Podcasts about Paclitaxel

"It's not entirely unique to IR, but it's something that's encountered more because it is so fast-moving, and it's what kind of drew me into the specialty. But having done this project has given me a new perspective on the importance of good, quality research and engaging with it."—Hayley Briody, MB, BCh, MSCIn this Journal of Vascular and Interventional Radiology (JVIR) audio episode, lead author Hayley Briody, MB, BCh, MSC, speaks with journal Managing Editor Ana Lewis about her October 2024 paper, Mortality, Safety, and Effectiveness of Paclitaxel-Containing Balloons and Stents in the Femoropopliteal Artery: Systematic Review and Meta-Analysis of Randomized Controlled Trials since 2018."Related resources:Read the original article, "Mortality, Safety, and Effectiveness of Paclitaxel-Containing Balloons and Stents in the Femoropopliteal Artery: Systematic Review and Meta-Analysis of Randomized Controlled Trials since 2018," by Haley Briody, MB, BCh, MSc; Conor A. Kearns, BA (Mod), MSc, MRes; and Michael J. Lee, MB, BCh, MScRead the related commentary, "Paclitaxel Meta-Analyses in the Lower Limbs: Missing the Trees for the Forest," by Konstantinos Katsanos, MD, PhDContact us with your ideas and questions, or read more about about interventional radiology in IR Quarterly magazine or SIR's Patient Center.(c) Society of Interventional Radiology.Support the show

This recording features audio versions of October 2024 Journal of Vascular and Interventional Radiology (JVIR) abstracts:Mortality, Safety, and Effectiveness of Paclitaxel-Containing Balloons and Stents in the Femoropopliteal Artery: Systematic Review and Meta-Analysis of Randomized Controlled Trials since 2018 ReadEffect of Filtered Blood Return on Outcomes of Pulmonary Aspiration Thrombectomy ReadThe Predictive Value of Qanadli and Miller Index Scores in Patients with Intermediate-High–Risk and High-Risk Pulmonary Emboli Undergoing Aspiration Thrombectomy ReadImageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial ReadMagnetic Resonance Imaging–Guided Cryoablation of Prostate Cancer Lymph Node Metastasis ReadCorrelation of Ablation Volume with Renal Function Loss after Cryoablation in Solitary Functioning Kidneys ReadIntra-arterial Pressure-Enabled Drug Delivery Significantly Increases Penetration of Glass Microspheres in a Porcine Liver Tumor Model ReadJVIR and SIR thank all those who helped record this episode:Host:Manbir Singh Sandhu, University of California Riverside School of MedicineAudio editor:Sonya Choe, University of California Riverside School of MedicineAbstract readers:Melissa Millett, MD, Southeast HealthSonya Choe, University of California Riverside School of MedicineAlena Khalil, Nova Southeastern University Dr. Kiran Patel College of Osteopathic MedicineAndrew Brandser, Frank H. Netter MD School of MedicineMark Oliinik, Loma Linda University School of MedicineDaniel Roh, Loma Linda University School of MedicineMillennie Chen, University of California Riverside School of MedicineSupport the showSupport the show

The use of drug-coated balloons (DCBs) for peripheral arterial disease has been controversial in the past. However, new data and updated FDA guidance have helped these devices regain popularity. In this episode of the BackTable Podcast, Dr. Ally Baheti hosts a discussion with Dr. Sahil Parikh, an interventional cardiologist in New York City, and Dr. John Park, a vascular surgeon in Omaha. --- CHECK OUT OUR SPONSOR BD Lutonix https://www.bd.com/en-us/products-and-solutions/products/product-families/lutonix-drug-coated-balloon-pta-catheters --- SYNPOSIS They review the historical controversy surrounding the potential late-mortality risks associated with Paclitaxel-coated devices, discuss more recent literature on the safety and efficacy of DCBs, and examine the implications of the FDA's updated guidance in 2023. This update was made possible through collaborative efforts across specialties and regulatory bodies to establish best practices for vascular interventions. They also delve into patient selection criteria, lesion characteristics, and practical considerations for choosing between DCBs and other revascularization options. Each provider shares their treatment algorithm for DCB use in peripheral arterial disease. Dr. Park uses DCBs as a first-line treatment for patients with complete occlusions, CLTI symptoms, or lifestyle-limiting claudication, with adjunctive stenting sometimes required afterwards. In his experience, DCBs work best in lesions shorter than 100 mm and are preferable in locations where stenting is not feasible, such as across the knee joint. Dr. Parikh similarly prefers DCBs over plain balloon angioplasty and places stents in longer lesions. He notes that Hunter's canal is a challenging area to treat with DCBs alone and may require atherectomy or intravascular lithotripsy. He recommends considering drug-eluting stents as a proactive measure to prevent more costly interventions for future restenosis. --- TIMESTAMPS 00:00 - Introduction 02:14 - History of DCB and Controversy 07:46 - Updated Research and 2023 FDA Guidelines 16:44 - Importance of Collaboration and Patient Preference 26:34 - DCB Treatment Algorithms 33:31 - Drug-Eluting Stents 35:46 - Approach for Patients with Claudication 37:22 - DCB Sizing and Dose --- RESOURCES Risk of Death Following Application of Paclitaxel‐Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials (2018): https://www.ahajournals.org/doi/10.1161/JAHA.118.011245 FDA- Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality–Letter to Health Care Providers (2018): www.fda.gov/medical-devices/letters-health-care-providers/update-treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel-eluting FDA- Paclitaxel-Coated Devices to Treat Peripheral Arterial Disease Unlikely to Increase Risk of Mortality - Letter to Health Care Providers (2023): https://www.fda.gov/medical-devices/letters-health-care-providers/update-paclitaxel-coated-devices-treat-peripheral-arterial-disease-unlikely-increase-risk-mortality Mortality in randomised controlled trials using paclitaxel-coated devices for femoropopliteal interventional procedures: an updated patient-level meta-analysis (2023): https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02189-X/abstract

BUFFALO, NY- July 10, 2024 – A new #editorial paper was #published in Oncotarget's Volume 15 on June 20, 2024, entitled, “Targeting ABC transporters in PDAC – past, present, or future?” In this new editorial, Cecilia Bergonzini, Elisa Giovannetti and Erik H.J. Danen from Leiden University discuss targeting ABC transporters in pancreatic ductal carcinoma (PDAC). Despite its lower incidence as compared to more common cancers such as lung or breast carcinomas, PDAC ranks as the third leading cause of cancer mortality in the US and the sixth worldwide. This is due to the fact that PDAC survival rates are among the lowest for cancer patients, around 13% in the US. ATP-binding cassette (ABC) transporters represent a family of transmembrane proteins that, using the energy from ATP hydrolysis, extrude molecules from the cytoplasm to the exterior or into vesicles. Some of these transporters have been associated with resistance to a spectrum of structurally diverse chemotherapeutic drugs, earning them the name of multidrug resistance (MDR) pumps. One of the best-characterized ABC transporters is ABCB1 (MDR1). It is physiologically expressed in tissues such as kidney, liver, pancreas, intestine, the blood-brain barrier, and more, where it exerts a protective role, by extruding xenobiotics and potentially toxic molecules. Moreover, increased ABCB1 expression in tumors has been associated with poor prognosis. “Paclitaxel is a bona fide substrate for ABCB1 [18] and ABCB1 has been implicated in paclitaxel and nab-paclitaxel resistance in multiple types of cancer [19, 20]. Could ABCB1 represent a therapeutic target in PDAC patients to suppress resistance against GnP? We have recently reported that ABCB1 can indeed play a critical role in paclitaxel resistance in PDAC cells [21].” DOI - https://doi.org/10.18632/oncotarget.28597 Correspondence to - Erik H.J. Danen - e.danen@lacdr.leidenuniv.nl Video short - https://www.youtube.com/watch?v=safa58X8NMY Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28597 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, PDAC, chemoresistance, ABCB1 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

In this episode of Cardiology Digest, we delve into three pivotal papers to help us navigate modern cardiology and patient care strategies.  STUDY #1: First, we explore findings from a Swedish study that questions the blanket application of beta-blockers after an acute myocardial infarction in patients with normal left ventricular ejection fraction. Are we witnessing the end of an era in how we manage these patients? The complexities and nuances of this study are thought-provoking!  Yndigegn, T, Lindahl, B, Mars, K, et al. 2024. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med. 15: 1372–1381. (https://doi.org/10.1056/NEJMoa2401479) Steg, PG. 2024. Routine beta-blockers in secondary prevention—On injured reserve. N Engl J Med. 15: 1434–1436. (https://doi.org/10.1056/NEJMe2402731) STUDY #2: Next, the integration of artificial intelligence in healthcare takes center stage, with a groundbreaking approach that uses AI in combination with routine chest x-rays. Could this offer a novel way to assess elevated risks for major adverse cardiovascular events, especially in settings where detailed clinical data might be lacking? The implications could transform patient screenings and prognostic assessments. Weiss, J, Raghu, VK, Paruchuri, K, et al. 2024. Deep learning to estimate cardiovascular risk from chest radiographs: A risk prediction study. Ann Intern Med. 4: 409–417. (https://doi.org/10.7326/M23-1898) STUDY #3: Lastly, we'll look into an exciting advancement in interventional cardiology with the introduction of drug-coated balloons. Fresh from their recent FDA approval in March of this year, these innovative devices represent a significant breakthrough for treating patients with in-stent restenosis, especially those who haven't responded well to multiple drug-eluting stents. Yeh, RW, Shlofmitz, R, Moses, J, et al. 2024. Paclitaxel-coated balloon vs uncoated balloon for coronary in-stent restenosis: The AGENT IDE randomized clinical trial. JAMA. 12: 1015–1024. (https://doi.org/10.1001/jama.2024.1361) Kundu, A and Moliterno, DJ. 2024. Drug-coated balloons for in-stent restenosis—Finally leaving nothing behind for US patients. JAMA. 12: 1011–1012. (https://doi.org/10.1001/jama.2024.0813) Join us to explore the potential impacts of these studies, the ongoing debates they spark within the cardiology community, and to see how these findings could influence your clinical decisions. Learn more with these courses: Chest X-Ray Essentials (7 CME) Chest X-Ray Essentials Workshop (1 CME) Get a Basic or Pro account, or, get a Trial account. Show notes: Visit us at  https://www.medmastery.com/podcasts/cardiology-podcast.

LATE BREAKING CLINICAL TRIAL: Paclitaxel-Coated Balloon Versus Uncoated Balloon for Coronary In-Stent Restenosis – Primary Outcomes from the Full Population of the AGENT IDE Trial

Cancer therapy has come a long way from its one-size-fits-all beginning to the awakening era of personalized medicine. This change has been largely driven by the discovery of biomarkers. Biomarkers can help refine patient selection for specific therapies. A blend of causal and correlative approaches is needed to elucidate the full potential of biomarkers in cancer research. This fusion of methodologies allows for a comprehensive exploration of biomarker efficacy, leading to more accurate predictions of drug response. In a new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from the Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México discuss causal and correlative approaches to identify potential biomarkers for predicting response to paclitaxel — a commonly used chemotherapeutic agent. On February 8, 2024, their research perspective was published in Oncotarget's Volume 15, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.” “[…] studying the combination of non-overlapping biomarkers' expression, in addition to clinical and sociodemographic data could generate predictive models for paclitaxel susceptibility.” Full blog - https://www.oncotarget.org/2024/03/28/identifying-biomarkers-for-predicting-paclitaxel-response/ Paper DOI - https://doi.org/10.18632/oncotarget.28549 Correspondence to - Crismita Dmello - crismita.dmello@northwestern.edu, and Adam M. Sonabend - adam.sonabend@northwestern.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28549 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, glioblastoma, predictive biomarker, CRISPR screen, paclitaxel 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

Editor's Summary by Kristin Walter, MD, MS, Deputy Editor of JAMA, the Journal of the American Medical Association, for the March 26, 2024, issue.

