy and potential risks [2:25:15]; Aging and cancer: Is cancer inevitable? [2:28:45]; Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30]; How and why Keith has straddled the line between science/research and industry/drug companies, and the importance of getting more voices of practitioners at the table [2:42:00]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

LLA Ep:#244: Dr. Mark Gordon - Addressing Growth Hormone Myths, IGF-1, Why Free Testosterone trumps Total Testosterone, & more   Dr. Gordon discusses the myths and fallacies regarding growth hormone, IGF-1, and IGF-2 How do binding proteins play a part in diabetes, heart disease, colon cancer and body fat increase   What is P53 and why is it important in cell repair, fighting against cancer, and what causes P53 to fail most of us What is Cositin and why is it effective in combating cancer How does magnesium play a part in growth hormone and IGF-1 Why should free testosterone not be overlooked, in favor of total testosterone Dr. Gordon addresses alcohol's effects on growth hormone Is it recommended taking IGF-1 and growth hormone together? Why or why not? How has growth hormone played a part in helping some of Dr. Gordon's patients heal from serious injuries How does growth hormone effect telemerase, which effects telemeres and cell life How difficult is it to get growth hormone prescribed     All this and much more: Links & Resources mentioned in the show: Listen to ad-free LLA Podcast Premium Episodes for Patreon Subscribers Only. Become a monthly supporter via $5 or more on Patreon: http://www.patreon.com/llapodcast Project Child Save: http://projectchildsave.org Warrior Angels Foundation: http://warriorangelsfoundation.org Purchase Aggressive Strength products: http://strengthbymahler.com Purchase Aggressive Strength Bundles:  http://budurl.com/mahlerbundles Purchase New Warrior Training products: http://newwarriortraining.com Dr. Gordon's site: https://tbimedicallegal.com   Listen and download archived free episodes at  http://strengthbymahler.com or http://newwarriortraining.com.  also subscribe, download, rate & review us at: iTunes: https://itunes.apple.com/us/podcast/live-life-aggressively-podcast/id646524617 Stitcher: http://www.stitcher.com/s?fid=34706&refid=stpr Also, be sure to "like" and connect with us on our Facebook fan page at http://facebook.com/llapodcast. 