Commentary by Dr. Valentin Fuster

BUFFALO, NY- February 21, 2024 – A new research #perspective was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.” As discussed in this new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. “To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680).” The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations. “Precision and personalized medicine can lead to a transition from a stochastic treatment response into predictable scenarios. Further identification of predictive biomarkers, validation, and study of combinations as predictive models is critical to generate a greater impact that can be translated to the bedside of patients.” DOI - https://doi.org/10.18632/oncotarget.28549 Correspondence to - Crismita Dmello - crismita.dmello@northwestern.edu, and Adam M. Sonabend - adam.sonabend@northwestern.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28549 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, glioblastoma, predictive biomarker, CRISPR screen, paclitaxel About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Rick Greene, MD, discusses with Susan Tsai, MD, MHS, the results of an analysis examining the efficacy of second-line gemcitabine/nab-paclitaxel (GnP) after first-line FOLFIRINOX in the neoadjuvant setting among patients with operable pancreatic cancer who were treated with a total neoadjuvant approach. Dr. Tsai is the senior author of, “CA19-9 Response to First-line Neoadjuvant FOLFIRINOX and Second-line Gemcitabine/nab- Paclitaxel in Patients with Operable Pancreatic Cancer.” Dr. Tsai is Professor of Surgery and Chief of the Division of Surgical Oncology at The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Primary Outcomes of a Pivotal Multicenter Randomized Trial Comparing the AGENT Paclitaxel-Coated Balloon with Conventional Balloon Angioplasty for In-Stent Restenosis

In this powerful episode, Tim talks with Debbie Potts of DAP VA Limited about her inspiring story of resilience. Debbie describes how she kept her dreams alive by keeping her anchor or north star in view at all times, even while adapting to remote work during the pandemic, battling ovarian cancer (twice!), and navigating the chaos of moving to a new country. Her tenacity, vulnerability, and never-ending positivity will both inspire and motivate any listener who needs encouragement to pursue their dreams without letting obstacles get in the way or define them. Debbie's story shows listeners how powerful you can be when you advocate for yourself, discover your goals, and trust your instincts. Tim shares the main lessons he's learned from working directly with Debbie and following her achievements, including how to keep your vision clear, break down impossible tasks into manageable pieces, and keep your momentum going against the odds. You'll learn about the importance of positivity and a little bit of Swedish coffee culture along the way. About Debbie Potts | Founder of DAP VA LimitedDebbie Potts is the entrepreneurial force behind DAP VA Limited, where she stands as an Online Business Manager and Executive Virtual Assistant. With a rich tapestry of experiences spanning over three decades in the corporate legal sector and educational management, Debbie's multifaceted expertise is matched only by her grounded, go-the-extra-mile ethos and her passion for the Swedish concept of 'fika'—taking a break to savour coffee and company.Debbie's philosophy centers around the notion that exceptional business support should be within reach for every entrepreneur and business owner. She extends this support across the globe, offering services that include website redesign, social media enhancement with a particular knack for leveraging Pinterest for Business, and comprehensive executive assistance—all tailored to help her clients reclaim precious time.Beyond her professional endeavours, Debbie dedicates her energy to advocating for two cancer charities. As a survivor herself, she generously shares her journey to uplift others and advance the mission of these organizations, which provide crucial support to those touched by cancer.Resources discussed in this episode:Working Genius - Patrick LencioniVA Mastery Course - Amanda JohnsonMacmillan Cancer SupportDebbie's Story on The Royal Marsden Cancer Charity WebsiteBBC Interview Highlighting Challenges of Cancer Patients During the Cost of Living CrisisIndividualism vs. Teamwork with Rita Ernst Part 1 (Apple)Individualism vs. Teamwork with Rita Ernst Part 2 (Apple)Individualism vs. Teamwork with Rita Ernst Part 1 (Spotify)Individualism vs. Teamwork with Rita Ernst Part 2 (Spotify)--Contact Tim Sweet | Team Work Excellence: WebsiteLinkedIn: Tim SweetInstagramLinkedin: Team Work ExcellenceContact Debbie Potts | DAP VA: WebsiteLinkedin: DAPVA--Transcipt:Debbie 00:01We need to believe that we are stronger than we think. We are more resilient than we think. And we absolutely can achieve. Yes. It's hard as you said, yes, the trajectory to the dream is tough. And I was pushed down that mountain 1000 times that I got up, I kept going. So it isn't so much about failing, because I did. But it's how do you pick yourself up after failing?Tim 00:31I'd like to ask you some questions. Do you consider yourself the kind of person that gets things done? Are you able to take a vision and transform that into action? Are you able to align others towards that vision and get them moving to create something truly remarkable? If any of these describe you, then you my friend, or a leader, and this show is all about an all for you. Welcome to our 20th episode, this is the Sweet on Leadership podcast. Tim 01:04Hey, everybody, welcome back to Sweet on Leadership. Thank you very much for joining me, I am absolutely over the moon to be talking and bringing to you one of the most amazing spirits that I have encountered on this planet. She is somebody that I have a great deal of love for. I never knew when we met how much I would jive with you and how much I would feel an immediate connection with you. And I really just can't wait for everybody else to experience a little bit of Debbie because it's the vitamin D and never knew you needed. And that's coming at you today. So welcome Debbie Potts, to this podcast. And thank you so much for taking the time to join me and sharing your amazing story. Debbie 01:49You're welcome, Tim. And thank you for inviting me. This is amazing. And yeah, I jive with you, too. So it's, it's mutual. And I have a lot of love and respect for you, too. So great. Let's let's do this. Tim 02:04Oh, yeah. So Debbie, I'm going to ask you to introduce yourself, let people know what you're all about. And then I've got some really big curiosities as we talk about your journey. And so yeah, please let everybody know who you are. Debbie 02:19Oh, sure. My name is Debbie Potts, as Tim said, and I am the director of a virtual assistant business, which is a business based in the United Kingdom. And registered in the United Kingdom. I serve my clients in all sorts of ways I provide services, to help them run their businesses, I do social media for them, I've fixed their websites, I redo their websites. Basically, I turn my hand to anything. I really plus myself as not only a business owner, but also a survivor and a conqueror of two-time ovarian cancer. So for me, that's kind of my biggest achievement. It doesn't define me, but it is something that has made me who I am today, and I'm so happy to join you. Tim 03:07I appreciate it. And in case you're wondering, dear listener, Debbie helps me all the time, and she's brought an entirely new level of control, and he's around my own business. But that's not why we're here. Today, we're not to talk about the power of an amazing assistant, although that is something we're going to get into. And I don't even think of it as an assistant, I think of a power of an amazing collaborator who rounds off your edges and supplements, your leadership style or your business in ways that you can't even imagine. Okay, that's part of it. But let's talk about the journey I'd love you to, to lead us into the story of The Red House. And I think for all of the leaders that are listening, this is an amazing parable around or amazing example of what happens when you set a vision and you achieve it and how it can have what I see from the outside being a profound effect on a person's trajectory. Notwithstanding Yeah, notwithstanding the the battles that you've been through, and I think that's part of the story. But the metaphor of the red house to me is just so inspiring. So that's what I'm really hoping that we can get into today. So could you give us a little bit of a background in terms of what the red house is, take us up to the lead-up of what was happening where you first had this dream. Debbie 04:36Okay, so basically my dream about living in a red house in the middle of the countryside near the forest and near the sea, started way back decades ago, really, when I first came to Sweden, and we took a trip into the countryside and I saw all these little red houses dotted around everywhere and the colour of these red houses is specific only to Sweden and it's called “Falu Röd” (Falu Red). So I had a dream to live in a follow red house. So there so at the time, Dan and I, my partner were living and working in London. And I thought, How on earth am I going to make this happen? I work in a school, I don't work remotely, I have to go to school every day. I can't, you know, work in London and live in a red house. It's just not going to work. What should I do? It was a lot, a lot of knockbacks. At first, I applied to many positions here in Stockholm thinking, Okay, I'll just change my job. But of course, not speaking the language was a big sort of negative. So every job that I applied for was a “no.” Tim 05:49Just to back us up. When did you have this vision? What year was that?  Debbie 05:54Oh, my gosh, that would have been 2009.  Tim 05:552009? Debbie 06:02Yes. The way I sort of drifted was after my visit to Sweden, I went back home and I printed a picture, any picture Tim of any red house, and I stuck it on the wall above my computer. And obviously, I would look at this, whenever I came to sit at my computer, I would see this. And it would just keep sort of the cogs turning. Okay, so how do I turn that picture into a reality? First, was job so that I could work in the country that I want to live. Second was, while I need money, houses don't fall from trees? Yeah, I've got to have some money. And of course, I'm working with my partner, Dan, on this dream. So you know, we decided to for now do sort of a feasibility study and look at where could we possibly live? Because a dream can only become reality to me when I physically see the possibility rather than think it or see it virtually. Tim 07:08In the late 2000s, you start to think of this. And you when you put these pictures out behind your computer as a bit of a vision board, you're approaching it practically you're not approaching it with a distant dream, you're bringing it close saying, ‘Where could this exist?' The default being Sweden, obviously. Debbie 07:28Absolutely. And I did have that dream aspect as well. I mean, I would go to sleep dreaming about The Red House, I would talk about it at work with my colleagues, I would talk about it with my friends and family. So and that's all I was obsessed by. Everybody kind of knew, ah, what does Debbie want? She wants to live in a red house that's been known for years. Tim 07:49So the red house was this picture, this avatar for something. What did the Red House represent to you?  Debbie 07:56Oh my gosh, it represented freedom, it represented achievements. It represented living life on my terms. And obviously, I love nature, as you do. And it just represented, you know, being able to be close to nature and, you know, completely do a 180 turnaround of my life. You know, I lived in a big city, London, full of people full of traffic full of everything. And I've now completely reversed that. And you know, I've told you about this before in our conversations, there's, you know, this little village I live in, there's 10 plots, but only eight houses. And that's us.  Tim 08:40And eight families that are collectively a community. When you think about that, then the red house was such a clear delineation, was such a clear, step off what you knew. It there was a polar opposite from that perspective. I do remember you sharing with me at one point, the red house was just a representation, and you'd identified all of those outcomes you were looking for. That could have manifested in a bunch of different ways. Right? You could have found nature somewhere else, you could have found peace somewhere else. Debbi 09:12Yea, but it also was my love of Sweden anyway. And because I love the country, and because, you know, so it was a whole mind shift change, because not only did I have the picture of the red house above my computer, but I also enrolled myself in London to have Swedish lessons. So then I could start learning the language. Okay, so sort of ticking off all the things that I needed to do for myself to be able to achieve this dream.  Tim 09:42So you were putting in the small things in place. Debbie 09:45All the little bits and pieces. Yes.  Tim 09:49Okay. So, late 2000. You're coming up with these plans. You've got this vision, you're starting to tick off the small items. What happened then what was the next thing that happened? Debbie 09:59It just became an impossible dream. If I'm honest with you, if I'm genuinely honest. Yeah, prior to the pandemic, it became an impossible dream.  Tim 10:09It was never gonna come close.  Debbie 10:10No, I could not see myself finding a job that would, you know, give me enough money to achieve this dream, nor could I see myself finding a job in Sweden and then achieving the dream. Tim 10:23The clarity around it started to take you farther away from it. The reality starting to pose, you know, real concrete frictions with your current life. Okay, all right, so, so you went through these exercises, then you faced this hero's journey of now the challenge was starting to appear as impassible. Debbie 10:46Absolutely.  Tim 10:47This is pre-pandemic. And pre-battle with ovarian cancer.  Debbie 10:54Pre-battle. I was healthy, Debbie, you know, working living in London enjoying life. And what I decided to do was I thought, okay, I'm not going to give it up totally. Because it's, you know, when you really want something, and you just are not prepared to kind of compromise or give it up. I thought, okay, these battles are here for now. Let me just plod along with my work. And you know, think about how do I overcome this obstacle of living in London, but I really need to be in Sweden? And there's a lot of little things you've got to do. I had to research, how do I get a Swedish visa? How do I you know, legally, all of these other little things? How do I get a bank account? How do I do this? So I thought, let's just do those little things. I started a spreadsheet and, I'm a spreadsheet queen, and honest, I had all the things I needed to achieve with a box, you know, tick off, okay, that done and then notes on the side that tell me, okay, so for a visa, you need to do this da-da-da-da-da. And I just sort of left that slide and kept going. I also subscribed to a property selling website marketing site, and they would just, yeah, I'd just look every morning. That's the first thing I did. I didn't check my work emails, I didn't do anything, I would just spend 15 minutes looking to see what's on the market.  Tim 12:18So, even though part of your conscience was telling you that this is not gonna, let's say the logical part of your brain is fighting you, saying this is not logical use that okay, broke it down to the little tasks, you know, you could action. And I mean, for any of you who've worked with me on Working Genius, which is Patrick Lencioni's new piece. This is very clearly the genius of tenacity, right? It's pulling things into manageable chunks that we then are going to accomplish, Debbie 12:50But also not giving up Tim. Because lots of people give up. And they just say okay, it's not gonna happen and they shelve it. Tim 12:58And where you disaggregated it down to its constituent parts that could start, instead of going for that great big island off in the distance. You swam to this sandbar, and then this sandbar, and then this sandbar, and slowly the island is coming a little closer and a little closer.  Debbie 13:17That's right, yeah. And in English, the saying, you know, I had all my ducks in a row. So I spent nearly five years putting all these little ducks in a row, you know, finding out okay, how, you know, what do I do to get a bank account? Okay, if we lived in this area, how far away is it from the airport? You know, in case I've got to travel back to London or anywhere, for that matter. How do we get broadband or internet connection to a house that's in the middle of the forest? What do I do? Tim 13:46I don't want to get into this too far. Because I think that's fodder for another conversation. But this is so you. I mean, this is what you do for me all the time. When I'm feeling, when I'm feeling overwhelmed. And I've got too many things on the goal. You're like, stop, Break it down. Let's get this into into the easiest thing you can do next, what's just the one easiest step you can take? Which is...  Debbie 14:11Can I just add a little bit more, just so that we can get to the Red House now. Tim 14:16You got it, go for it.   Debbie 14:17So far, all of this happened and I sort of like okay, I'll just do these bits and find out so that I'm totally prepared. If and when they're… not even if, when the time comes. So fast forward to 2020. 2020 Okay, it's 20th of March 2020. The whole of the UK shut down completely. And I was like, oh, now I have to work from home for my school. This is great for me who absolutely loves tech, and absolutely loves working from home. Now my red house popped up front and center because it's, I soon clocked on that, oh my god, if I can work from home for my school, I can work from anywhere. This is it, I got my answer. It's, it's that's it, I got my answer. So in the middle of the pandemic, I decided, okay, I had a conversation with my executive head. And I said to her, Would you be happy? They knew I go to Sweden, you know, six, seven times a year, would you be happy for me to work remotely, from Sweden, for the schools? I supported four schools at the time. Of course, she said, “No, we need you here, Debbie physically.” So that's a no. So I thought, okay, what do I do then to make this remote working dream become reality? Since we're in a pandemic, people have now understood that you can work remotely globally, as you and I do. Yeah. And I decided, what job can I do that will allow me to be able to do this? And I researched, I Googled, I watched so many podcasts, or listened to so many podcasts, watched videos. And finally, yeah, why don't you be a virtual assistant on your own terms? So on the fourth of August 2020, during the pandemic, I started my own business. Tim 16:24You had to step away from your…  Debbie 16:27No, I did it simultaneously, because I needed the income. But I started because I don't know if my business is going to be a success. Of course, I'm going to put everything into it. But I thought, okay, I can do it on a part-time basis. I was lucky enough to have fantastic training, I found this amazing VA Mastery Course, with this lady called Amanda Johnson. I absolutely adore her.  Tim 16:48We can put a link to that. Debbie 16:50Yeah, totally. Yeah, I did her course. And that's what changed everything for me completely. It then made the steps to the Red House, achievable. And I knew it's gonna happen, there was absolutely not one iota of doubt in my mind that this was going to happen in the next two years. Tim 17:11Okay, so 2020, lockdown happens, suddenly we have this new reality of working remotely, and that opens a door that you're ready to step through. Debbie 17:21100% I stepped through it. My business did take off really well, which was great.  Tim 17:30Right, I remember that's when we met.  Debbie 17:32Yes, something had to give because I couldn't continue with my full-time school job, and run DAP VA limited. So I had to, in February of 2021, I then handed in my notice, and the period of notice I had to give was six months. So, I said to them, You know what, don't worry, I'll give you until the end of this academic year ie July 2021. And then I'm gone. Not only will I work full-time on my business, but I'll also be leaving the country to move to Sweden. So up pops another spreadsheet, because now I have to do all the removal costs and all that sort of you know, get the van or the lorry come and take all what will we be taking them since we are left Europe and and you know, Brexit happened. So we classed as a third country to Sweden, so I have to pay import charges, all of these things. Whereas before you could just literally drive your whole house to Sweden, and that would not be a problem.  Tim 18:34So what's amazing about this to me is you made this decision, the move starts the unhooking from life, as it was, begins. Although I mean, you still do have deep connection to London. Your Hill was getting steeper, not more shallow. I mean, Debbie 18:52Yeah. But it looks achievable to me. I don't know.  Tim 18:55Oh absolutely. It was achievable. What I mean is that the difficulty level went up. That didn't stop you. It wasn't as easy as it would have been a few years prior. But that didn't stop Debbie  Debbie 19:09That's true. This point actually, is spot on Tim, because a few years prior, I wouldn't need a visa nor would I have needed to pay all those 1000s of pounds in imports. Tim 19:19You had momentum at this point. And that inertia was carrying you up that change curve. That wasn't the end of your struggles.  Debbie 19:29No, not at all. So obviously, you know, the beginning or the first half, I'd say of 2021 I was working so hard with two jobs and being a school business manager is a stressful full-on job even though my contract was term time only. So I thought okay, you know, I will have vacation time or holiday time and I will work on my business during those times and I'll make it work somehow, Tim, I always make it work. So it was full of excitement, anticipation. If I could literally, you know, see and touch the dream. I'd set up house viewings for Dan and I to go, and you know, view all these beautiful houses. The next visit we had to Sweden. So it became it started becoming, you know, when you can just taste something and you just have a little taste. It's so nice. You want to eat the whole thing. That's what was happening. So we did all these house viewings, and we listed the our favorites and blah, blah, went back to the UK, started winding down, packed up all our stuff in boxes that we wanted to bring to Sweden. Found a company that was great that would come and pick it off from door to door. And literally, one day before we were due to fly to Sweden, or the move, I'd applied for my visa at this stage as well. And they said, Look, you can come to Sweden anyway, even if it's isn't quite granted yet. Because, you know, you can stay on the 90-day rule that the UK nationals are allowed to stay in Sweden for 90 days per year. And your visa should come during that time. So it all was good. So you can come now, I was like, okay, great. Everything's great. One day, Tim, the fourth of August 2021. We had our British Airways flights booked on, on Thursday, the fifth of August, we were going to meet the removal van in Stockholm on Friday, the sixth of August. But on the fourth, I should just back up a week or so I went for what I thought was a routine scan and had the scan and left it and it usually takes about 10 days before you find out the results. I got a call from my GP on the fourth of August, saying the morning of, no sorry, she found me on the Monday. So that was the fourth was a Wednesday. She phoned me on the Monday and said, Debbie, I don't think you'll be going to Sweden. And I said now of course I'm going everything's sorted. We flying on Thursday. She said no, we have your scan and it's you have cancer basically. So I'm like “What? No,” she goes just to be sure. Let me do another scan. So I said okay, can you do it before Wednesday? Because I'm flying on Thursday. She said I really don't think you're flying. But yes, we'll see you on Wednesday. So still, I didn't believe it. Tim, I just thought nah, it's a mistake. And you know, these scans are misread sometimes. But anyway, I'll go on. I'll go on Wednesday. Yeah, so off, I went alone. Had a more detailed scan. First I had just a pelvic ultrasound. And then I said I can't wait for the results 10 days because I'm flying tomorrow. So can you just tell me what's on your screen? And he said, I remember the radiologist saying, see these dark clouds over here. And on both sides here. That's your left ovary. That's your right ovary, these dark clouds covering both ovaries. That's cancer. See these other dark clouds? That's your upper abdomen? Yep. See all how they floating looks like a skyline? That's cancer. You have cancer. Yeah, we don't know the staging yet. Because we've got to do more details. And I was like, oh, shock. I'm alone. What do I do? So I asked them, what would happen next? They said, Okay, we do an MRI, which is more detailed. And that will definitively tell us what's going on. So I asked if they could fit me in that afternoon. And they did. It was about 2:30. I had my scan on the fourth of August. After the MRI. straightaway. Yeah. Confirmed. So obviously I was a little bit. Yeah, I was in shock. I was numb. I was, it when I'm telling you this. Now it doesn't even feel like it's me I'm talking about, but it is me, though. I called Dan. I actually didn't even call him first. I called Dan's best friend. And his name is Anders. And I said, Look, I'm probably going to die. So I need you to take care of them for me. So can you do that? And at this point, I was crying. He couldn't even hear me. And I'm you know, so I just said, just promise me that you'll do this for me because, you know. It's important. Yeah, of course, whatever you do, blah, blah, blah. Then I phoned Dan. I told him, he came over straightaway to the hospital, along with my two daughters. And yeah, we just were a little bit in shock. The doctor came, spoke to us all. And it was at that point I knew well, we're not going to Sweden. So we went home and we played a board game and ate sandwiches. That's the first thing we did, which ,I don't like, I'll tell you why.  Tim 24:57That Red House that was so close. You could almost taste it. Debbie 25:00I was on my way.  Tim 25:02And you wanted more suddenly was suddenly like it was right there. And suddenly, it's just now thrust farther and farther away. It's not about the house. It's just that, you know, as the as a backdrop to your cancer journey, that you weren't going to Sweden.  Debbie 25:16Not at this time. Tim 25:18No, but you went home and you ate sandwiches. Debbie 25:20And played a board game. God knows why. Tim 25:22Played a board game. What happened next from now you're redoing all the math. This point was, Debbie 25:31No, I didn't even. Now I thought about life and death. So now my, my whole... Tim 24:33Your spreadsheet changed, now it had two columns.  Debbie 25:36I didn't even look at that for about a year. Actually. Tim 25:42If you know what I mean, is if you may have met one, it would have been pretty stark it would have been like, yeah, that's it.  Debbie 25:48Yea, so I just decided to, again, because I'm such a practical organized person. Okay, now death is coming. Let's get all my ducks in a row before I die. You know, so I need to do this, this, this, this and this. Okay, what should I do? Well, I didn't have a will, believe it or not. Okay, I need to get a well done. And even then, kind of, you know, Dan would say, Look, that's not priority. Right now, we need to see what can we do about this disease, we have an appointment in two weeks' time, everything in the UK is two-week wait under our national health system. And I said, I'm sorry, I can't sit here or lie here, knowing I have ovarian cancer and wait two weeks to hear how they can help me. Anybody at all who's had any kind of diagnosis of a terminal illness, it does not just cancer loads. You can't wait, Tim, two weeks and just stew over all the sooner you know, and the most dangerous thing is you go to Google and you start Googling. And Google is the worst thing you can do when you've been diagnosed, because the results it gives are not your results. They could be someone else's. And you know, you could be reading into it in the wrong way, which I did. I Googled how long can people with ovarian cancer live? And they, you know, maximum two years is what I was reading, and I'm like, Oh my God, I've got two years to live. No, I can't. Tim 27:21So you were literally Doom scrolling? Well, like without, we use the term Doom scrolling, like lightly now. But you were. Debbie 27:29Yea, I was.  