 S1EP7 Lauren Turk: Discusses her life and EP "Bloom"  We play Lauren’s new song “See You Again” at end of episode! Lauren Turk: Lauren Turk's debut song and music video "Love Left Over" premiered on The FADER with an appearance from Amandla Stenberg. Lauren is known for her one-woman shows, singing in French, English and Spanish, live looping beats, piano, violin and her voice to soundscape from scratch, as well as her "Stories to Songs" concerts, where she transforms audience stories into songs live. She performs around the world for conferences, festivals and brands such as TEDx, Airbnb, OZY, Sandbox, Hatch, C2, VidCon, La Calaca, Kiss the Ground, USC, Amnesty International, and more. Lauren also composes for film (Bright; Netflix / Will Smith, Mexico Pelagico; Netflix). Calabria, Italy: Calabria, in southwest Italy, occupies the "toe" of the country’s boot-shaped peninsula. It's a sun-baked region of rugged mountains, old-fashioned villages and dramatic coastline, with many popular beaches. Coastal Reggio Calabria, its largest city, is home to the Museo Archeologico Nazionale and its Riace Bronzes, a famous pair of Greek warriors dating back to the 5th century B.C.E. Calabria Song: "Calabria" is a song by Danish DJ/producer Rune Reilly Kölsch. It was originally released in 2003 by Credence, a sub label of Parlophone Records. Istanbul, Turkey:Istanbul (UK: /ˌɪstænˈbʊl/, /-ˈbuːl/ or US: /-stɑːn-/ or /ˈɪstənbʊl/;Turkish: İstanbul [isˈtanbuɫ], historically known as Byzantium and before 1924 as Constantinople, is the most populous city in Turkey and the country's economic, cultural, and historic center. Istanbul is a transcontinental city in Eurasia, straddling the Bosporus strait (which separates Europe and Asia) between the Sea of Marmara and the Black Sea. Its commercial and historical center lies on the European side and about a third of its population lives on the Asian side. The city is the administrative center of the Istanbul Metropolitan Municipality (coterminous with Istanbul Province), both hosting a population of around 15 million residents. Istanbul is one of the world's most populous cities and ranks as the world's fourth-largest city proper and the largest European city. Istanbul is viewed as a bridge between the East and West. Istanbul not Constantinople: "Istanbul (Not Constantinople)" is a 1953 novelty song, with lyrics by Jimmy Kennedy and music by Nat Simon. Written on the 500th anniversary of the fall of Constantinople to the Ottomans, the lyrics humorously refer to the official 1930 renaming of the city of Constantinople to Istanbul. The song's original release, performed by The Four Lads, was certified as a gold record. Pink’s NY: Hip hotspot for craft cocktails, upscale pub food & live music in an industrial-chic setting. Paris, France: Paris (French pronunciation: ​[paʁi] is the capital and most populous city of France, with an area of 105 square kilometres (41 square miles) and a population of 2,206,488. Since the 17th century, Paris has been one of Europe's major centres of finance, commerce, fashion, science, and the arts. Sciences Po: The Paris Institute of Political Studies, commonly referred to as Sciences Po, is a prestigious and influential academic institution in the social sciences in France. Buckminster Fuller: Richard Buckminster "Bucky" Fuller (/ˈfʊlər/; July 12, 1895 – July 1, 1983) was an American architect, systems theorist, author, designer, inventor and futurist. Fuller published more than 30 books, coining or popularizing terms such as "Spaceship Earth", "Dymaxion" house/car, ephemeralization, synergetic, and "tensegrity". He also developed numerous inventions, mainly architectural designs, and popularized the widely known geodesic dome. Carbon molecules known as fullerenes were later named by scientists for their structural and mathematical resemblance to geodesic spheres. Fuller was the second World President of Mensa from 1974 to 1983. Natural hair movement: The natural hair movement is a movement which encourages women of African descent to keep their natural afro-textured hair. Originating in the United States during the 2000s, this movement is called mouvement nappy in French-speaking countries. The Way of the Superior Man-David Deida:Though much has changed in society since the first publication of The Way of the Superior Man, men of all ages still “tussle with the challenges of women, work, and sexual desire.” Including an all-new preface by author David Deida, this 20th-anniversary edition of the classic guide to male spirituality offers the next generation the opportunity to cultivate trust in the moment and put forth the best versions of themselves in an ever-changing world. Women's studies:Women's studies is an academic field that draws on feminist and interdisciplinary methods in order to place women’s lives and experiences at the center of study, while examining social and cultural constructs of gender; systems of privilege and oppression; and the relationships between power and gender as they intersect with other identities and social locations such as race, sexual orientation, socio-economic class, and disability. Identity Politics:political positions based on the interests and perspectives of social groups with which people identify. Identity politics includes the ways in which people's politics are shaped by aspects of their identity through loosely[clarification needed] correlated social organizations. Examples include social organizations based on age, religion, social class or caste, culture, dialect, disability, education, ethnicity, language, nationality, sex, gender identity, generation, occupation, profession, race, political party affiliation, sexual orientation, settlement, urban and rural habitation, and veteran status.The term "identity politics" has been in use in various forms since the 1960s or 1970s, but has been applied with, at times, radically different meanings by different populations. Gender Norms:What are gender roles?Gender roles in society means how we’re expected to act, speak, dress, groom, and conduct ourselves based upon our assigned sex. For example, girls and women are generally expected to dress in typically feminine ways and be polite, accommodating, and nurturing. Men are generally expected to be strong, aggressive, and bold. Every society, ethnic group, and culture has gender role expectations, but they can be very different from group to group. They can also change in the same society over time. For example, pink used to be considered a masculine color in the U.S. while blue was considered feminine. Ethnography:(from Greek ἔθνος ethnos "folk, people, nation" and γράφω grapho "I write") is the systematic study of people and cultures. It is designed to explore cultural phenomena where the researcher observes society from the point of view of the subject of the study. An ethnography is a means to represent graphically and in writing the culture of a group. The word can thus be said to have a double meaning, which partly depends on whether it is used as a count noun or uncountable. The resulting field study or a case report reflects the knowledge and the system of meanings in the lives of a cultural group. The Alchemist by Paulo Coelho: Paulo Coelho's masterpiece tells the magical story of Santiago, an Andalusian shepherd boy who yearns to travel in search of a worldly treasure as extravagant as any ever found. Destructive Emotions: A Scientific Dialogue with the Dalai Lama: Imagine sitting with the Dalai Lama in his private meeting room with a small group of world-class scientists and philosophers. The talk is lively and fascinating as these leading minds grapple with age-old questions of compelling contemporary urgency. Daniel Goleman, the internationally bestselling author of Emotional Intelligence, provides the illuminating commentary—and reports on the breakthrough research this historic gathering inspired. The Californians:A soap opera parody featuring Fred Armisen, Bill Hader, Kristen Wiig, and others as wealthy blondes with Valley Girl accents (Valleyspeak) exaggerated almost to the point of incoherence. Each "episode" opens with the Soapnet logo with Bill Hader's voice-over announcement: "The Californians". The title sequence shows the pouring of a glass of white wine and some beach front property, with an acoustic guitar lick and chords that imitate America's "Ventura Highway" on the soundtrack. NYC vs. LA:A few years ago, I received a frantic call from a friend. For months he’d been mulling over whether to stay in New York or give acting a go in Los Angeles. “I love New York,” he said. “But I want to do more TV and film.” Smartphone zombie: A smartphone zombie is a pedestrian who walks slowly and without attention to their surroundings because they are focused upon their smartphone. This is now a significant safety hazard as distracted pedestrians cause accidents. Cities such as Chongqing and Antwerp have introduced special lanes for smartphone users to help direct and manage them. Limbic System: The limbic system is a set of brain structures located on both sides of the thalamus, immediately beneath the cerebrum. It has also been referred to as the paleomammalian cortex. It is not a separate system but a collection of structures from the telencephalon, diencephalon, and mesencephalon. It includes the olfactory bulbs, hippocampus, hypothalamus, amygdala, anterior thalamic nuclei, fornix, columns of fornix, mammillary body, septum pellucidum, habenular commissure, cingulate gyrus, parahippocampal gyrus, entorhinal cortex, and limbic midbrain areas. Sound In Space:You’ve heard it before: In space, no one can hear you scream. That’s because sound doesn’t move through a vacuum, and everyone knows that space is a vacuum. The thing is, that’s not completely true. The Orchard: As a pioneering music, film and TV dis­tri­b­u­tion company and top-ranked video network, The Orchard has local reps in more than 30 global markets. From digital retailers and physical stores to performance rights societies and mobile outlets, our partnerships help amplify your reach and revenue across multiple business verticals. Tardigrade:Tardigrades (/ˈtɑːrdɪˌɡreɪd/; also known colloquially as water bears, or moss piglets) are a phylum of water-dwelling, eight-legged, segmented micro-animals. Cosmo Sheldrake - Tardigrade Song:Cosmo Sheldrake is a 28 year old multi-instrumentalist musician, composer and producer. He released his first single ‘The Moss’ in 2014, which was followed by the ‘Pelicans We’ EP in 2015. This April he will release his debut album ‘The Much Much How How and I’ on Transgressive Records. Much of his work is to do with play, nonsense and the sonorous environment. Sound and Light Differences:Sound you hear, light you see. Sound is a mechanical wave whereas light is an electromagnetic one. Light travels at 300.000.000 m/s meanwhile sound travels at 353 m/s. Light does not need a medium to travel to, sound does. They are both waves but only light is also a particle. Wave Particle Duality of Light:Wave–particle duality is the concept in quantum mechanics that every particle or quantic entity may be partly described in terms not only of particles, but also of waves. It expresses the inability of the classical concepts "particle" or "wave" to fully describe the behavior of quantum-scale objects. As Albert Einstein wrote: “It seems as though we must use sometimes the one theory and sometimes the other, while at times we may use either. We are faced with a new kind of difficulty. We have two contradictory pictures of reality; separately neither of them fully explains the phenomena of light, but together they do.” Using infrared light to help deaf people hear and blind people see:Normally, implants use electrical signals to help people hear and see. However, University of Utah bioengineer Richard Rabbitt has discovered a different way to activate cells. Rabbitt figured out how to use infrared light to send signals to the brain. Instead of using electrical signals, pulses of invisible wavelengths activate nearby nerve cells and communicate with the brain. What the Bleep do We know?: takes viewers on a journey to unlock the secrets of life. Follow Amanda (Academy Award-winner Marlee Matlin), a divorced, middle-aged woman who is thrust into a world where science and spirituality converge. As her entire concept of reality is challenged, yours will be too. See for yourself why this groundbreaking movie became one of the most compelling and talked about films of the last decade. Schrodinger's Cat:is a thought experiment, sometimes described as a paradox, devised by Austrian physicist Erwin Schrödinger in 1935. It illustrates what he saw as the problem of the Copenhagen interpretation of quantum mechanics applied to everyday objects. The scenario presents a cat that may be simultaneously both alive and dead, a state known as a quantum superposition, as a result of being linked to a random subatomic event that may or may not occur. The thought experiment is also often featured in theoretical discussions of the interpretations of quantum mechanics. Schrödinger coined the term Verschränkung (entanglement) in the course of developing the thought experiment. Free will:Free will is the ability to choose between different possible courses of action unimpeded. THE PHYSICS OF FREE WILL: “You’re playing a game of pool. You line up your cue stick behind the cue ball. You practice your stroke…one…two…three… On the fourth stroke, you follow through and the cue stick makes contact. If we could stop time in this moment, we could predict with reasonable certainty the outcome of your shot. The cue stick determines the path of the cue ball. The path of the cue ball determines if and how it will hit the target ball. How it hits the target ball determines the path of both, and whether either will reach a pocket.” Viking Funeral:  Norse funerals, or the burial customs of Viking Age North Germanic Norsemen (early medieval Scandinavians), are known both from archaeology and from historical accounts such as the Icelandic sagas, Old Norse poetry, and probably from the account of Ahmad ibn Fadlan. The Book of Secrets: Unlocking the Hidden Dimensions of Your Life:  Every life is a book of secrets, ready to be opened. The secret of perfect love is found there, along with the secrets of healing, compassion, faith, and the most elusive one of all: who we really are. We are still mysteries to ourselves, despite the proximity of these answers, and what we most long to know remains lodged deep inside. Gene p53: p53, also known as TP53 or tumor protein (EC :2.7.1.37) is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. It is very important for cells in multicellular organisms to suppress cancer. P53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation (Strachan and Read, 1999). The name is due to its molecular mass: it is in the 53 kilodalton fraction of cell proteins. Lauren Turk See you Again Video:Concept by Lauren TurkDirected by James Bloniarz & Billy Ferguson / Lake Effect Films Generation Wealth: “Generation Wealth” is a multi-platform project that Lauren Greenfield has been working on since 2008, and is being released in 2017 as a museum exhibition, a photographic monograph, and a documentary film. Ascribe vs subscribe:Ascribe and subscribe are two words that are very similar in pronunciation and spelling, but have two different meanings. We’ll examine the difference between ascribe and subscribe, their meanings and origin. We’ll also look at a few examples of their use in sentences. Edward Bernais: Edward Louis Bernays (/bərˈneɪz/; German: [bɛɐ̯ˈnaɪs]; November 22, 1891 − March 9, 1995) was an Austrian-American pioneer in the field of public relations and propaganda, referred to in his obituary as "the father of public relations".[2] Bernays was named one of the 100 most influential Americans of the 20th century by Life. He was the subject of a full length biography by Larry Tye called The Father of Spin (1999) and later an award-winning 2002 documentary for the BBC by Adam Curtis called The Century of the Self. More recently, Bernays is noted as the great-uncle of Netflix co-founder, Marc Randolph. Whitney Houston Documentary: An in-depth look at the life and music of Whitney Houston. Won’t you be My Neighbor:An exploration of the life, lessons, and legacy of iconic children's television host, Fred Rogers. Support Foxes and Hedgehogs by donating to their Tip Jar: https://tips.pinecast.com/jar/foxes-and-hedgehogsThis podcast is powered by Pinecast.

  Tucker Goodrich is a Wall Street tech extraordinaire and nutrition science enthusiast. After doctors and the healthcare system let him down in severe and avoidable ways, he took his health into his own hands and had amazing results. He’s done a ton of research on Omega 6 fatty acids otherwise known as seed oils otherwise known as vegetable oils previously known as an industrial waste product before we started feeding them to humans. He makes a compelling case for them being a major factor in many, if not all, modern diseases. You’ll definitely not want to be eating fast food fries cooked in old, rancid vegetable oils after this episode. The sunburn stuff at the end is legit. I won’t spoil it, but just know Robb Wolf just backed this up on his podcast with science. There is a mechanism there that makes total sense and I’ve seen it anecdotally as well. We seem to have stalled out with the Food Lies film Indiegogo campaign. Please keep supporting us there. This documentary and podcast is all done by support of people like you. We’re not taking any outside money other than from my own pocket to fund this. Thanks so much, I sincerely appreciate it. http://indiegogo.com/projects/food-lies-post Show Notes Works on Wall Street and developed software that deals with trillions of dollars of assets Had a stroke-like event at age 38 Then got acute diverticulitis Got a colon resection and followed “healthy” diet and doctor’s advice and was still sick He called himself “Mr. Whole Wheat” - stopped eating sugar when he was 19 so that wasn’t it 16 years of IBS… finally found Stephan Guyenet’s blog http://stephanguyenet.com Started fixing himself in 2 days using dietary change His surgery was probably unnecessary He is well connected to Daniel Lieberman and The Story of the Human Body Diseases of civilization Agriculture allowed us to build cities, paved the way for written language to keep track of grains, etc. We over-hunted all the very large animals From eating grains we got shorter, got cavities, lesions on bones, all while our population exploded We used to be more robust and have bigger brains Diabetes used to be super rare - we have medical records of this Cancer a huge problem in Germany Heart disease in England Diseases went around the world as eating patterns went around the world We even give other species diabetes and our diseases when we feed them our foods - monkeys, dogs, cats - even racoons who eat human garbage Weston A. Price needs to be mentioned for his great work Realization came at the salad bar with the dressings Cut all vegetable oils and cured himself Cut out carbs and processed foods and exercised less and lost tons of weight Started doing more research - lots of people said seed oils are bad, but nobody really explained the mechanism back then Maybe the largest epidemiological study ever on saturated fat in India looking at the northern and southern populations The south who ate like our food pyramid suggests had 7-15 times the heart disease rate How about England? Heart disease skyrocketed with the intro of seed oils Okinawa is a Blue Zone - place where people live abnormally long First fast food restaurant opened in Okinawa Okinawa went from the longest lifespan in Japan to the shortest Seed oil consumption tracks modern disease all over the world These cultures were eating a high carb diet so it's likely not the carbs - the carb consumption actually went down Japanese and chinese are some of the shortest populations and they subsist on high carb, low meat diet. We know we got shorter when agriculture was invented. We know when we lower carb intake and up meat intake populations get taller Grains are a “fallback food” It’s funny that rich people in Santa Monica purposely try to live in the Failed Environment Metabolic State while thinking they’re morally superior to us Tarahumara Indians eat this way - their children have a malnutrition rate of 80% Carbohydrate is a cofactor. 5 key studies: rats and diabetes & heart failure; (Ghosh 2004); LA and obesity (Alvheim 2012) Lyon Diet Heart (De Lorgeril 1994); Seed oils and insulin resistance in India (Nigam 2014); Seed oils and NAFLD, (Maciejewska 2015) Lyon heart study - lowered Omega 6 and raised Omega 3 to improve heart attack risk of repeat by 70% William Lands: “I’ve studied saturated fat for 50 years and never found a mechanism that it could kill somebody” American Heart Association’s “Prudent Diet” proved to be outright harmful to people in this study History of LDL cholesterol and heart disease To make LDL atherogenic omega 6 fats need to be oxidized Researchers found this mechanism before De Lorgeril had success with replacing Omega 6s with olive oil, where he improved heart attack outcomes without knowing the mechanism Researchers prime rats to get cancer and can’t do this unless they use omega 6s Western Cancers and the P53 gene mutation Japanese women moving to America breast cancer went up 7 fold Why is there DNA damage present in all western diseases? Mitochondrial dysfunction is a hallmark of all western diseases Avoiding heated seed oils is not good enough - damage still happens inside cells damaged cardiolipin cause mitochondria to stop working properly and is primarily caused by excess carbohydrates in the diet A lot of disease is teed up by excess carbs but the seed oils are what activate the damage Asian countries and rice consumption Knockout gene and detoxifying seed oils Selenium deficiency in China and glutathione Omega 6 fats combined with glucose causes oxidation and can be seen in a petri dish Women in CHina were getting lung cancer that didn’t smoke - turned out it was cooking with seed oils and inhaling the fumes Seed oils break down into one of the same toxins as in cigarette smoke Seed oils used to be an industrial waste product There’s no conspiracy theory - they thought these oils were fine. They aren't acutely toxic, it takes years to do damage Everything has a U-shaped curve - too little or too much is bad There’s essential fats in dairy and maybe more we don’t know about How do vegans temporarily survive? Kitavans Sunburn and diet - how could they possibly be related? His wife with dark skin and his light skin What’s the mechanism? His radiation research Evolutionary context for omega 6 causing sunburn (or lack of omega 6 making us able to not get sunburned) Now are omega 3 to omega 6 ratio is a nightmare Giving omega 3 and a better diet to prisoners helped with their behavior Weston Prices studied diet and its effects on troubled youth as well Not everyone needs to cut out wheat, but just know it’s effects. Everyone should cut out sugar, refined grains, and seed oils though Gabor Erdosi lecture https://www.youtube.com/watch?v=8rcfvRGZsDs The amount of physical grinding of starch affects your digestion and health in a negative way Gabor is actually the next podcast guest Japanese people eat high starch but it’s in its whole form, not ground People are confused on what healthy even is, so it’s hard to be healthy Going to restaurants is not even worth it anymore when you can make things better at home Tucker’s blog http://yelling-stop.blogspot.com/ Tucker on Twitter https://twitter.com/TuckerGoodrich     Preorder the film here: http://indiegogo.com/projects/food-lies-post     Film site: http://FoodLies.org YouTube: https://www.youtube.com/c/FoodLies Sapien Movement: http://SapienMovement.com   Follow along: http://twitter.com/FoodLiesOrg http://instagram.com/food.lies http://facebook.com/FoodLiesOrg   Theme music by https://kylewardmusic.com/