Tim 27:30You were building up the doom. Debbie 27:31I decided to try and speed up things again, make it happen, you know, using my power. And I just woke up one morning, and after two days, I think from diagnosis, so this would have been a Saturday morning. I woke up at 5am. And I said, Dan, I'm getting dressed. I'm going to the hospital. He goes, baby, it's 5am Where are you going? I said, I'm just gonna sit there until I can speak to someone. I'm not waiting two weeks, I really can't. And that's exactly what I did. I woke up. He came with me. We'd sold our car as well by this time. So we because we were moving to Sweden, so we didn't have a car, got an Uber to the hospital. Tim 28:09And all your stuff is in a truck as well. Right? Debbie 28:10Well, it's in Sweden. It's already made the journey. We had to get Anders and other friends to come and offload for us. It was a nightmare, an absolute nightmare. And so at the hospital, I just waited. I went in there six o'clock, as soon as the oncology department opened, I just there was sort of seating just outside. And I sat there and waited for a staff member that came through. I'm like, I need to speak to someone right now. Tim 28:41Right? So you were advocating for yourself, you're advocating for knowledge for not being left in the lurch. And saying Debbie 28:48I'm also knowing, I need to know, you know, is this? You know, I know that there are so many advances in, you know, the treatment of cancer today, it's not as it was 20 or 30 years ago. It's far advanced. So I just want to know, will I live? Or will I die? Can you put a timeline on it? Or can you not? What's the deal? And so yeah, I did actually happen to speak to a really nice oncologist who looked at all my sort of notes and my scan results and everything. And he said, and this is where it got even worse. It's it. This looks so complicated. We actually can't treat you in this hospital. So we need to refer you to one of my colleagues. Her name is Angela. And she's, you know, the hospital just 20 minutes down the road. It's one of the best cancer research hospitals, certainly in the country and certainly in the world. And you'll be in good, good hands. I'm making you an appointment for Monday. So yeah, go go and see. No, no, he saw kind of the distress and then sometimes I'm Tim, you have to go with your feelings. You have to trust what you feel like doing rather than keep second-guessing yourself.  Tim 30:08Yeah, you weren't on anybody else's schedule. You weren't in anyone else's rules.  Debbie 30:12Yeah, I was on my own. Yeah. So that's another good sort of characteristic to develop because, you know best and you know how things should be. So yeah, I will just fast forward. I went to see Angela, Dan and I, it was our first time ever stepping over the threshold of a cancer hospital. Surprisingly, it was a lovely place. Even today, it's still my happy place. And saw Angela, she did more tests looked at me and said, Debbie, I'm so happy to tell you that we have developed a curative care plan for you and that word curative. I will never forget the emotion. The rush of emotion, our shoulders, both Dan and I, our shoulders dropped. We just breathed, exhaled a deep breath out. We both started crying. But smiling at the same time, because now I knew I'm not gonna die. So now I was... Tim 31:22Knew, not hoped.  Debbie 31:26Knew. 100% knew. Yeah, she said curative? While I was talking to Dr. Angela. George. I googled her just to see. And I saw that wow, this woman is, she's a kick-ass boss lady. I mean, she is like, head of genomics head of research. She's fabulous. She's known the world over. So when I saw her credential, I almost then and I still joke with her today I say, Oh my God, you're a goddess. She's from New Zealand. And I always say to her, I didn't see her for two weeks one time, and because she was on vacation, and when she got back, I was like, Oh my god. Dr. Jordan, I missed you. Where have you been? Oh, I went home to New Zealand. Ah, great. What did you do there? You know, my mom had a long list of chores for me to do. What? Does your mother not know who you are? You are Dr. Angela? Can I, I need to speak to your mom. You should be home eating grapes with somebody standing fanning you and you know caring to your every need and whim. And she's like Debbie, I'm a human being just like you are. Tim 32:27It's funny when I wouldn't give to hear Dr. Angela's perspective and perception of you through all of this. Man, that would be would be something to hear.  Debbie 32:38Yeah, I have heard it. Yeah, that's for another time. Okay. Anyway, so once she said that, and we knew both Dan and I, almost in unison, said, Okay, what should we do? Tell us what to do, and we will do it. And that was our mindset going forwards, even till today. It's tell us what to do. We'll do it. And of course, by they then you know, just to speed it up to them. Otherwise, we'll be here forever. She put a you know, six months chemo, followed by surgery, followed by monitoring tests. And basically, that's the plan. Yeah. And, you know, had all sorts of ups and downs during that time had nearly had my right leg amputated. I reacted badly to my first chemo drug. Paclitaxel, I'll never forget that I'm allergic to Paclitaxel. And on a scale of one to five, one being the not-so-bad. I'm a five. So basically, I passed out and woke up three hours or four hours later, with all these things attached my beautiful red dress split in half, because time was of the essence. So they have no time to, oh, let's not spoil her dress. And, you know, I'm here. I'm a fighter. I'm here. I'm resilient. Tim 33:54You gave yourself over to the process. That process was a curative process. That process was one more thing that you needed to do…  Debbie 33:59To achieve my red house. Tim 34:05To achieve this red house. Debbie 34:09So I had to also have some psychotherapy whilst I was being treated for cancer because, yeah, it's an aggressive cancer that I have and it's also an aggressive treatment for it. So, during my, one of my therapy sessions, I remember my therapist said, Debbie, you need an anchor, you need something to hold on to throughout this process. And we call it an anchor and that's going to anchor you and keep you steady. And so what is your anchor, and immediately I blurted out, The Red House. That's my anchor. I'm just going to live and fight this battle for the Red House. Of course you do it for your, you know, my beautiful partner, Dan, for my children, and for the grandson I didn't yet have at that time. So you know, I'm doing it for all of them. But I'm also doing it for the Red House. Tim 35:02And the Red House is so much more than just a building. I mean, it is an expression of everything that you were heading towards, what an optimum life looked like for you. I mean, often when we're doing, we're doing career, when I'm coaching, and we're looking at somebody's career, I ask them the question, “What is what is this all for? What's your future look like?” And when it comes to a job, I'll say, “What is the best day of the last year you're ever going to work look like?”, or the last year of your career going to look like, and then that's our North Star, that's the one that we're going towards. And this Red House was your North Star. Debbie 35:42It was indeed, it was indeed. But also it was place, because both Dan and I are very sociable people. We are gregarious we are. We love friends and family. And we said, we're not going to get a little red house that just fits us too. We're going to get a red house where everybody can come our friends, our family. It's just a place of community and socializing, and fun and laughing and enjoyment and love and sitting around the fight. It's all of that, Tim. So the red house is that red house, but it is a bigger vision than just the red house. Tim 36:22Let's maybe use this then to talk about and, and like not to gloss over this. You have still, you still had to battle. You've still had other aspects when it comes to the cancer journey. You are thankfully healthy now. But it has come at no small amount of effort, right? At the same time, you are now in the dream. You are, the dream is now reality. So give us a sense of what were the surprises? What were the surprises, the little things that this house has meant to you, that this new life has meant to you, that achieving this goal has meant to you? And also, perhaps the things that you never thought were going to happen that suddenly are realities. What does life look like now in the dream?  Debbie 37:06Oh, it's wonderful. I can't… I actually have another dream because I can't live without a dream. We always have to have a dream. But that's something else. I'll tell you at the end. Remember to ask me what my dream is now. It's wonderful. I really cannot stress enough how as human beings, we need to believe that we are stronger than we think we are more resilient than we think. And we absolutely can achieve. Yes, it's hard, as you said, Yes. You know, the trajectory to the dream is tough. And you know, I was pushed down that mountain 1000 times, Tim. But I got up. And I kept going. So it isn't so much about failing, because I did. But it's how do you pick yourself up after failing? Do you hold on to that North Star, that anchor? What do you do? And that's exactly what I did. I held on and held on. And you know, I made sure I shared my dream with everybody. I came in contact with Dr. Georgia. And when I had my second, my recurrence, my cancer came back after five months of being clear. And she knew I had this dream. And she said, Debbie, don't get the stress because we can we can treat this by surgery. So look at this as a big boulder in you, going along the road to your dream, all of a sudden a boulder comes and gets in your way. What do you do? Just go around it and then continue. So that's what we're going to do. We're going to go around the bouider and put you back on your road. And yeah, again, you know, that was so close, Tim. We came back in June of 2022. After being given the all-clear. We were here for days, the surgeon in London phoned and said I'm sorry, we your scan you had two weeks ago showed two masses one, seven and a half centimetres, one three and a half centimetres. Do you need to come back? For days, Tim? Yeah, I went back and then in February of this year, it all came to be I didn't wait for the all-clear. I made an arrangement with my hospital in London that, you know, I'll come back every three months for treatment and tests and scans. So in February, we looked at 13 houses in two days. And it's a big area that we had to cover. Everything is like 30-40 minutes apart. And we looked at thirteen. I actually got sick from looking at so many, all the houses and then went back to London and packed up the few things that we could now bring with us. By this time we bought another car so we packed the car up, drove to Sweden from London with our stuff, put an offer into the house that we saw, which was this one. It was accepted by the lovely Gustaf, who is the developer, and he built this house with his own hands. And when we finally met, we shared our story with him. He started crying, we started crying. He goes, as I was building this house, I was hoping that it would go to someone with love and who saw it for what it was. And he goes... Tim 40:19He had no idea.  Debbie 40:21Yea, he had no idea it was for me or for us. He even said I was going to paint it white because I'd ordered the red paint. And then I thought,  no, all the other houses are white, I need to paint this one white. So you phoned the company where he ordered the paint from and said, look, can I change from red to white? And the company said, sorry, no, we've already mixed your paint for you. It's coming. So he said oh, okay, don't worry, I'll just paint it red. How about that? Tim 40:52Well, it's, you know, we can talk about serendipity for sure. But I'm sure Gustaf, he had no idea of when he was looking for somebody that would love that house, just how much meaning it would represent. Debbie 41:04Oh, he said that. And we actually invited him back after we'd moved in and, you know, changed things. That garden was developed. And it's now furnished, and it's got our stamp on it. And he came over, and again, he was filled with tears. And he's like, this is exactly what I had in mind that you would do in this room when I built it. This is how I, you know, our open plan kitchen and living room has a Fika area. Remember Fika? Very important. He actually said I want this to be the heart. And where we all gather? And for sure, Tim, everything happens in the Fika area. Tim 41:41Yea, and Fika, for those that don't know, what's the word? Debbie 41:44Fika is the art of Swedish coffee, drinking, where you go, you take time to be in the moment with friends, colleagues, family, whoever, no electronics, nothing, you just are present, and enjoy each other over a cup of coffee or tea, and a bun or a sweet treat. Tim 42:03I think I think that's really interesting to think I see you living always in two zones, you were very clear about what your vision was. But you didn't step too far away from the moment. Because you were always working. You were always working in the moment you worked. Not in somebody's two-week timeframe. But you said no, I gotta go advocate for myself, and you did. And then and then everything for you has been a balance between things being far away and having that Northstar, but then doing what makes immediate sense in order to leverage the situation that's in front of you. Debbie 42:39But I think it all circles back to what you said in the very beginning. You know, the Red House signifies this dream or vision or lifestyle that I wanted to have. And without that clear, definitive dream or vision, I don't feel I could have achieved it. So if I've said, Well, I could live in a red house, maybe a green one would do. Oh, I don't mind if it's close to the city or, you know, maybe it can just be in a field. I'm so sort of wishy-washy. Tim 43:11But but in this case, you did not compromise.  Debbie 43:15No, it was a definitive kind of vision where it had to be. And the picture said it all I wish I knew whose house that was, but it was, you know, close to water with the forest. There, right there and clearly in the countryside. And that is that's how I wanted to live. Yeah, Tim 43:33Yea, it will be a question whether or not that was predetermined? Or if that is something that you made the most likely most statistically possible.  Debbie 43:44I think it's a bit of both. Yeah, I think it's a bit of both because I believe this is my path. And you know, throughout it, I didn't sort of say I'm the cancer person, even though I introduced myself as that. But I always do put a caveat that cancer has never defined me, I still worked on DAP VA limited during my chemotherapy, I'm in the hospital. And, you know, I still did all the things I could do until I couldn't. And when I couldn't I took an eight month break because I had to focus on my recovery and beating this disease. But as soon as I was able to, I came back, and here I am. I've been working ever since. Tim 44:24And it's a life without compromise in many ways, is what I see, like there's of course you make small adjustments. But would you say that through all this, your ability to yes, both flow with things and move around the boulders as you need to. That's a skill that you've obviously developed but also, you're not living by anybody else's rules. Would you say that anything's changed from you and just that level of sort of determination of? Debbie 44:53I've gained a resilience I never thought I had, you know before a pre-cancer, you kind of or even pre-DAP VA limited, you kind of hear the word resilience, people talk about being resilient. And it kind of sort of doesn't settle. But since I've now had to prove resilience, I feel that now I totally understand what that word means. I also understand what self-discovery means. Because never did I look inward, I would always just do things and never sort of think, how am I doing this? And what's my driver? What's the goal? I would just do it, you know. And so, this whole becoming a business owner, having this dream, having cancer has taught me and showed me that yeah, I'm sorry to use the cliche, but we are so much stronger than we think. Tim 45:51You have to be careful not to believe what you think. That's so yeah. Debbie 45:55Yea, and I kept sort of feeding my brain with positive things. You know, funny thing is Tim, this house before we even moved, or even had viewed it, in London, I bought all the soft furnishings, for a four-bedroom house. And, you know, Dan was like, You're crazy. You don't even know it's gonna have three bedrooms or four. But I said, No, I know, I'm just buying this room, this room, this room, I bought enough stuff for two bathrooms. It's like, we don't know if we can have two bathrooms, baby. I said, no, I know. Tim 46:30Not everybody is going to always understand. And I think for those of the people that are listening, if this story doesn't give them some perspective, in terms of just how, you know, if you think your life is difficult, take a look, take a look at what Debbie's overcome and adopt some of her principles. And I mean, what I'm what I've jotted down here, as we've been talking is that North Star, that vision is, among the first the ability to break things down into into manageable chunks, the ability to then build a momentum. That's just incredible. And I remember back in the day, we used to say, you know, put yourself between the immovable object and the irresistible force, right? And then, you know, you know, Your situation may change and you're ready to be resilient for what unknowns are going to come up or what things how the environment or how the situation is going to change. You need to flow with that.  Debbie 47:27And I think it's also the power of positivity, you know, I read her book at the time that I was actually I was staying in hospital. And you know, it's just that positivity, Tim, I know, it sounds like nothing, but oh, my God, the power of positivity is a force that you cannot reckon with. I'm sorry, it's staying positive. That's also another thing I learned. You know, I did consider myself a positive person before cancer, pre-cancer, but I didn't realize that positivity actually can change your life. Tim 48:06Well, I'm for those of you that are interested. Read has been on the show a couple of times, or we've got two episodes with read on it. We'll put links to those in the shownotes.  Debbie 48:12Yeah, definitely.  Tim 48:15Your story about how you're able to advocate for yourself is one of the things that I love most about that is just when you are willing to stand up for yourself, how many people will then stand up with you. Whereas if you're willing, if you're just going to relegate yourself to you know, being part of some predetermined process, people will keep moving the way they were moving anyway. And I think back to Dolly Parton, she had this saying if you don't like the road, you're on pave a new one. In your story, I just so many times you found yourself on a road more rocky than perhaps you had anticipated. Debbie 48:56Yea, so true. Dolly's words.  Tim 48:59Yea, as we wrap up here, let's, let's talk a little bit about some of the amazing things that are happening now. Your story has inspired many other people. Debbie 49:08I'm filled with gratitude, really, Tim. You know, every day I wake up, I'm alive, I'm healthy, I can do all the things that I could be for my cancer, despite having body parts missing, ie, I have a stoma, that colostomy bag on my left side. And I can still do everything. So I'm really grateful. So then I just kind of thought, now I'm on my feet. I'm back at work. You know, I'm enjoying working with my clients, who I love and adore all of you, all of them. And how can I give back? How do we, what do I do? What should I do? I can't just sit here and bask in the glory of the grid house. So I decided to put myself in the most uncomfortable position ever, which is speaking in public. And so I share my story wherever I'm invited. In order to you know, spread awareness that we can achieve that getting a terminal or a serious illness diagnosis perhaps is the better term is not the end of the road. There is light at the end of the tunnel. And you know, just maybe adjusting our mindset a little because you do have to contend with dealing with your illness as well. But you know, within that, try your hardest to see the positive side of these things. For example, having Chloe, that's the name of my stoma. Chloe, the colostomy, gives me priority boarding on any flight. So wow, I love, I love Chloe and airport security. I just go present myself at the fast track with my little badge. And there I go on the fast track. I never queue. Tim 50:55There you go, so many silver linings. Debbie 50:58They are so yeah, yeah, absolutely. And also, I enjoy speaking, one on one like this. Very nervous about speaking in public. And so yesterday, I was invited to speak for a charity that actually helped us, Dan and I in 2021, when we were down and out, it's called the Macmillan Cancer Charity, based in the UK. I love them to death. Well, no, I love them not to death, but I love them. And so I love them to live. And they said, would you come and share your story as our away day so that, you know, all the people who support and donate and work in this charity understand, and just are reminded of why they do the job they do. It's because of people like me, they literally gave me life. They supported me when I was in my darkest moments in so many ways, Tim. And so I thought yeah, of course I'll do it even though my stomach was doing somersaults the whole time. And I felt like throwing up and pay off with me lunch and I couldn't eat. But I just thought now I've got to do this. And you know, there was not a dry eye in the room. And I didn't do it to make them cry. I said to them, no, I'm I'm emotional. Because I'm so grateful to have this platform, not only to share, but also to actually thank you, each and every single one of you, how much you, you know, helped us to thank you for, you turned our lives around. And so, you know what you do, please do not minimize it. You actually do change lives.  Tim 52:38Again, it's a story for another time, but we can talk about, you've shared with me how influential you're being locally around local government and other areas. You're exercising your advocacy  Debbie 52:45My a voice.  Tim 52:49Yeah, yeah, your voice without making it too cute. If you weren't operating from this dream achieved, in a sense, you're in the red house. Now if you, if you didn't have this new these set of of traumatic and like, this amazing, but very treacherous journey that you've been on. You're seeing things with new eyes. If you if that hadn't happened? Would you have the voice you have today? Debbie 53:19No, absolutely not. I'd be on the treadmill that I had been on for 34 years. Same old, same old, nothing new. Tim 53:26So I'm gonna ask you two things. One is, let people know where they can connect with you.  Debbie 53:35Absolutely.  Tim 53:36Where would you like them to connect with you? And the second thing is, if you had a wish for people that are listening to this today, what would that wish be? Okay, so where can people find you? Debbie 53:44where can people find you so people can find me? I'm on LinkedIn. So it's just Google Debbie Potts. My company is DAP VA Limited. They can also just Google DAP VA Limited. Tim 53:58We'll put those in the show notes. Debbie 53:59Perfect. So yeah, I think my one wish for everybody who's listening and facing any kind of challenge, uncertainty, you know, indecisive. Don't give up; find your anchor, find your north star and work towards it. Because you'll get there. Tim 54:22And every step towards that star is going to be a discovery about who we really are. Debbie 54:29Absolutely. But it also takes you that one step closer. No matter what it takes you step, it takes you closer, so please don't give up whoever you are, wherever you are. Tim 54:40Keep coming back to that even when it seems that it's pulled away from you a little further, you know? Debbie 54:45Yeah, totally. Oh, you got it, Tim, you understand. Tim 54:49Right. Well, Debbie, love you so much. And thank you for spending time with me.  Debbie 54:55That's okay.  Tim 54:56Okay. Well, Debbie 54:57You're so welcome. Thank you very much Tim 54:58Till next time. Buh-bye  Debbie 55:00Bye.  Tim 55:01There's so much more we could talk about. We didn't even get to talk about your next dream.  Debbie 55:07Well, Do you want to know what it is, Tim?  Tim 55:09Yea, I do?  Debbie 55:10It's a Yamarin, six and a half foot, boat, speed boat. It has a sundeck at the back enough for six to seven people. It's got a little table so we can have our dinner in the middle of the archipelago in the ocean.  Tim 55:20There we go.  Debbie 55:22It's got to cover so that Dan and I can go and camp out in the archipelago should we wish. So I have a picture of a boat. So I'm working towards it. I'm close. I'm very close. The deadline or the timeline is March 2024 to purchase it. If not before. And then they will put it in the water. So I've been to speak to them. I've spoken I'm a regular visitor, I go sort of every two weeks, and they all know my name. They go ideally, you ready to buy the boat? I go no, no, no, not yet. But I have a question. So they're gonna put it in the water for us in April next year, already and good to go. And then we're going to use it throughout the summer season. And then in September, October, they're going to pick it up and store it for us. Ready for the following year. And they're going to clean it services, fix it and we don't even have to worry about any of that. So in order to achieve that dream, I first need a spot to moor my boat during the summer season. So, before I can buy the boat, because it's pointless having a boat and got nowhere to put it. During the summer season. I had to go and find the spot and of course all the spots are taken because we live close to the water. And you know, everybody has the boats in the summer. So everyone was like no, the spot is a two-year waiting list. Now I can't wait to use that spot. There's no hardly anybody changes. You know what I did? I went old school Tim. I typed on a piece of A4 paper. And we invite everybody new to the area. We live in (area of Sweden) and we're looking for a spot to moor boats. If anyone knows of anybody who's giving up this spot and will please remember this number. Old guy rang the number. And he says, oh, yeah, I know a spot over, maybe it's a five-minute drive from us that okay? And we go absolutely. We got a spot.  Tim 57:24There you go.  Debbie 57:26Got a spot. Tim 57:29So Debbie's next dream is the boat. The boat, the blue boat. What color is it?  Debbie 57:38It's white. It's called a Yamarin. I'll send you a picture after this. Tim 57:42Sounds great. All right. Can't wait to hear about Debbie's next adventure soon. Tim 57:53Thank you so much for listening to Sweet on Leadership. If you found today's podcast valuable, consider visiting our website and signing up for the companion newsletter. You can find the link in the show notes. If, like us, you think it's important to bring new ideas and skills into the practice of leadership. Please give us positive rating and review on Apple podcasts. This helps us spread the word to other committed leaders. And you can spread the word to by sharing this with your friends, teams and colleagues. Thanks again for listening. And be sure to tune in in two weeks time for another episode of Sweet on Leadership. In the meantime, I'm your host, Tim Sweet, encouraging you to keep on leading 