Welcome to the self-evaluation episode of the ASCO University weekly podcast. My name is Shadia Jalal, and I am a thoracic oncologist at Indiana University. Today, we feature a self-evaluation question on the treatment of limited-stage small-cell lung cancer. And we begin by the question. A 58-year-old man with a 40-pack-year history of cigarette smoking is found to have a spiculated 2.1-centimeter left upper lobe mass on CAT scan imaging that was performed for a suspected pneumonia. His physicians decided to immediately take him to the operating room for a wedge resection of that mass. A preliminary analysis of the pathology from the wedge resection during the operation revealed small-cell lung cancer. A completion left upper lobectomy and mediastinal lymph node dissection was performed. The final pathology confirmed a T1a small-cell lung cancer with negative margins and no lymph-node involvement. Subsequent work-up included an MRI of the brain with and without gadolinium contrast and a Positron Emission Tomography, or PET scan, both of which showed no evidence of distant metastatic disease. Molecular profiling of the tumor revealed concurrent P53 and retinoblastoma mutations, as is usually seen in small-cell lung cancer. The question is, which of the following is the most appropriate next step? A, the administration of four cycles of cisplatin and etoposide in an adjuvant fashion; B, definitive radiation to the chest with concurrent cisplatin and paclitaxel; C, four cycles of carboplatin and pemetrexed; D, definitive radiation to the chest with concurrent cyclophosphamide; E, four cycles of cyclophosphamide, doxorubicin, and vincristine. The correct answer is A, four cycles of cisplatin and etoposide in an adjuvant fashion. The role of surgery in patients with limited-stage small-cell lung cancer is really limited to a very small number of those patients that might present with a peripheral small tumor. As is known, small-cell lung cancer is usually more of a central tumor with lymph node involvement. In a patient like this with limited-stage small-cell lung cancer and node-negative disease, adjuvant chemotherapy with a platinum doublet-- cisplatin or carboplatin and etoposide-- is recommended after definitive surgery, including mediastinal lymph-node dissection. Small-cell lung cancer is a cancer known for early hematogenous spread, and therefore adjuvant chemotherapy is indicated. CAV, or cyclophosphamide, doxorubicin, and vincristine, or carboplatin with pemetrexed are not appropriate treatment options in limited-stage small-cell lung cancer. In fact, pemetrexed does not have activity in small-cell lung cancer. Concurrent chemotherapy and radiation could be recommended and considered in the presence of node-positive disease, which was not the case in this situation. And if concurrent chemotherapy and radiation is to be given, cisplatin with etoposide would be the appropriate regimen administered at the time of radiation. Thank you for listening to this weekly podcast recording, "Small-Cell Lung Cancer."

The entire TWiV team visits The University of Texas in Austin to record episode #500 with guests Jinny Suh, Jason McClellan, and Jon Huibregtse. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler Guests: Jinny Suh, Jason McClellan, and Jon Huibregtse Become a patron of TWiV! Links for this episode A big list of science podcasts Immunize Texas McClellan Lab Huibregtse Lab John Ring LaMontagne Center for Infectious Disease Video of this episode (YouTube) Weekly Science Picks Alan - The Airplane Cabin Microbiome Rich - Coalition for Epidemic Preparedness Innovations (CEPI)(wiki) Dickson - The Big Five Mass Extinctions Kathy - Virus scarves at Red Bubble phage-specific     variety Vincent - Science podcasts Listener Pick Maureen- 12 year old takes on Flint's Water Crisis Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Vinny Lynch joins Nels and Vincent to discuss how a zombie gene in elephants protects these large, long lived animals from cancer. Hosts: Nels Elde and Vincent Racaniello Guest: Vinny Lynch   Become a patron of TWiEVO Lynch Lab Elephant zombie LIF gene induces apoptosis (bioRxiv) Image credit Science Picks Nels - Animalism Vincent - Voyager I fires up thrusters after 37 years Vinny - Rollin' Wild Music on TWiEVO is performed by Trampled by Turtles Send your evolution questions and comments to twievo@microbe.tv

P53 by Ilyaspeaker

Our Scientific Director Megan Hall (née Roberts) recently had some of the work from her Master’s degree published in the journal Cell Metabolism, which is seriously impressive. The paper appeared on Science Daily, and generally caused a bit of a stir in the low carb community. As we have direct access to the horse’s mouth, I’ve asked Megan to join me in this episode of the podcast to summarise the findings and give some thoughts on how it might relate to human health. Here’s the outline of this interview with Megan Hall: [00:00:55] Mastermind Talks. [00:01:47] The lead up to the study. [00:02:17] Time-restricted feeding. [00:02:38] Are they eating longer because of a less crappy diet? [00:04:21] Calorie restriction was the focus of Megan's lab. [00:05:27] Stephen Phinney, MD, PhD and Jon Ramsey, PhD. [00:06:13] Study design. [00:07:36] High-fat diets in rodents. [00:08:39] Two arms: longevity and healthspan. [00:10:55] Grip strength in a rodent. [00:11:40] Novel object test. [00:12:55] fMRI for body composition using the EchoMRI. [00:13:13] The results. Study: Roberts, Megan N., et al. "A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice." Cell Metabolism 26.3 (2017): 539-546. [00:15:40] Valter Longo, PhD and USC Longevity Institute. Studies: Brandhorst, Sebastian, et al. "A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan." Cell metabolism 22.1 (2015): 86-99 and Wei, Min, et al. "Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease." Science translational medicine 9.377 (2017): eaai8700. [00:16:27] Study: Sleiman, Sama F., et al. "Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate." Elife 5 (2016): e15092. [00:17:34] Motor function and coordination. [00:18:58] The importance of preserving type IIA muscle fibers. Podcast: The Most Reliable Way to Lose Weight with Dr Tommy Wood and The High-Performance Athlete with Drs Tommy Wood and Andy Galpin. [00:19:18] Study: Zou, Xiaoting, et al. "Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice." Journal of Biological Chemistry291.5 (2016): 2181-2195. [00:20:04] Exercise performance. [00:21:13] Physiologic insulin resistance. [00:22:06] Podcast: Real Food for Gestational Diabetes with Lily Nichols. [00:24:21] Keto vs low-carb. [00:27:05] Studies: β-Hydroxybutyrate: A Signaling Metabolite and Ketone bodies as signalling metabolites. [00:27:49] YouTube: Histone deacetylation and inhibition. [00:29:19] I mentioned the Khan Academy, but in the end Megan liked these videos on HDAC inhibitors and cancer and Histone deacetylation and inhibition (also mentions p53!). [00:30:49] FOXO proteins. [00:31:30] Lysine residues. [00:31:48] Mn SOD. [00:32:10] mTOR, Dr. Ron Rosedale. [00:34:04] REDD1 protein. [00:34:32] P53 protein, metformin. [00:35:30] Less cancer in KD mice. [00:36:00] Warburg Effect. [00:36:21] Replicability. [00:36:57] Study: Newman, John C., et al. "Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice." Cell Metabolism 26.3 (2017): 547-557. [00:38:28] Press coverage of the study, “Eat Fat, Live Longer” at Sciencedaily.com. [00:41:01] Soybean oil in rodent diets. [00:41:34] Sex-dependent differences. [00:43:23] Takeaways. [00:44:21] Dogma displacement inertia. [00:45:19] Exogenous ketones. Study: Stubbs, Brianna Jane, et al. "On the metabolism of exogenous ketones in humans." Frontiers in Physiology 8 (2017): 848. [00:46:34] What does this mean for humans? [00:47:42] Weightloss. [00:48:36] Micromanaging the details. [00:50:33] Who are you and what are your goals -- Robb Wolf. Podcast: Wired to Eat with Robb Wolf. [00:51:55] Nourish Balance Thrive Highlights Series sign up. [00:53:11] Megan's purpose. [00:53:39] Book: Find Your Why: A Practical Guide for Discovering Purpose for You and Your Team by Simon Sinek and David Mead.