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.      

It's another Landmarks of OncoPharm episode looking at the carboplatin-paclitaxel regimen in ovarian cancer from 20 years ago. carboplatin/paclitaxel vs. cisplatin/paclitaxel: https://pubmed.ncbi.nlm.nih.gov/?term=37643542

A Foundations of OncoPharm episode on nab-paclitaxel, with a focus on the pharmaceutical differences from conventional paclitaxel.

First over-the-counter birth control pill; expanded approval for Leqvio; Gavreto has an indication withdrawn; batches of Albuterol inhalers recalled; results from analysis of paclitaxel-coated devices.

Olympus this week announced positive study data for its minimally invasive iTind treatment for enlarged prostate symptoms. Fast Five hosts Sean Whooley and Danielle Kirsh go over what that treatment option is, how it works and what some of the study results showed.  Eitan Medical's launch of a cloud-based infusion management platform reflects the integration of digital technologies into healthcare, aiming to enhance patient safety and optimize medication administration. Learn more about what Eitan Insights is and what the company designed the technology for in today's episode.  Urotronic designed Optilume as a minimally invasive surgical therapy to alleviate urinary symptoms caused by BPH – and the FDA approved its use this week. Whooley explains what the technology does and how optimistic executives are after news of the approval.  FDA's updated guidance on paclitaxel-coated devices provides important insights into the ongoing evaluation and monitoring of device safety. Hear about why it updated the guidance and the recommendations for provider action with the new guidance.  The EU's significant fine imposed on Illumina over the Grail deal highlights the increasing scrutiny and regulation within the medtech industry, particularly regarding mergers and acquisitions. Whooley and Kirsh discuss why the fine was issued, as well as a brief history of the acquisition and what Illumina plans to do next. Check out the show notes for links to the stories we discussed today at MassDevice.com/podcast.

This recording features audio versions of July 2023 Journal of Vascular and Interventional Radiology (JVIR) abstracts:Short-Term Effects of Genicular Artery Embolization on Symptoms and Bone Marrow Abnormalities in Patients with Refractory Knee Osteoarthritis ReadReal-World Safety Analysis of Paclitaxel Devices Used for the Treatment of Peripheral Artery Disease ReadMedian Arcuate Ligament Compression Associated with Flow-Related Visceral Aneurysms ReadPregnancy Rate and Outcomes following Uterine Artery Embolization for Uterine Arteriovenous Malformations: A Systematic Review and Meta-Analysis ReadResolution of Pain after Percutaneous Image-Guided Cryoablation of Extraperitoneal Endometriosis ReadYttrium-90 Radiation Segmentectomy of Hepatocellular Carcinoma: A Comparative Study of the Effectiveness, Safety, and Dosimetry of Glass-Based versus Resin-Based Microspheres ReadJVIR and SIR thank all those who helped record this episode:Host and audio editor:Rommell Noche, Frank H. Netter MD School of Medicine at Quinnipiac University, ConnecticutAbstract readers:Jamie Lee, A.T. Still University School of Osteopathic Medicine, ArizonaManbir Sandhu, University of California Riverside School of MedicineAnna Hu, George Washington University School of Medicine and Health Sciences, D.C.Emily Barr, MBA, Burrell College of Osteopathic Medicine at New Mexico State UniversityIsabelle Barbosa, Frank H. Netter MD School of Medicine at Quinnipiac University, ConnecticutPriya Gupta, MD, Henry Ford Hospital, Michigan ©  Society of Interventional RadiologySupport the show

In this episode, host Dr. Christopher Beck interviews Dr. Peter Soukas about his algorithm for below the knee (BTK) critical limb ischemia (CLI) interventions as well as his implementation of new evidence-based guidance. --- CHECK OUT OUR SPONSOR Medtronic HawkOne Directional Atherectomy System https://www.medtronic.com/hawkone --- SHOW NOTES Dr. Soukas serves as the director of vascular medicine, the interventional peripheral vascular lab, and the endovascular medicine fellowship at Brown University in Providence, RI. In addition, he holds the position of associate professor of medicine at The Warren Alpert Medical School at Brown University. Dr. Soukas began his career as an interventional cardiologist. Over the course of his 13-year tenure in Providence, he has dedicated his career to the treatment of CLI and BTK disease. Prior to any interventional work, Dr. Soukas follows a comprehensive work-up including an ankle-brachial index (ABI), arterial duplex, and evaluating kidney function for safe administration of contrast. For a majority of cases, he uses the common femoral artery as the access point, but prefers to prep multiple access sites in the event of needing both anterograde and retrograde, or pedal, access. He discusses the use of the chronic total occlusion crossing approach based on plaque cap morphology (CTOP) classification on angiogram in determining the need for a retrograde approach. The type I morphology is characterized by the convexity of the plaque pointing away and is often treated successfully by an anterograde approach alone, as CTOP types II, III, and IV benefited from the addition of retrograde tibiopedal access. Once access is gained and the plaque morphology is evaluated using angiography, it becomes crucial to address any issues with the inflow to the affected vessel. This step ensures proper blood flow and provides a stable foundation for further interventions. Intravascular ultrasound is then used to assess the size and extent of the plaque, and then depending on the amount of calcification, either intravascular lithotripsy or calcium modifying technology can be used. Scoring balloons with low pressure may also be used for vessels that are moderately calcified and have been shown to have low rates of recoil and dissection. The main initiative of the procedure is to provide blood flow to the target angiosome which is dependent on the location of the wound. During his last remarks, Dr. Soukas comments on the future of BTK interventions, including Paclitaxel vs Sirolimus eluting stents, the use of self-expanding stents, and LimFlow, a minimally invasive technology that creates a channel between an artery and vein allowing the vein to provide blood flow to the foot. With the increasing prevalence of critical limb-threatening ischemia (CLTI) and high 12-month mortality rates in patients with amputations, Dr. Soukas ends the discussion by emphasizing how revascularization should be the preferred initial approach in treating CLTI due to the potential benefits it offers in terms of limb preservation and mortality reduction, urging practitioners to educate patients in being aggressive in their care. --- RESOURCES CTOP article: https://evtoday.com/articles/2018-may/using-plaque-cap-morphology-to-determine-cto-crossing-approach Disrupt PAD III Observational study: https://pubmed.ncbi.nlm.nih.gov/34380334/ PRELUDE BTK Study: https://pubmed.ncbi.nlm.nih.gov/34802313/ Intravascular Ultrasound study: https://www.jacc.org/doi/10.1016/j.jcin.2022.01.001 Intravascular US in Medicare Beneficiaries: https://pubmed.ncbi.nlm.nih.gov/35998803/ PROMISE II study: https://limflow.com/us/clinical-evidence/promise-ii-study-results/

Olaparib + Abiraterone is FDA approved for mutated-BRCA prostate cancers. Olaparib has a bit of convoluted story to unpack in this patient population. Have we finally found a way to minimize the peripheral neuropathy from paclitaxel.....with cilostazol? PROpel: https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043 Cilostazol RCT: https://doi.org/10.1002/phar.2830 Cilostazol effect on Schwann cells: https://doi.org/10.1016/j.neuropharm.2021.108514

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.12.528175v1?rss=1 Authors: Kume, M., Ahmad, A., DeFea, K. A., Vagner, J., Dussor, G., Boitano, S., Price, T. J. Abstract: Background and Purpose: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, dose-limiting side effect of cancer therapy. Protease-activated receptor 2 (PAR2) is implicated in a variety of pathologies, including CIPN. In this study, we demonstrate the role of PAR2 expressed in sensory neurons in a paclitaxel (PTX)-induced model of CIPN in mice. Experimental Approach: CIPN was induced in both PAR2 knockout/WT mice and mice with PAR2 ablated in sensory neurons via the intraperitoneal injection of paclitaxel. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. We then examined immunohistochemical staining of dorsal root ganglion (DRG) and hind paw skin samples from CIPN mice to measure satellite cell gliosis and intra-epidermal nerve fiber (IENF) density. Pharmacological reversal of CIPN pain was tested with the PAR2 antagonist C781 Key Results: Mechanical allodynia caused by paclitaxel treatment was alleviated in PAR2 knockout mice of both sexes. In the PAR2 sensory neuronal conditional knockout (cKO) mice, both mechanical allodynia and facial grimacing were attenuated in mice of both sexes. In the dorsal root ganglion of the paclitaxel-treated PAR2 cKO mice, satellite glial cell activation was reduced compared to control mice. IENF density analysis of the skin showed that the paclitaxel-treated control mice have a reduction in nerve fiber density while the PAR2 cKO mice had a comparable skin innervation as the vehicle-treated animals. Similar results were seen with satellite cell gliosis in the DRG where gliosis induced by PTX was absent in PAR cKO mice. Finally, C781 was able to transiently reverse established PTX-evoked mechanical allodynia. Conclusions and Implications: Our work demonstrates that PAR2 expressed in sensory neurons plays a key role in paclitaxel-induced mechanical allodynia, spontaneous pain and signs of neuropathy, suggesting PAR2 as a possible therapeutic target in multiple aspects of paclitaxel CIPN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Andrea Necchi describes his paper and the future of this combination. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.14.516419v1?rss=1 Authors: Sankaranarayanan, I., Tavares-Ferreira, D., Mwrigi, J. M., Mejia, G. L., Burton, M. D., Price, T. J. Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. This causes damage to peripheral nerves and the dorsal root ganglia (DRG). Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors. Neuro-immune interactions occur in CIPN and have been implicated both in the development and progression of the disease and disease resolution. We investigated the potential role of Inducible co-stimulatory molecule (ICOS) in the resolution of CIPN pain-like behaviors in mice. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. We found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of mechanical sensitivity in female mice. Administration of ICOSaa reduced astrocyte-gliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa intrathecal treatment promoted pain resolution by increasing interleukin 10 (IL-10) expression in the dorsal root ganglion. In line with these observations, blocking IL-10 receptor (IL-10R) activity occluded the effects of ICOSaa treatment on CIPN behavior in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy - CIPN clinical trials. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this episode,Susana Banerjee, MBBS, MA, PhD, and Mansoor Raza Mirza, MD, share their thoughts on key studies of interested presented at the IGCS 2022 Annual Global Meeting for ovarian and cervical cancers including:Post-hoc analyses from SOLO-3: olaparib vs physician's choice chemotherapy in germline BRCA mutant platinum-sensitive recurrent ovarian cancerPhase III CALLA trial: durvalumab combined with and following chemoradiation for locally-advanced cervical cancerPhase III ARIEL3: final OS for maintenance rucaparib vs placebo following response to platinum-based chemotherapy for recurrent high-grade serous ovarian cancerRetrospective NeCTuR study: outcomes with topotecan, paclitaxel, and bevacizumab (TPB) vs non-TPB regimens for recurrent high-grade neuroendocrine carcinoma of the cervixPresenters:Susana Banerjee, MBBS, MA, PhD, FRCPConsultant Medical Oncologist and Research LeadGynaecology UnitRoyal Marsden NHS Foundation TrustLondon, United KingdomMansoor Raza Mirza, MDChief OncologistDepartment of OncologyRigshopitalet – Copenhagen University HospitalCopenhagen, DenmarkContent supported by educational grants from AstraZeneca, GlaxoSmithKline, Karyopharm Therapeutics, and Merck Sharp & Dohme Corp.Link to full program, including a downloadable highlights slideset, and ClinicalThought commentaries:https://bit.ly/38xuRBv