This month we're zooming in on cancer, finding out how researchers are tackling tumours in unprecedented detail. Plus, our gene of the month is the guardian of your genome, rather than the galaxy. Like this podcast? Please help us by supporting the Naked Scientists

How Chlamydia help mitochondria keep it together The obligate intracellular bacterium Chlamydia trachomatis must keep its host cell alive, even though it produces reactive oxygen species that expose the host cell to oxidative stress. Chowdhury et al. reveal that Chlamydia mitigates this oxidative stress by down-regulating the mitochondrial fission protein DRP1 via a microRNA- and p53-dependent pathway, thereby maintaining the mitochondrial network and ATP production to promote host cell survival and bacterial growth. This biosights episode presents the paper by Chowdhury et al. from the April 3rd, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Suvagata Roy Chowdhury and Thomas Rudel (University of Würzburg, Würzburg, Germany). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

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. Our feature discussion is regarding the exciting results of the masked hypertension study showing that clinical blood pressure underestimates ambulatory blood pressure, but first here's your summary of this week's issue.     The first study reviews the largest clinical experience so far with pulmonary vein stenosis following ablation for atrial fibrillation. First author Dr. Fender, corresponding author Dr. Packer and colleagues from Mayo Clinic Rochester, Minnesota evaluated the presentation of 124 patients with severe pulmonary stenosis between 2000 and 2014 and examined the risk for re-stenosis after intervention utilizing either balloon angioplasty alone or balloon angioplasty with stenting. All 124 patients were identified as having severe pulmonary vein stenosis by CT in 219 veins. 82% were symptomatic at diagnosis with the most common symptoms being dyspnea, cough, fatigue and decreased exercise tolerance. 92 veins were treated with balloon angioplasty, 86 with stenting and 41 veins were not intervened on. The acute procedural success rate was 94% and did not differ by initial management. Overall, 42% of veins developed re-stenosis, including 27% of veins treated with stenting and 57% of veins treated with balloon angioplasty.     The three-year overall rate of re-stenosis was 37% with 49% of balloon angioplasty treated veins compared to 25% of stented veins developing re-stenosis. This was a difference that remained significant even after adjusting for age, CHADS2 VASC score, hypertension and time period of the study with an adjusted [inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with balloon angioplasty versus stenting. In summary, this study shows that the risk for pulmonary vein re-stenosis is significant following atrial fibrillation ablation. The diagnosis is challenging due to non-specific symptoms and while there is no difference in acute success by type of initial intervention, stenting significantly reduces the risk of subsequent pulmonary vein re-stenosis compared to balloon angioplasty.     The next paper shows that the index of microvascular resistance, which is a novel invasive mreasure of coronary microvascular function, has emerging clinical utility as a test for the efficacy of myocardial re-perfusion in invasively managed patients with acute ST elevation myocardial infarction. In this study by first author Dr. [Carrick 00:03:30], corresponding author Dr. Barry and colleagues from the University of Glasgow in Scotland, index of microvascular resistance and coronary flow reserve were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST elevation myocardial infarction. Authors found that compared with standard clinical measures of the efficacy of myocardial re-perfusion, such as ischemic time, ST segment elevation and angiographic blush grade, the index of microvascular resistance was more consistently and strongly associated with myocardial hemorrhage, microvascular obstruction, changes in left ventricular ejection fraction and left ventricular end diastolic volume at six months as well as all caused death of heart failure during the median follow up of 845 days.     In fact, compared with an index of microvascular resistance greater than 40, the combination of this index and coronary flow reserve less than two did not have incremental prognostic value. The take-home message is therefore that an index of microvascular resistance above 40 represents a prognostically validated reference test for failed myocardial re-perfusion at the end of primary percutaneous coronary intervention. This study supports further research into microvascular resistance based therapeutic strategies in these patients.     The next study provides experimental data regarding molecular mechanisms underlying calcific aortic valve disease. First author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose 00:05:24] from the Quebec Heart and Lung Institute in Canada performed genomic profiling and in-depth functional assays in human aortic valves. They demonstrated for the first time that the promotor region of the long non-coding RNA H19 is hypomethylated in patients with calcific aortic valve disease. This hypomethylation in turn increases H19 expression in the valve interstitial cells where it prevents Notch 1 transcription by blocking or out-competing P53's recruitment to the Notch 1 promotor. Thus, H19 appears to be the missing link connecting Notch 1 to idiopathic calcific aortic valve disease. It may therefore represent a novel target in calcific aortic valve disease to decrease osteogenic activity in the aortic valve.     The next paper describes the largest cohort of mycotic abdominal aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and colleagues of Uppsala University in Sweden.  These authors identified all patients treated for mycotic abdominal aortic aneurysms in Sweden between 1994 and 2014. Among the 132 patients, they noted that the preferred operative technique shifted from open repair to endovascular repair after 2001 with the proportion treated with endovascular repair increasing from 0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at three months was lower for open repair compared to endovascular repair at 74% versus 96% respectively with a similar trend present at one year. A propensity score adjusted analysis confirmed the early better survival associated with endovascular repair. During a median follow up of 36 months for open repair and 41 months for endovascular repair. There was no difference in long-term survival, infection-related complications or re-operation. The take-home message is that endovascular repair appears to be a durable surgical option for treatment of mycotic abdominal aortic aneurysms.     The final study provides insights into the molecular mechanisms by which aldosterone triggers inflammation and highlights the particular role of NLRP3 inflammasome, which is a pivotal immune sensor that recognizes endogenous danger signals and triggers sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr. [Tostes 00:08:33] and colleagues from the University of Sao Paulo in Brazil analyzed vascular function and inflammatory profiles of wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1 receptor knockout mice, all treated with vehicle or aldosterone while receiving 1% saline. They found that mice lacking the interleukin-1 beta receptor or lacking inflammasome components such as NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In-vitro, aldosterone stimulated NLRP3-dependent interleukin-1 beta secretion by bone marrow derived macrophages. Chimeric mice reconstituted with NLRP3 deficient hematopoietic cells showed that NLRP3 in immune cells mediated the aldosterone-induced vascular damage.     In addition, aldosterone increased the expressions of NLRP3, caspase-1 and mature interleukin-1 beta in human peripheral blood mononuclear cells. Finally, hypertensive patients exhibited increased activity of NLRP3 inflammasome. Together these data demonstrate that NLRP3 inflammasome via activation of interleukin-1 receptor is critically involved in the deleterious vascular effects of aldosterone, thus NLRP3 is a potential target for therapeutic interventions in conditions with high aldosterone levels.     That wraps it up for our summaries. Now for our feature discussion.     On today's podcast we are going to be discussing the very important issue of masked hypertension. This is an issue that gets a lot less attention than I think compared to white coat hypertension. I'm so pleased to have the first and corresponding author of the masked hypertension study, Dr. Joseph Schwartz, from Stony Brook University and Columbia University in New York. Welcome to the show, Joe.   Dr. J. Schwartz: My pleasure. I'm delighted to join you.   Dr. Carolyn Lam: We have a regular on the show today as well, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back Wanpen.   Dr. Wanpen V.: Thank you so much. Happy to be here.   Dr. Carolyn Lam: Joe, I want to start by addressing the common misperception that ambulatory blood pressure is usually lower than clinical blood pressure. That seems to make a lot of sense to us clinically because, for example, I always use ambulatory blood pressure to diagnose white coat hypertension and so the assumption there is that my clinically measured blood pressure is higher than what I'm going to be finding if this patient measures the blood pressure on an ambulatory 24-hour basis. It's also from the cutoffs that we use. For example, ambulatory blood pressure we use a 24-hour cutoff of 130/80 to make the diagnosis whereas with clinical blood pressure we use a cutoff of 140/90 so all of this kind of reinforces that ambulatory blood pressure is usually lower. Your study, though, tells us otherwise so please fill us in here.    Dr. J. Schwartz: You're right that in the doctor's office there are a certain set of people who probably get anxious when they're around a doctor and with that anxiety may cause a temporary increase in their blood pressure, a temporary elevation, and that's the basis of where we think white coat hypertension comes from. That's a very widespread belief among doctors and it's even been in previous guidelines, there have been statements to that effect. When I talk to people out in the general public and tell them I'm doing a study comparing blood pressure out in the real world compared to blood pressure in the doctor's office, all of them tell me, "Well, usually when I'm in a doctor's office that's a relatively calm period for me unless there's really something wrong with me and out in the everyday world I have to face a variety of stressors. I have deadlines. I have places I need to get to. Sometimes I have people yelling at me. Sometimes I'm just in a hurry."     All these things elevate your blood pressure out in the real world and so when we were trying to recruit people for the study, and we were very agnostic in recruiting them, telling them that we were interested in the differences in blood pressures between the doctor's office and the ambulatory blood pressure and they might go in either direction. When I told them about the fact that their ambulatory blood pressure or real world blood pressure might be higher than in the doctor's office, the vast majority of people nodded affirmatively and said, "It wouldn't surprise me at all."   