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.13.507857v1?rss=1 Authors: Sankaranarayanan, I., Tavares-Ferreira, D., He, L., Kume, M., Mwirigi, J. M., Madsen, T. M., Petersen, K. A., Munro, G., Price, T. J. Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 x 4mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (0.5 and 1.8mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin (0.5 and 1.8mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), blocked the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin43 protein expression in the DRG. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for CIPN treatment. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

L-glutamine is a "conditionally essential" amino acid. What's that? Tune in & find out: what glutamine is, what it does, and when you shouldn't be taking it. Tina & Leah discuss generalities and then delve into specifics, particularly for those who have (or had!) cancer.Glutamine is one of those supplements that many people take…. willy-nilly. That's a bad idea. There is a time and a place for glutamine supplementation. Listen in to find out more.Why is glutamine so tricky to use as a supplement:1-Fact: Glutamine can lessen peripheral neuropathy when taken alongside certain chemo drugs. 2- Fact: Cancers often have a high appetite for glutamine and use it as fuel o grow (proliferate).  As always, Tina & Leah speak from experience and stick to the data. (All while introducing you to oddities like “meat sweats.”)Please like, subscribe/ follow, and leave us a review! If you find this info helpful, please share the show with others you think could benefit.  Or, you can support the show directly with a donation, so we can keep making content and help more people! Support the show

Dr. Allison Zibelli, of the Sidney Kimmel Cancer Center – Jefferson Health, and Dr. Hope Rugo, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discuss the practice-changing DESTINY-Breast04 trial as well as novel therapies in metastatic HR+/HER2- breast cancer from the TROPiCS-02 and MAINTAIN studies, all of which were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your host for the ASCO Daily News Podcast today. I'm a vice-chair and breast medical oncologist at the Sidney Kimmel Cancer Center, Jefferson Health in Philadelphia. My guest today is Dr. Hope Rugo, a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. We'll be discussing key advances in breast cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes, and disclosures of all guests on the podcasts can be found on our transcripts at asco.org/podcasts. Hope, it's great to talk to you today. Dr. Hope Rugo: Nice to talk to you, too. Dr. Allison Zibelli: Let's begin with perhaps the most exciting abstract at ASCO this year, which was the DESTINY-Breast04 study, that's LBA3, a randomized phase 3 study of trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-low, unresectable and/or metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: Well, of course, this is a hugely practice-changing study as was noted in the second-to-last slide by the discussant [Dr.] Pat LoRusso. So, antibody-drug conjugates are really the next step in delivering chemotherapy to cancer cells. The antibody-drug conjugates allow targeted delivery of a toxin to the cancer cell. I think we didn't understand how important this was going to be. These second, sort of, verging on third-generation antibody-drug conjugates use an antibody approach and to then have a new generation of linkers, which allow the drug to be released locally, but to then have drugs which pack a big bang for the buck. So, the way antibody-drug conjugates are constructed, you need to have a drug that actually can't be given as a naked drug because it's too toxic because you're giving just very small amounts of this drug that are delivered directly to the cancer cell. And the other really critical part of this is that the drug-to-antibody ratio of at least the successful and new antibody-drug conjugates (ADC) is quite high in the 7.5 to 8 toxins per antibody. Now, what that's resulted in is really interesting, is that there's a bystander effect. So, the toxin itself can leak out of the cancer cell that it's targeted and kill neighboring cells, but also because of the construct of these antibody-drug conjugates, what's likely happening is even if the cancer cell's a very low expression of the target, really low, you're able to actually get that ADC into the cancer cell to kill the cancer cell. So that may be a big part of the so-called bystander effect. So trastuzumab deruxtecan is biosimilar trastuzumab linked to a topoisomerase inhibitor deruxtecan, and what happened here was that of course, we saw remarkable data in HER2+ disease, unbelievable p-values in DESTINY-Breast03 compared to T-DM1, a first-generation ADC. But in DESTINY-Breast04, we targeted a population of patients largely with hormone receptor-positive disease who had a little expression of HER2, 1 plus or 2 plus by immunohistochemistry and no gene amplification. And this trial, which randomly assigned patients 2:1 and included just 58 patients with triple-negative disease. So in this trial, 480 had hormone receptor-positive breast cancer, a median of 1 line of prior chemotherapy. They were only allowed up to 2. They were refractory to endocrine therapy, a median of 3 lines of endocrine therapy. In the overall patients and in the hormone receptor-positive patients, there was actually a doubling in progression-free survival (PFS). It started very early, and it continued throughout, and at every landmark analysis, T-DXd was better than the treatment of physician choice that patients were randomly assigned to. It's also important when you're thinking about trials like this to think about what the treatment of physician choice was, and it was all chemotherapy regimens we would use. Paclitaxel, nab-paclitaxel, capecitabine, eribulin, or gemcitabine. And, so, I think that that doesn't bring up any questions. When they looked at the hormone receptor-positive group, they saw, if anything, even a bigger benefit overall. Now, the other endpoint of this trial was overall survival, and at this first analysis, they saw an improvement in overall survival that was quite dramatic. The absolute difference was 6.4 months, which is pretty amazing for an overall survival difference. And then they looked at this exploratory endpoint at the 58 patients who were valuable at triple-negative breast cancer, and then that group of patients, also saw an improvement in PFS of 5.6 months, an improvement in overall survival of 9.9 months, very small group, but amazing data. The forest plots are exactly what you want to see, all the dots line up to the left of 1, and overall responses improved. One of the concerns with this drug has been toxicity. The toxicity showed no new toxicity signals, which is really important. Nausea is the biggest issue that we deal with. It's mostly grade 1 and 2, but still something that's important to manage. A little bit of hair loss, not much in the way of bone marrow suppression, which is interesting. Interstitial lung disease (ILD) or pneumonitis continues to be an important issue to follow. 12% of patients had ILD of any grade. Most of it was grade 1 and 2, but 3 patients died, representing 0.8%. So, this really highlights the importance of monitoring and managing pneumonitis. Regardless of that, few patients had a reduced ejection fraction, but again, very, in general, low grade. This is really a new standard of care, and the standing ovation was really due to the fact that all we do is dedicate ourselves to trying to help patients live longer and better with their cancers, and in this trial, we have a huge win that has no qualifications. We can help patients not only control their disease longer but live longer with T-Dxd compared to standard chemotherapy. Dr. Allison Zibelli: So, Hope, I know as a practicing medical oncologist, I find that our metastatic triple-negative patients are often the biggest therapeutic challenges for us. Will they be doing larger studies with these patients that are HER2-low? Dr. Hope Rugo: It's a really good point. About 65% of patients with hormone receptor-positive disease or so-called HER2-low, centrally confirmed in the study. So, a fair number of people, about a quarter, did not have HER2-low disease when they were tested centrally. In the triple-negative population, who really are ER, PR, HER2- by standard definitions, about a third of the patients might have HER2-low disease. So, there's a lot of interest in further exploring that and looking at the patients who have ultra-HER2-low disease, so between and 1 plus a little bit of expression. That's been studied in the hormone receptor-positive population in DESTINY-Breast06. But there's a lot of interesting further defining that triple-negative population, so to speak, they're going to be triple-negative plus now and understanding what the benefit is in that population. So definitely will be looked at more now moving forward. Dr. Allison Zibelli: Thank you. So, let's move on to Abstract 1002. And the results from the phase 1, 2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, and patients with HER3 expressing metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: That's a really interesting, another one of these second- to third-generation antibody-drug conjugates. It's just the antibody, instead of being the usual, sort of, HER2 or TROP2 that we're used to thinking about is directed to HER3, 1 of the HER family of proteins. This is interesting. There's actually been a lot of work trying to target HER3 with naked antibodies with disappointing results, although I have to say most of the studies really didn't push it too far. So, with this antibody drug construct, deruxtecan, which is the same as in T-DXd and another TROP2 ADC Dato-DXd is used. So, I will say they do need to change the toxin in the next generation of ADCs. But they looked at, at first did a dose-finding study which has previously been presented, and then a dose expansion in both hormone receptor-positive HER2-negative disease and triple-negative disease. All the triple-negative patients had HER3 high disease by immunohistochemistry, and the hormone-receptor-positive patients were enrolled in 2 cohorts, HER3 high and HER3 low. And the median number of prior treatment regimens that patients had received in the hormone-receptor-positive group was 6 and 2 for the triple-negative group, but there was a huge range, up to 13 lines of treatment. They only had 14 patients with HER2+ disease. So, it's a little bit hard to know what to do with that patient group, but they were heavily pretreated 5.5 prior lines of therapy. The confirmed overall response rate in the 113 patients with combined HER3 high and low was 30%, very impressive, heavily pretreated patients. For triple-negative disease all HER3 high, it was 23%. Again, very nice. And there were 14 patients with HER2+ disease that also were HER3 high. It was about 43%. So those are nice responses, but we always want to know how durable is that. The duration of response ranged from 6 to over 8 months in those 3 different groups. So, these were quite durable. It wasn't any 2- to 3-month duration of response. So very impressive. And then when they looked to see, did it matter whether you had HER3 expression that was high or low in the hormone-receptor positive group, they actually did see responses in the HER3-low group, some very good responses. Overall, there were less patients in that group, but it does suggest that maybe you would still see responses in the HER3-low group, very impressive. And then 1 really interesting correlative study they did was they looked to see what happened to the HER3 expression on the tumor cell over time, and it went down. So, you treated the HER3 expression in most of the patients just dropped off completely, which is really interesting. It didn't have any association with clinical activity, but it's sort of an interesting correlative endpoint. This is a drug that overall was pretty well tolerated. They saw a similar toxicity to T-DXd with a lot of nauseous, a little bit of alopecia, a little bit more bone marrow suppression than we're used to seeing with T-DXd. So, neutropenia was seen in about 10% of patients at the lower dose and about a quarter of the patients at the higher dose. Overall, pretty well tolerated. Now, interstitial lung disease is a toxicity with this construct, and they saw ILD of 7% but most cases were grade 1 and 2. The other interesting toxicity that's unique to this agent is thrombocytopenia. So, they saw a grade 3 or greater rate of thrombocytopenia of 27% in the lower dose group, and in the larger group that received the higher dose, 39% of grade 3 or greater thrombocytopenia, so platelets less than 100,000. Turns out that when you stop the drug, the platelets do come back, so that's a good thing. Sometimes we saw long-term thrombocytopenia with T-DM1. They didn't see bad toxicity like bleeding, but it is something that needs to be managed with this drug because we're not great at managing thrombocytopenia. In any case, it has fast-track designation for another solid tumor, not breast cancer, and we'll have to see where this fits into our dizzying array of very effective ADCs now. Dr. Allison Zibelli: The practicing medical oncologist is not used to testing for HER3 in our patients with breast cancer. How common is it? Dr. Hope Rugo: HER3 expression is quite common in hormone receptor-positive disease, a little less common in triple-negative breast cancer. So, I think that we would see expression if we were going to be treating patients with this particular approach. Dr. Allison Zibelli: All right. Let's move on to Abstract 507, which reported long-term outcomes of adjuvant denosumab in breast cancer, specifically fracture reduction and survival results from 3,425 patients in a randomized double-blind, placebo-controlled ABCSG-18 trial. What are your thoughts about this study? Dr. Hope Rugo: Well, this trial, this is an update of a study that previously has been presented and published, most recent publication was in Lancet Oncology in 2019, and these patients were randomly assigned to receive denosumab at 60 milligrams, important to note the dose, subcutaneously every 6 months versus placebo every 6 months, and they did get placebo subcutaneous injections. And this treatment continued through their endocrine therapy. They showed a dramatic reduction in fracture rate, and that has been maintained over time. We were really surprised enough to suggest that maybe Austrian people didn't go into the sun, so they got more Vitamin D deficiency, hard to know, but the hazard ratio is 0.5. It's unbelievable the number of fractures, 92 for denosumab but 176 for placebo, a P value of less than .0001. So, this is a real endpoint, treating patients who are receiving endocrine therapy that, in this case, non-steroidal aromatase inhibitor therapy that can increase bone loss, have a reduced fracture rate when they received denosumab. So that is the big take-home message, and a medium follow-up of 8 years. But the secondary endpoints included disease-free survival. They had about 20% disease-free survival events and 8% deaths, and what they saw was really interesting. So, the caveat is that 16% of patients were unblinded at the first analysis and half of them got denosumab, so it messed up their results a little bit, but the disease-free survival was significantly better in patients who received denosumab, and the hazard ratio of 0.83 and the hazard ratio does not cross 1. So that's very interesting, and even overall survival, they looked at 2 other endpoints, bone metastasis-free survival, and overall survival. They also trend towards an improvement with a hazard ratio of 0.8 for both of them. And they didn't actually see toxicity. So, patients' brittle bone fractures and osteonecrosis of the jaw (ONJ) are all concerning, but they really just did not see any risks in this patient population. I think there was 1 patient that had what they thought was a brittle bone fracture. Obviously, they watched the mouth very carefully as well. Really dramatic, and I think it's kind of disappointing that we never had any registration approach in this, and also not well-understood why the D-CARE study did not show a benefit, but I think D-CARE was designed differently. This is a better design to focus on our patients and the specific issues, and I think it's intriguing and should be considered as part of our treatment regimen for patients who are at risk for bone loss and have early-stage breast cancer on an aromatase inhibitor. Dr. Allison Zibelli: I've been using DEXA scans and offering denosumab to my patients on AIs that have osteopenia or osteoporosis. Should we be considering it in women with normal bone mass? Dr. Hope Rugo: I think not yet. Unfortunately, this trial was not immediately powered for cancer outcome, although the data are very encouraging. We don't know what the relationship is to bone loss, and providing an environment that's friendlier for cancer cells. So, do you have to have bone loss in order to have the risk that you're reducing with these agents? Certainly, that's what we've seen with zoledronate. So, I think that we don't have sufficient data to use this simply to treat cancer, but I do think that we should be considering this as an agent to give patients who have bone loss, either when you're starting an aromatase inhibitor or during the course of therapy. I think it's well tolerated, and a subcutaneous injection is not difficult. One of the questions that's come up for people is do you get bone loss that increases your risk of fracture after you stop therapy. But clearly from these updated data, these patients were off therapy. They did not have an increase of fractures and the patients treated with denosumab fared much better, I mean the hazard ratio of 0.5. Dr. Allison Zibelli: Let's move on to TROPiCS-02. That's LBA1001. This is a randomized phase 3 study of sacituzumab govitecan versus treatment of physician's choice in patients with hormone receptor-positive, HER2-negative advanced breast cancer. How do you think this study will impact practice? Dr. Hope Rugo: That's a great question. I presented this data, and I think I presented it on a Saturday, and on Sunday we saw the plenary talk of DESTINY-Breast04. These patients enrolled in TROPiCs-02 had a median number of lines of prior chemo 3 with a range of up to 8 actually, compared to a median number of lines as 1 in the DESTINY-Breast04 population. We included all hormone receptor-positive HER2 negative-advanced breast cancer, not centrally confirmed. They included just the HER2 low subset that was centrally confirmed. Everybody in our study had received prior CDK4/6 inhibitors compared to about 70% in DB04. And then 95% of patients in this trial had visceral mets. So, we did really treat a patient population who had very advanced high risk hormone receptor-positive breast cancer. As you know, we saw an improvement and progression-free survival with a hazard ratio of 0.66 meeting the endpoint. We needed a hazard ratio of 0.7, highly statistically significant P value .0003, but the median difference in PFS was only 1.5 months, and overall survival data is not yet mature. So that's brought up the question about how this drug should be used because there was a big fall off in the first 2 months where patients had rapid disease progression with heavily pretreated chemotherapy-resistant disease. We did landmark analyses and there were big separations in PFS at 6, 9, and 12 months, and 12 months, it was 21% patients free of progression and death at 1 year versus 7% for the TPC arm. So, it was a tripling of patients who were free of progression at one year. I think that's clinically relevant. This drug is associated with more neutropenia. That's the primary issue to manage, and probably half of the patients need growth factors at some point. When we looked at other endpoints response to ratio response, etc., we're better with Sacituzumab. So where does this all fit into our treatment paradigm. I think there's the HER2-low patients who will now receive T-DXd up in the, I hope, second line and not in lieu of endocrine therapy, when they're ready for chemo. But there are patients who don't have HER2-low disease and then there are patients who are going to be in the later line setting. So, I do think it still has a place in the treatment department, receptor-positive metastatic breast cancer. The results show that it was better than chemotherapy, physician choice based on our national and international guidelines, and that's better for our patients to have that option. Overall survival data obviously is looked for with great interest and that will help us put this into the right paradigm. And then I also hope that real world data will help us understand how sequential treatment with these different ADCs will benefit our patients. Dr. Allison Zibelli: This is really exciting. Do you think that we're maybe coming toward the end of conventional chemotherapy, especially for women with HER2-positive disease? Dr. Hope Rugo: I wonder if we are. I think we were interested in T-DM1 for HER2-positive disease early on. We've seen some really nice pathologic complete response data as well as adjuvant data in the attempt trial in patients who had stage I disease. Now that we have these second-, third-generation ADCs, T-DXd, I think this could potentially completely replace our chemotherapy. We still have to deal with alopecia. And I will point out ADCs are still chemotherapy. They're just a much more efficient and effective way of delivering treatment, and we need to be very careful to manage the toxicity. Dr. Allison Zibelli: Next, we're going to talk about the main pain trial that's LBA1004, which is a randomized phase 2 trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or hormone receptor-positive HER2-negative metastatic breast cancer, in other words CDK4/6 after CDK4/6. What are your takeaways here? Dr. Hope Rugo: First, just amazing that an investigator-initiated trial could do this well and be placebo-controlled. So, kudos to the principal investigator (PI) [Dr.] Kevin Kalinsky. This trial is a small phase 2 trial. A reasonable number, 119 patients were randomly assigned and evaluable patients could have received up to 1 line of prior chemotherapy for metastatic disease. If you had received prior exemestane, you received fulvestrant, if you received prior fulvestrant, you received exemestane, and actually if you looked at the number of patients who had received fulvestrant, it was 99 versus only 20 with exemestane. So important to keep in mind. If you looked at the overall population where the primary endpoint was progression-free survival, the hazard ratio is 0.57, just median PFS of 2.8 months in patients receiving endocrine therapy and placebo and 5.3 months for patients receiving endocrine therapy and ribociclib. So was this ribociclib after ribociclib or ribociclib after something else. 86% of patients had received palbociclib as their prior CDK4/6 inhibitor, and only about 10% to 14% had received prior ribociclib. So, there's a predominance of palbociclib followed by ribociclib. The other thing that's important to keep in mind is how sick this patient population was. Very few had received prior chemotherapy in the less than 10% range, visceral metastases in about 60%. So that's helpful. Only 19% or so had received 2 or more endocrine therapies from metastases. So, most people did this as their second line treatment. The PFS, when you looked at fulvestrant or exemestane, looked like the benefit was relatively similar, but you know you got 20 patients in the exemestane arm. The hazard ratios, looking at the subgroup analyses, all looked pretty similar, and the overall response and clinical benefit rate were better with continuing the cyclin dependent kinases (CDK) inhibitor. There was interesting sub-analysis looking at mutations and how that affected things. And they looked at patients who had ESR1 mutations or had wild-type ESR1. 42% had ESR1 mutations at study entry, very similar to what we've seen. In that group of patients, remember it's only 33 where they had this analysis, they saw a lot of other mutations. So p53, PIK3CA, FGFR, CCND1—those patients did not benefit. Only 33 patients. No benefit at all, very short PFS, about 3 months. The patients who had ESR1 wild type seemed to benefit a lot, 45 patients going from about 3 months to a little over 8 months. So, this is all hypothesis-generating data. I wouldn't run out and use this as your standard of care now because it is small data. But when the patient doesn't have other good options, I certainly would consider switching the CDK and going on, add that to the next line endocrine therapy. It's important to switch the endocrine therapy. I think we really need to look at the ongoing phase 3 trials to give us better evidence basis and understand the impact of mutations and prior therapy on who might benefit from continued CDK inhibitors after progression on a CDK inhibitor. Dr. Allison Zibelli: I think this is a really exciting trial. We all have a lot of patients on palbociclib and letrozole who've been on for 4, 5 years, and would like to continue with this kind of treatment because the side effects are really manageable. So, I look forward to seeing what's coming in the future with the phase 3 trials. So, let's talk about Abstract 1015, which I thought is a great idea. It looks at the quality of life with ribociclib plus aromatase inhibitor versus abemaciclib plus AI as first-line treatment of hormone receptor-positive, HER2-negative advanced breast cancer, assessed via matching adjusted indirect comparison. Could you tell us what matching adjusted indirect comparison is and why you chose this for the study? Dr. Hope Rugo: It's an interesting question. How do you compare across trials? So, matching this kind of make analysis, we'll call it a make analysis for the purposes of this discussion, allows you to match patients and weight based on their characteristics that might affect patient reported outcomes. And that actually is a way of trying to do a fair cross-trial comparison. So basically, take the study population, you match the inclusion and exclusion criteria, and then you weigh the different criteria so that you can try and make a better association. It's the best way we know of comparing across trials. You know, a lot of people ask why we didn't have PALOMA-2 in here, and that's because they used a different patient reported outcome tool. So, you have to use the same patient reported outcome tool in order to compare. So that's why we did this analysis, and it sort of came on the heels of a survey that Fatima Cardoso presented at San Antonio in 2021, where patients identified diarrhea as a symptom they really didn't like more than everything else. And you can imagine, I think we all have that experience in practice, the unexpected nature of diarrhea and the fact that it does limit your activities and, therefore, quality of life are important. In this analysis, interestingly but not surprisingly, ribociclib favored abemaciclib in diarrhea, and there can be associated appetite loss, so ribociclib also favored abemaciclib for appetite loss. And I thought the last one was interesting—fatigue—because I wouldn't have assumed that fatigue would be different. And maybe it's associated with diarrhea. They have these funny arm symptoms that were better. We don't really know why that was, and it's hard to assess again. We're really not clear based on the differences between the drugs. So, there are limitations to the analysis, but I think that it helps us really in individual patients try and match patients' underlying symptoms with the best treatment to offer them the best quality of life as they're being treated in the metastatic setting. Dr. Allison Zibelli: I thought this study was great because it really centered the experience of the patient and the wishes of the patient. You don't see that designed into many clinical trials, the way this was. So, I thought that was a great feature of this study. Dr. Hope Rugo: I will say that all of the 3 studies that looked at CDK inhibitors, all those 3 studies included patient-reported outcomes. That's an important new approach that is really being focused on. Dr. Allison Zibelli: Do you consider the CDK4/6 inhibitors equivalent in efficacy, and could you substitute them to try to get the side effect profile that you want? Dr. Hope Rugo: Well, I think that we saw in the early stage setting that there are differences. Now, across the different trials, there are big differences in patient populations and inclusions as we saw in the PALOMA-2 results that were presented at ASCO [Annual Meeting], whether the patients had prior chemotherapy like in PALOMA-3, whether they had a short disease-free interval, the higher risk patients in PALOMA-2. The PALOMA trials were more broadly inclusive than the other 2 studies, the MONALEESA and MONARCH series of trials. So, we do have to be a little bit careful about comparing apples to oranges, but we have the early-stage results of MONARCH E showing a clinically important difference in outcome whereas the PALLAS and Penelope-B trials didn't. So that sort of puts us into a little bit of a question period. Are these all patient populations or are there differences between the agents? The PFS and the metastatic setting, all the hazard ratios line up. So, in truth, although I know the activity against cyclin-independent kinases are different between agents, we don't still really understand the clinical differences in efficacy, but I think we all are practicing using evidence-based medicine. I wouldn't, for example, substitute a different CDK4/6 inhibitor for abemaciclib in the treatment of early-stage breast cancer. We have to just learn how to manage the diarrhea and use prophylaxis and dose reduce early to manage this and make it tolerable for our patients. And in the metastatic setting, I think we need to follow evidence-based guidelines and use the best data available to decide on the right treatment approach and sequencing for our patients. Dr. Allison Zibelli: Thank you, Hope, for coming on the podcast today. This was a really interesting review of one of the most exciting ASCO [Annual Meetings] I've been to. And thanks for sharing your valuable insights with us and helping us make sense of all this really new exciting data. We really appreciate it. Dr. Hope Rugo: Thank you. And thank you so much for inviting me. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You will find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. That really helps other listeners find us. Thank you.   Disclosures: Dr. Allison Zibelli: None disclosed. Dr. Hope Rugo: Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint Medicines Consulting or Advisory Role: Napo Pharmaceuticals Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor 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.