Dr. Carolyn Lam: Could you define masked hypertension compared to white coat hypertension and tell us a little bit about the population you studied.   Dr. J. Schwartz: Sure. First with the definition. I'm going to say something a little bit different from something you said before. You mentioned cutoffs that we typically used for ambulatory blood pressure of 130/80 and those are the cutoffs that are used if you compute an average blood pressure over the entire 24 hours. What many people do, and what we did for this study, was compare the average blood pressure when people were awake to their blood pressure in the doctor's office because obviously in the doctor's office everybody is awake. The typical cutoffs there are 135/85, recommended by numerous guidelines in this country and with our international collaborators. The definition of masked hypertension is having a blood pressure in the clinic setting that's below 140/90 but having an ambulatory blood pressure where either the systolic blood pressure is above 135 or the diastolic is above 85 millimeters of mercury.     In terms of the sample, for years I've had a particular strategy for trying to recruit participants. I do worksite-based studies and so I identify large organizations that will allow me to recruit their employees and then what we did for this study is go to individual departments, both here at Stony Brook University, at Columbia University, at a residential veterans' home that's affiliated with Stony Brook University and then also at a local private hedge fund management company. We would go to these sites, I talk to the head of a department and tell them a little bit about masked hypertension and what the study was about and ask them if they would be willing to have their employees participate in the study. Once I had the okay from the department head then we would conduct public health screenings, blood pressure screenings. My staff and I would go into the department for multiple days and invite anybody who was interested to have their blood pressure taken on site and while we were taking those blood pressures carefully.     The proper way to take those is to take three readings and leave a minute or two interval between them and rather than just have silence then between the readings we would tell them a little bit about our study. At the end of the study if they didn't have extremely high blood pressure and were not taking blood pressure medication we would ask them if they might be interested in participating in the study that we just described. That's how we identified potential participants and about 2/3 of the people that we talked to who looked eligible indeed chose to participate.                   Dr. J. Schwartz: The one other thing I might mention that I think we mentioned, I hope we mentioned as a limitation of the study, is that everybody in the study had health insurance and at least until recently there were very large portions of the population that didn't have health insurance, everybody by virtue of their employment by the organizations that participated in the study, did have employer-based health insurance.   Dr. Carolyn Lam: Thanks for clarifying the population so well. Could you just give us the top line of your findings. How big a difference did you find, which direction and that intriguing effect of age?   Dr. J. Schwartz: Sure. The first thing we found is that on average the systolic blood pressure is seven millimeters mercury higher out in everyday life than it is in the clinic setting where we take our clinic readings. I should mention that unlike most studies, and all studies at the time that we began our study, we brought people in three separate times to take the clinic blood pressure. Up until that, almost all of the studies of ambulatory blood pressure monitoring only had clinic blood pressures from a single visit. I think we have a very reliable measure of the clinic blood pressure as well as reliable measure of ambulatory blood pressure. We see a seven millimeter difference in the systolic blood pressure and a 2 millimeter difference, again the ambulatory being higher for diastolic blood pressure.     What's more remarkable is if you think about what's a sizable difference. If you think if we perhaps somewhat arbitrarily say 10 millimeters of systolic blood pressure is a large difference. More than 35% of the population has an ambulatory blood pressure that is more than 10 millimeters higher than their clinic blood pressure whereas only 3% of our sample had that large a difference in the opposite direction, what many people would call a white coat effect. It's more than a 10 to 1 difference in numbers of people who have elevated ambulatory versus elevated clinic.     You asked me to mention something about the age difference. When you look at how that difference in systolic blood pressure varies by age, it's quite a bit larger for people who are younger. If you're under 30 the difference is, on average, 10 millimeters rather than seven millimeters and if you go up as you approach 60 years of age or so the difference becomes relatively small, perhaps in the neighborhood of two millimeters. We don't have enough people because it's a working population over 65 to say very much about what would happen. In fairness to prior research, which often is on older populations and particularly hypertensive populations, the studies that have historically shown that ambulatory blood pressure tends to be lower than clinic blood pressure are in these older populations and populations that have elevated blood pressure to start with.     My speculation there, and you haven't asked me to mention it but I will, is that older people and those with hypertension have a reason to be more nervous or more anxious when they go to the doctor than people who are not taking medication and probably don't even know that they have hypertension. People who are just being screened perhaps during a routine physical for the possibility of hypertension, because the doctors take a blood pressure reading every time you go in, they're doing that in order to see whether you might have hypertension, but most people who are going in for what we call a well patient visit are not nervous about their blood pressure being high.   Dr. Carolyn Lam: I have to say, the take-home message for me when I read this was, I am not paying enough attention to masked hypertension and then another thing was, maybe I need to think about more white coat hypertension in the older and masked hypertension in the younger. Wanpen, do you think it's as simple as that? What were your take-home messages?   Dr. Wanpen V.: I think this is a very important study that examines this in a systematic way. I'm not surprised that Joe found as much masked hypertension here. I think that he's absolutely right. We looked at this in Dallas Heart Study as well recently and we found that in the population-based sample in Dallas almost 20% of people have masked hypertension and white coat we found only like 3% and the average in the Dallas Heart Study was very close to those samples, about mid-40s. I think that's a very important finding in that the people with masked hypertension would not be suspected otherwise to have problems. Also, in the Dallas Heart Study they used home readings but Dr. Schwartz used ambulatory blood pressure monitoring. Unless extra out of office monitoring is being done we will totally miss these people who are more likely to have target organ damage from high blood pressure. I think that's absolutely important.   Dr. Carolyn Lam: Actually, Wanpen you brought up something I was going to bring up as well. Where does home blood pressure fit in with this? Do you think it's home blood pressure versus ambulatory blood pressure?   Dr. Wanpen V.: The US Preventive Services Task Force has issued a little bit of recommendations recently that we need to either use ambulatory blood pressure monitoring or home blood pressure monitoring to confirm diagnosis of hypertension in the office. If someone shows up with elevated blood pressure in the office either home blood pressure or ambulatory blood pressure needs to be done. If we just followed that guidelines we're still going to miss people with masked hypertension because by definition they don't have elevated blood pressure in the office. I think that from these findings and Dr. Schwartz' study I think to catch these people we really need to pay attention to people with pre-hypertension type of blood pressure because it seems like those are the group that has the most probability to have elevated ambulatory blood pressure so anyone with borderline blood pressure in the clinic, those are the ones who the doctor needs to tell the patient to monitor blood pressure at home or order ambulatory blood pressure themselves if that's available in their facility.   Dr. Carolyn Lam: Wanpen, I fully agree. What an important message. Joe, I'd like to give you the final word but I'd love to hear how you have maybe taken this into your own practice.   Dr. J. Schwartz: I think we mostly focused on and indeed the paper mostly focuses on the difference between clinic blood pressure and ambulatory blood pressure. When we talk about the young people, the young people have a bigger difference but those differences are for the most part all in the normal range. You might see a 10- or a 12-point difference but it might be that the ambulatory is 124 and the clinic is 112 and no doctor is going to worry about that very much. There are really always two things that we're trying to look at simultaneously: The first is what is that difference between the ambulatory and the clinic, but the second is for whom does the clinic stay under the threshold for diagnosis of hypertension but the ambulatory is over? That's the diagnosis of masked hypertension.     We haven't said it today so I'll say it: Of those people who had normal clinic blood pressures averaged across three repeated visits, 15.7% of them had elevated ambulatory blood pressure and would have been diagnosed as having hypertension based on their average daytime ambulatory blood pressure reading. That's one message.     The last message is unfortunately there is almost no research yet telling us what we should do in terms of treating people with masked hypertension. We are now at the point where we can identify these people and we're also at the point where we now know that there are a lot of such people and we don't even have any research to base guidelines on for deciding what we should do with them. The most obvious thing is to recommend lifestyle changes. If they're overweight we could suggest that they lose weight. We could suggest that they exercise more. We might think about treating some of those people, especially if their ambulatory blood pressure is well above 140/90. There are no statements out in the literature by any of the organizations, and in fact there's no research examining whether there's a benefit or not a benefit to perhaps putting some of those people on medications. I think that's a big question that future research needs to address.   Dr. Carolyn Lam: Joe, thank you so much. I think your last statements just really emphasize how important this paper is. It increases awareness and it's going to open the door to much more needed research in this area. Thank you so much. Thank you Joe and Wanpen for being on the show today.     Thank you listeners for joining us. Don't forget to join us next week for even more news and exciting discussions.  

Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Kathy Spindler Guest: Mark Fuccio The TWiVome reveal the first eukaryotic genes found in a bacteriophage of Wolbachia, and how DNA tumor virus oncogenes antagonize sensing of cytoplasmic DNA by the cell.   Become a patron of TWiV! Links for this episode Zika virus in vaginal secretions (EID) Zika virus in semen (EID) Eukaryotic genes in a bacteriophage (Nat Commun) Seth Bordenstein on TWiV 332 DNA tumor virus oncogenes antagonize cGAS-STING (Science) Letters read on TWiV 412 This episode is brought to you by CuriosityStream, a subscription streaming service that offers over 1,400 documentaries and non­fiction series from the world's best filmmakers. Get unlimited access starting at just $2.99 a month, and for our audience, the first two months are completely free if you sign up at curiositystream.com/microbe and use the promo code MICROBE. This episode is also brought to you by Drobo, a family of safe, expandable, yet simple to use storage arrays. Drobos are designed to protect your important data forever. Visit www.drobo.com to learn more. Listeners can save $100 on a Drobo system at drobostore.com by using the discount code Microbe100. Weekly Science Picks Mark - EFN Enterprise Futures Network and Mission Log Podcast Alan - 2016 Wildlife Comedy Photography Rich -  ZuTA, portable robotic printerKathy - How LEGO help blind people see Vincent - Airplane photos of Mike Kelley Listener Pick Hannah - Frozen Flow Glass (Instagram) Send your virology questions and comments to twiv@microbe.tv

P53 is a cancer gene with a Jekyll and Hyde personality. It stops cancer tumours growing, but mutant versions of the gene actually cause cancer.

P53 is a cancer gene with a Jekyll and Hyde personality. It stops cancer tumours growing, but mutant versions of the gene actually cause cancer.

【小听童中英文双语故事】原始人斯坦利 Stanley2下集 P36. Stanley saw a field. “Does anybody mind if I live here?” he asked. 斯坦利看见田野。 “有人介意我住这里吗？”他问。 P37. “I don't mind if you don't snore,” said an animal who was going to sleep. “只要你不打呼噜，我就不介意。”正在睡觉的一只动物说。 P38. “I don't mind if you don't eat too much grass.” said an animal who was eating. “只要你不吃太多的草，我就不介意。”正在吃草的动物说。 P39. “I don't mind if you don't take up too much room.” said a very, very big animal. “只要你不占用太多的空间，我就不介意。”一个很大很大的动物说。 P40. Stanley made himeself at home. “This is not bad,” he said. 斯坦利像在家里一样。“这里还不太糟”他说。 P41. But suddenly the wind blew and Stanley was cold. The rain fell and he was wet. 但是，忽然风吹过来，斯坦利觉得很冷。 下雨了，他浑身湿透。 P42. “This is worse than the cave,” said Stantley. He made walls to keep out the wind. “这里比洞穴还糟糕。”斯坦利说。 他砌墙来阻挡风。 P43. He made a roof to keep out the rain. 他做屋顶来阻挡雨。 P44. He made a door, windows and chimney. He made a house! 他制作了门、窗子和烟囱。 他建造了一个房子！ P45. “That's the first house I ever saw,” said a field mouse. “这是我见过的第一个房子。”一只田鼠说。 P46. “It's the first one I ever made,” said Stanley. “Won't you stay here and live with me?” “它是我建的第一个房子。”斯坦利说。“你愿意留下来和我一起住吗？” P47. “I can't. I belong in the field. But I will come and visit you from time to time,” said the field mouse. “我不能。我住在田野里。但是我会不时的拜访您的。”田鼠说。 P48. Stanley painted pictures. 斯坦利绘画。 P49. He planted seeds in the ground and watched them grow. 他在地里播种，看着作物长大。 P50. He loved his house. But he was lonesome. “I wonder how my friends are,” he said. 他喜爱他的房子。但是他很孤单。 “我想知道我的朋友们怎么样了。”他说。 P51. The cavemen were out hunting for animals. They carried their clubs. 洞穴人出去狩猎动物，他们扛着棍棒。 P52. “Look who's after us with their silly clubs,” said the animals. “Let's chase them out of here!” “快看，我们后面那些拿着愚蠢的棍棒的家伙们”动物们说。“让我们把他们赶出这里！” P53. They chased the cavemen. Stanley saw the cavemen running. 他们追赶洞穴人。斯坦利看到洞穴人在跑。 P54. “Don't be afraid,” he said. “I won't let them hurt you.” “不要怕”他说。“我不会让他们伤害你们。” P55. He made the animals go away. 他让动物们离开。 P56. “You saved us, Stanley,” said the cavemen. “Thank you.” “你救了我们，斯坦利。”洞穴人说。“谢谢你。” P57. “Come back and live in our cave,” said one caveman. “回洞穴来住吧。”一个洞穴人说。 P58. “Cave are old-fashioned,” said Stanley. “Come and see where I live.” “洞穴都过时了。”斯坦利说。“来，看看我住的地方。” P59. He showed them his house. 他给他们展示他的房子。 P60. “A cave is for bears. A house is for people,” said Stanley. “洞穴是熊住的。房子才是人住的。”斯坦利说。 P61. “Yor are right, Stanley,” said the cavemen. “This is the way we want to live.” “你说的对，斯坦利。”洞穴人说。“这才是我们要居住的方式。” P62. They all made houses. 他们都开始建房子。 P63. Stanley showed them how to paint pictures and plant seeds. 斯坦利给大家演示怎样绘画和种植。 P64. He showed them how to be nice to each other and kind to animals, and everybody was happy. 他给他们演示怎样对人友好，和对动物友善，每个人都很快乐。

The protein P53 could hold the key to tackling cancer. Much of what we know about it comes from the work of Professor Karen Vousden, Director of Cancer Research UK at the Beatson Institute in Glasgow. In Brainwaves, Pennie Latin discovers how Karen's career path led her into the world of cancer research.

Ann-Kathrin Eisfeld and Albert de la Chapelle describe how an oncogenic microRNA drives leukemia progression.

A multifunctional protein promotes acetylation and activation of the tumor suppressor p53.

A transcription factor protects the heart from radiation-induced damage.

Apoptosi o morte cellulare programmata (PCD) Dal greco απο- πτοσισ (separazione

In der Pathophysiologie des Schädel-Hirn Traumas unterscheidet man Primär- und Sekundärschaden. Der Primärschaden kommt durch die initiale Gewalteinwirkung zustande und kann therapeutisch nicht beeinflusst werden. Der Sekundärschaden setzt nach einer gewissen Zeit (Stunden bis Tage) ein, und führt zur Progression von Verletzung und neurologischer Dysfunktion. Apoptotischer Zelluntergang von Neuronen kann im Kortex von Patienten nach Schädel-Hirn Trauma nachgewiesen werden und stellt möglicherweise eine Ursache für die sekundäre klinische Verschlechterung dar. In der Regulation der neuronalen Apoptose besitzt p53 und NFкB eine Schlüsselfunktion. P53 kann als übergeordnetes Steuermolekül den Zelluntergang initiieren, NFкB kann durch Transkriptionssteigerung von anti-apoptotisch wirksamen Proteinen möglicherweise den neuronalen Untergang verhindern. Die vorliegenden Arbeit untersucht die Rolle der Wechselwirkung von p53 und NFкB für den sekundären Hirnschaden nach Trauma. Nach experimentellem Schädel-Hirn Trauma der Maus nach dem Modell des Controlled Cortical Impact nimmt dass das Kontusionsvolumen nach initialer Verletzung des Mauskortex durch einen pneumatisch getriebenen Kolben, innerhalb von 24 Stunden sekundär um bis zu 60% zu. Dies geht einher mit einer gesteigerten kortikalen p53-Expression: Western Blot-Analysen von Hirnlysaten zeigen, dass es im Bereich der Kontusion und des eng benachbarten unverletzten Kortex bereits 15 Minuten nach Trauma zum signifikanten Anstieg der p53-Expression kommt. Dieser Anstieg ist über 24 Stunden nachweisbar. Immunhistochemische Analysen von Hirngewebe nach Trauma zeigen weiterhin, dass p53 selektiv im Bereich der Kontusion sowie im perikontusionellen Hirngewebe akkumuliert. Die Hemmung von p53 durch Pifithrin kann den sekundären Hirnschaden signifikant um bis zu 60% reduzieren. Bemerkenswert ist hierbei die Tatsache, dass eine einzelne Applikation bis zu sechs Stunden nach Trauma neuroprotektive Wirksamkeit besitzt. Die vorliegende Arbeit zeigt weiterhin, dass es nach Trauma zum signifikanten Abfall der NFкB- Transkriptionsaktivität kommt. Inhibitorische, p53-abhängige Effekte auf die Transkriptionsaktivität von NFкB sind bekannt. Hierbei spielt die kompetitive Bindung beider Transkriptionsfaktoren an den aktivierenden Kofaktor p300 eine Rolle. Die Untersuchung der NFкB-Transkriptionsaktivität unter p53-Inhibition mit Pifithrin zeigt, dass es zum signifikanten Anstieg der, ohne Therapie, supprimierten NFкB-Transkriptionsaktivität nach Trauma kommt. P53-abhängige Effekte auf den Sekundärschaden nach Trauma involvieren somit neben der p53-abhängigen Expressionssteigerung pro-apoptotischer Zielgene die Inhibition NFкB-vermittelter, endogener, neuroprotektiver Mechanismen.Die Inhibition von p53 durch Pifithrin stellt einen viel versprechenden Ansatzpunkt in der Therapie nach Schädel-Hirn Trauma dar, die bei guter Verträglichkeit, einem klinisch relevanten therapeutische Fenster und vielfach belegter zerebroprotektiver Wirksamkeit viel Potential besitzt

Visit the lab of Hunter College's Jill Bargonetti, a biologist researching cancer. Her team studies P53, a natural tumor-suppressor protein found in our bodies with a Dr. Jekyll and Mr. Hyde personality.

Zusammenfassend bleibt festzuhalten, dass bei der P53-Expression als Zeichen einer Gen-Mutation eine fortgeschrittene Infiltration als auch eine zunehmende Entdifferenzierung des Urothelkarzinoms mit der Rezidivrate positiv korreliert. Aus der signifikanten und nachweisbaren Auftritthäufigkeit des Tumor-Suppressor-Proteins P53 in dem Übergangszellkarzinom der Blase und der nachgewiesenen positiven Korrelation zwischen Tumor-Stage und –Grade mit der Rezidivhäufigkeit und der Tatsache, dass die BCG/Mitomycin-Therapie mit der Rezidivrate nicht korreliert, kann man einen effizienten Nutzen bei der Auswahl eines adäquaten Therapieverfahrens insbesondere in der Gruppe häufig rezidivierender PTa/PT1-Karzinome ziehen. Dass der prozentuale Anteil der P53 mit der Rezidivhäufigkeit nicht korreliert, bestreitet aber nicht die schlechte Prognose der P53-Überexpression in den fortgeschrittenen Tumorstadien. Die Tatsache, dass die Tumorpatienten ohne nachweisbaren P53-Marker den höchsten Anteil an Rezidivfreiheit zeigen, lässt die Beurteilung der Tumorprognose auf eine möglichst breite Basis stellen, was die ärztliche Therapieentscheidung mit ihren weitreichenden Konsequenzen für die Lebensqualität des Patienten erheblich erleichtern könnte.