CME credits: 1.50 Valid until: 25-04-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-chocolate-touch-study-a-randomized-trial-to-confirm-the-safety-and-effectiveness-of-chocolate-touch-paclitaxel-coated-pta-balloon-catheter-in-above-the-knee-lesions/14054/ tbd

In this episode from the series “Key Decisions in HIV Care,” Cristina Mussini, MD, and William R. Short, MD, MPH, AAHIVS, discuss important considerations for ART with opportunistic infections, including: When to start ART with pneumocystis pneumonia including discussion of the ACTG 5164 study of immediate vs delayed ART with opportunistic infectionsEACS, DHHS, and IAS-USA guideline recommendations for starting ART in the setting of most opportunistic infectionsConsiderations for the administration of ART to patients who are unable to swallow or critically ill and intubatedTreatment of Kaposi sarcoma and considerations for starting ART to avoid drug–drug interactions with Kaposi sarcoma treatmentConsiderations for starting ART with cytomegalovirus and the risk for IRIS from cytomegalovirusDiscussion of treatment of cytomegalovirus and overlapping toxicities between its treatment and ARTWhen to start ART with cryptococcal meningitis and the data to support delayed treatment initiation with this particular opportunistic infectionEACS, DHHS, and IAS-USA guideline recommendations for starting ART in the setting of cryptococcal meningitis specificallyTreatment of cryptococcal meningitis and managing drug–drug interactions between ART and antifungal therapyPresenters:Cristina Mussini, MDHead of Department of Infectious Diseases and Tropical MedicineFull Professor of Infectious DiseasesInfectious Diseases Clinics University HospitalUniversity of Modena and Reggio EmiliaReggio Emilia, Italy William R. Short, MD, MPH, AAHIVSAssociate Professor of MedicineDivision of Infectious DiseasesDepartment of MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphia, Pennsylvania Content based on an online CME program supported by educational grants from Gilead Sciences, Inc.; Janssen Therapeutics, Division of Janssen Products, LP; and ViiV Healthcare.Follow along with the slides at:https://bit.ly/3uktrm1Link to full program:https://bit.ly/3q2DlGd

Commentary by Dr. Yundai Chen

We look at two recent studies that illustrate a framework for how we identify risk factors and possible predictors of chemotherapy toxicity. Paclitaxel and skeletal muscle mass: https://doi.org/10.1111/bcp.15244 Sex differences of toxicity risk: https://doi.org/10.1200/jco.21.02377

In this episode, Eileen M. O'Reilly, MD, and Naureen Starling, MD, FRCP,  discuss emerging therapeutic strategies involving PARP inhibitor therapy in the treatment of pancreatic cancer. Topics include:Current treatment landscape and testing in the United States vs the United Kingdom  Testing for molecular subgroups beyond BRCAmUsing PARP inhibitors in earlier stages of the diseaseLearning from other cancers, such as prostate, breast, and ovarian  Presenters:Eileen M. O'Reilly, MDWinthrop Rockefeller Chair in Medical OncologySection Head, Hepatopancreaticobiliary/Neuroendocrine CancersGastrointestinal Oncology ServiceAssociate DirectorDavid M. Rubenstein Center for Pancreatic CancerAttending Physician, MemberMemorial Sloan Kettering Cancer CenterProfessor of MedicineWeill Medical CollegeNew York, New York, USANaureen Starling, MD, FRCPAssociate Director of Clinical ResearchDepartment of GI CancersConsultant Medical Oncologist, GI CancersThe Royal Marsden HospitalLondon, United KingdomContent based on an online CME program supported by an educational grant from AstraZeneca.Link to full program:https://bit.ly/3s6AnSz

Commentary by Dr. Valentin Fuster

In this very special episode, we are joined by Professor Ramon Varcoe to discuss his updated meta-analysis on the mortality rates after paclitaxel coated device use in patients with occlusive femoropopliteal disease.Found in the Journal of Endovascular Therapy: https://pubmed.ncbi.nlm.nih.gov/34106028/

In this episode, José Ignacio Nolazco, MD, and Alejandro Nolazco, MD, discuss in Spanish the latest immuno-oncology developments in the treatment of urothelial cancer from an Argentinian perspective.  Presenters:José Ignacio Nolazco, MD  Urology FollowHospital Universitario AustralBuenos Aires, ArgentinaAlejandro Nolazco, MDAssociate ProfessorDepartment of UrologyUniversidad Austral and Universidad Católica ArgentinaBuenos Aires, ArgentinaContent based on an online IME program supported by educational grants from EMD Serono, Inc and Pfizer.Link to full program, including associated downloadable slidesets and on-demand Webcast:https://bit.ly/3kJC5SL 

This episode covers paclitaxel!

The Filtrate:Swapnil HiremathSamira FaroukMatt SparksJoel TopfAnd two special guests:Vandana Dua Niyyar, Professor of Medicine at Emory University and the president elect of American Society of Diagnostic and Interventional Nephrology. Wears lead.Sophia Ambruso, assistant professor and nephrologist at the University of Colorado.Show Notes:Drug-Coated Balloons for Dysfunctional Dialysis Arteriovenous FistulasThe NephJC summaryThe article in the NEJMThe Haskal study, Stent Graft versus Balloon Angioplasty for Failing Dialysis-Access Grafts in the NEJM from 2010Accuracy of physical examination in the detection of arteriovenous fistula stenosisThe Big Three was a trio of Major League Baseball starting pitchers for the Atlanta Braves from 1993-2002 which consisted of Greg Maddux, Tom Glavine, and John Smoltz. The Big Three combined to win seven National League Cy Young Awards in the 1990s and helped lead the Atlanta Braves to a 1995 World Series win. Each member of the Big Three has had their jersey retired by the Atlanta Braves and has been inducted into the Baseball Hall of Fame. (From Wikipedia)The Trerotola study, Drug Coated Balloon Angioplasty in Failing AV FistulaeScathing anti-interventional nephrologist editorial by TrerotolaRebuttal though data by Beathard, Effectiveness and safety of dialysis vascular access procedures performed by interventional nephrologistsAnd then a walk back and update by Tretola…What is the current and future status of interventional nephrology?Paclitaxel mechanism of action video with awesome musicThe role of fungus in the paclitaxel story Twitter comment on the half life of balloon delivered paclitaxelThe meta analysis of peripheral revasculaization having a mortality signal with paclitaxel: Risk of Death Following Application of Paclitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review and Meta-Analysis of Randomized Controlled TrialsFDA warning about paclitaxel balloons: Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased MortalityThe NephJC primer on non-inferiority trials: Understanding the vortex of non-inferiority trialsASN Distinguished Clinical Service Award 2020 goes to Vandana Dua Niyyar! (and Derek Fine, who is also a great guy)ASN Kidney Week Sessions:Samira: Embracing Technology: Nephrology 2.0Swapnil: Hard-to-Control Hypertension: What to Do Next?Vandana: A Look Inside: Noninvasive Imaging of Kidney Diseases

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336412v1?rss=1 Authors: Zhen, Y., Ewert, K. K., Fisher, W. S., Steffes, V. M., Li, Y., Safinya, C. R. Abstract: Lipid-based carriers of the hydrophobic drug paclitaxel (PTX) are used in clinical trials as next-generation agents for cancer chemotherapy. Improving the loading capacity of these carriers requires enhanced PTX solubilization. We compared the solubility of PTX in cationic liposomes (CLs) with lipid tails containing one (oleoyl; C18:1 {Delta}9 DOTAP/DOPC) or two (linoleoyl; C18:2 {Delta}9 DLinTAP/DLinPC) cis double bonds with newly synthesized cationic DLinTAP (2,3-dilinoleoyloxy-propyl-trimethyl-ammonium methylsufate). We used differential-interference-contrast microscopy to directly observe PTX crystal formation and generate kinetic phase diagrams representing the time-dependence of PTX solubility as a function of PTX content in the membrane. Replacing tails bearing one cis double bond (DO lipids) with those bearing two (DLin lipids) significantly increased PTX membrane solubility in CLs. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the membrane solubility limit which has been the focus of most previous fundamental studies and clinical trials) in DOTAP/DOPC CLs. The large increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX upon replacement of oleoyl by linoleoyl tails, rather than by the transition in membrane structure from lipid bilayers to inverse cylindrical micelles observed in small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against human prostate cancer (PC3) cells from measurements of the IC50 of PTX cytotoxicity was unaffected by changing the lipid tails, and toxicity of the CL carrier alone was negligible. Moreover, efficacy was approximately doubled against human melanoma (M21) cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. The findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading well over the typically used 3 mol% while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs. Copy rights belong to original authors. Visit the link for more info

Hematology-Oncology News:  Divergent findings with paclitaxel and nab-paclitaxel in TNBC (https://bit.ly/33vemjS) Palbociclib plus letrozole improves PFS in advanced endometrial cancer (https://bit.ly/2GIUl08) Global stomach cancer deaths decline as colorectal cancer deaths stagnate, rise (https://bit.ly/33zBVs1) You can email the show at podcasts@mdedge.com and you can learn more about the show at https://www.mdedge.com/podcasts/blood-cancer    

Should patients with hypertension who are hospitalized due to COVID-19 continue to take angiotensin-converting enzyme inhibitors and angiotensin receptor blockers? Find out about this and more in today’s PV Roundup podcast.

We'll discuss the efficacy of a triplet combination therapy in BRCA-mutated, HER2-negative advanced breast cancer. Then, we'll move on to a report that detailed multiorgan immunotherapy-related adverse events in patients treated with atezolizumab. Last, we'll review the FDA's approval of the RET-targeted therapy pralsetinib in patients with metastatic RET fusion–positive non–small cell lung cancer.Coverage of stories discussed this week on ascopost.com:Addition of Veliparib to Carboplatin/Paclitaxel in Previously Treated Patients With BRCA-Mutated Advanced Breast Cancer: BROCADE3 TrialNew Study Focuses on Multiorgan Immunotherapy-Related Adverse Events in Clinical TrialsFDA Approves Pralsetinib for Metastatic RET Fusion–Positive NSCLCTo listen to more podcasts from ASCO, visit asco.org/podcasts.

Invitado: Dr. Ignacio Escotto Trabajo a analizar: (01:30) Safety of Paclitaxel-Coated Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease. Ouriel K et al. JACC: CARDIOVASCULAR INTERVENTIONS https://doi.org/10.1016/j.jcin.2019.08.025 (04:58) Características del Paclitaxel (06:25) Metodología para análisis de causa de muerte (10:00) Uso de balón medicado como primera intención (12:02) Futuro del balón medicado (15:10) TLR y mortalidad (20:22) Panorama en México

Human herpes virus 8 (HHV-8) or Kaposi sarcoma associated herpes virus is the cause of all forms of Kaposi sarcoma. Kaposi sarcoma occurs primarily in homosexual men with HIV infection as an AIDS defining illness and can complicate immunosuppressive therapy. Improvement is often seen after the immunosuppression is stopped. The patient will typically present with red or purple plaques or nodules on cutaneous or mucosal surfaces. Marked edema can occur with few or no skin lesions. Kaposi sarcoma commonly involves the GI tract and can be screened with fecal occult blood testing. In asymptomatic patients, these lesions are not sought or treated. Pulmonary Kaposi sarcoma, which can be asymptomatic and appear only on chest radiography, can present with shortness of breath, cough, hemoptysis, or chest pain. Chronic Kaposi sarcoma can develop in patients with HIV infection, high CD4 counts, and low viral loads. Here, the Kaposi sarcoma is in its endemic form and is indolent as well as localized. The sarcoma can be clinically aggressive, though. The presence of Kaposi sarcoma at the time of antiretroviral initiation is associated with Kaposi sarcoma-immune reconstitution inflammatory syndrome which has an especially aggressive course in patients with visceral disease. As far as treatment is concerned, in more seasoned patients, palliative local therapy with intralesional chemotherapy or radiation is usually all that is required. If the patient has iatrogenic immunosuppression, treatment consists of reduced doses of immunosuppressive medications. On the other hand, if the patient has AIDS associated Kaposi sarcoma, she or he should be given ART. Other therapeutic options include cryotherapy or intralesional vinblastine (0.1-0.5 mg/mL) for cosmetically objectionable lesions; radiation therapy for accessible and space occupying lesions; and laser surgery for certain intraoral and pharyngeal lesions. Systemic therapy is indicated in patients with rapidly progressive skin disease, edema or pain, and symptomatic visceral disease or pulmonary disease. Liposomal doxorubicin is highly effective in severe cases and may be used alone or in combination with bleomycin and vincristine. Paclitaxel and other taxanes can be effective even in patients who do not respond to anthracycline treatment. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

A reexposição à platina é, atualmente, o padrão de tratamento para mulheres com câncer de ovário que recorrem após 6 meses da primeira exposição. Esse é um conceito comum para caracterizar as pacientes como “platina sensíveis”...Neste episódio, os colegas Reitan Ribeiro, Tiago Biachi e Angélica Nogueira, comentam o estudo GOG 0213 que teve por objetivo explorar os papéis da citorredução cirúrgica secundária e bevacizumabe nesta populaçãoCom mais de 65 Centros incluídos, este é um estudo fase III randomizado muito importante que recrutou mais 700 mulheres numa randomização (1: 1) para QT padrão (6 x 3 semanas de paclitaxel e carboplatina) ou o mesmo regime com a adição de bevacizumabe a cada 3 semanas e continuado como manutenção a cada 3 semanas até a progressão da doença ou toxicidade inaceitável...Tiago está com a língua afiada, mas Angélica realmente mostrou pra que veio!...Aprenda mais sobre o que é o GOG Group, além de novos conceitos sobre pacientes “platina sensíveis” e todos os comentários sobre o paper.Sejam bem vindos ao episódio 63 do Clinical Papers Podcast!Para saber mais sobre o paper, acesse gratuitamente: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715461/

EJVES Editor's Choice

Commentary by Dr. Valentin Fuster

Kim Hodgson, MD is the David Sumner endowed Chair of vascular and endovascular surgery at Southern Illinois University School of Medicine in Springfield, Ill. and is the current president of the Society for Vascular Surgery.  He received his medical degree at the University of Pennsylvania, did his general surgery residency at Albany medical college and vascular surgery fellowship at the Southern Illinois University. He has over 100 peer-reviewed publications, 40 book chapters and has been the PI on numerous clinical trials.  He was the inaugural editor of VESAP and co-editor in chief of the second and third editions of VESAP. Dr. Hodgson served on the Vascular Surgery Board and recently presented as the SVS representative at the multidisciplinary panel for the Circulatory system devices and medical devices advisory committee as part of the FDA oversight into paclitaxel devices in PAD. These are the opinions of Dr. Hodgson and do not necessarily represent a formal stance by the SVS.  Updates from The FDA Circulatory System Devices Panel Meeting, June 19-20th, 2019: US FDA Panel Reviews Paclitaxel Device Data: No Recommendations Issued as More Work is Needed. VascularNews.com. June 20, 2019. FDA Letter to Health Care Providers, UPDATE: Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality. FDA.gov. June 20, 2019. FDA Executive Summary, Circulatory System Devices Panel Meeting, Paclitaxel-Coated Balloon and Paclitaxel-Eluting Stent Late Mortality Panel, June 19-20, 2019 Next steps: Society for Vascular Surgery’s VQI Adds New Analysis to Paclitaxel Device Discussion. VascularNews.com. June 14, 2019. The problems with Target Lesion Revascularization (TLR) as an endpoint. Vascular Specialist. January 25, 2015. Support Audible Bleeding!

This week's top stories in cardiology: FDA Panel: Continue using paclitaxel-eluting PAD Devices, with caveats.  Although the benefits of the devices were clear, the panel felt there should be a label change to warn of the late mortality signal seen in a key meta-analysis. Many cardiac cath, electrophysiology lab directors receive big industry payments These payments were substantially higher than those made to local interventional cardiologists and electrophysiologist. Two trials support shorter DAPT DAPT with a twist: Continuing the P2Y12 inhibitor instead of aspirin. Do black patients with type 2 diabetes gain cardiac benefit from the SGLT2 and GLP-1 drugs? New findings suggest there is no effect on cardiovascular outcomes, although the analysis has limitations

On this episode we discuss the recent controversy regarding an article showing increased risk of death following application of paclitaxel‐coated devices, Palliative Interventional Radiology and increasing need for clinical radiology, and the debate regarding USMLE testing. Music for the IR SuiteTalk mini-series is [Corporate Success](http://freemusicarchive.org/music/Scott_Holmes/Corporate__Motivational_Music/Corporate_Success) by Scott Holmes From the [Free Music Archive](http://freemusicarchive.org) CC BY-NC 4.0